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Differences of Sex Development v1.10 | UGGT1 | Krithika Murali Marked gene: UGGT1 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v1.9 | UGGT1 |
Krithika Murali changed review comment from: Genitourinary anomalies such as cryptorchidism reported -- PMID: 40267907 Dardas et al 2025 report 15 affected individuals from 10 unrelated families with biallelic UGGT1 variants. Affected individuals had GDD and intellectual disability of varying severity. Other cardinal clinical features included microcephaly, seizures, craniofacial dysmorphism, and behavioral abnormalities (autism, ADHD). More variable features included congenital heart disease, cryptorchism; renal anomalies; hepatomegaly; recurrent infections; and skeletal anomalies (scoliosis and/or vertebral anomalies). Supportive functional evidence also provided. Sources: Literature; to: Genitourinary anomalies such as cryptorchidism reported -- PMID: 40267907 Dardas et al 2025 report 15 affected individuals from 10 unrelated families with biallelic UGGT1 variants. Affected individuals had GDD and intellectual disability of varying severity. Other cardinal clinical features included microcephaly, seizures, craniofacial dysmorphism, and behavioral abnormalities (autism, ADHD). More variable features included congenital heart disease, cryptorchism; renal anomalies; hepatomegaly; recurrent infections; and skeletal anomalies (scoliosis and/or vertebral anomalies). Supportive functional evidence also provided. Sources: Literature |
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Differences of Sex Development v1.9 | UGGT1 |
Krithika Murali changed review comment from: Genitourinary anomalies such as cryptorchidism reported -- PMID: 40267907 Dardas et al 2025 report 15 affected individuals from 10 unrelated families with biallelic UGGT1 variants. Affected individuals had GDD and intellectual disability of varying severity. Other cardinal clinical features included microcephaly, seizures, craniofacial dysmorphism, and behavioral abnormalities (autism, ADHD). More variable features included congenital heart disease, cryptorchism; renal anomalies; hepatomegaly; recurrent infections; and skeletal anomalies (scoliosis and/or vertebral anomalies). Supportive functional evidence also provided. Sources: Literature; to: Genitourinary anomalies such as cryptorchidism reported -- PMID: 40267907 Dardas et al 2025 report 15 affected individuals from 10 unrelated families with biallelic UGGT1 variants. Affected individuals had GDD and intellectual disability of varying severity. Other cardinal clinical features included microcephaly, seizures, craniofacial dysmorphism, and behavioral abnormalities (autism, ADHD). More variable features included congenital heart disease, cryptorchism; renal anomalies; hepatomegaly; recurrent infections; and skeletal anomalies (scoliosis and/or vertebral anomalies). Supportive functional evidence also provided. Sources: Literature |
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Differences of Sex Development v1.9 | UGGT1 |
Krithika Murali gene: UGGT1 was added gene: UGGT1 was added to Differences of Sex Development. Sources: Literature Mode of inheritance for gene: UGGT1 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: UGGT1 were set to Congenital disorder of glycosylation - MONDO:0015286; UGGT1-CDG Review for gene: UGGT1 was set to GREEN Added comment: Genitourinary anomalies such as cryptorchidism reported -- PMID: 40267907 Dardas et al 2025 report 15 affected individuals from 10 unrelated families with biallelic UGGT1 variants. Affected individuals had GDD and intellectual disability of varying severity. Other cardinal clinical features included microcephaly, seizures, craniofacial dysmorphism, and behavioral abnormalities (autism, ADHD). More variable features included congenital heart disease, cryptorchism; renal anomalies; hepatomegaly; recurrent infections; and skeletal anomalies (scoliosis and/or vertebral anomalies). Supportive functional evidence also provided. Sources: Literature |
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Differences of Sex Development v1.2 | NR0B1 | Tashunka Taylor-Miller reviewed gene: NR0B1: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 28295047; Phenotypes: http://purl.obolibrary.org/obo/MONDO_0020040; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v1.2 | DMRT1 | Tashunka Taylor-Miller reviewed gene: DMRT1: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 26005864, 28295047; Phenotypes: http://purl.obolibrary.org/obo/MONDO_0020040; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v1.2 | UBR5 | Bryony Thompson Marked gene: UBR5 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v1.1 | UBR5 |
Bryony Thompson gene: UBR5 was added gene: UBR5 was added to Differences of Sex Development. Sources: Literature Mode of inheritance for gene: UBR5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: UBR5 were set to 39721588 Phenotypes for gene: UBR5 were set to Neurodevelopmental disorder MONDO:0700092, UBR5-related Review for gene: UBR5 was set to GREEN Added comment: 29 individuals with a neurodevelopment syndrome (24 de novo variants) with a core phenotype characterised by developmental delay (26/28), autism (16/26), and intellectual disability (56%). Additionally, some individuals presented with epilepsy/seizures (11/27), movement disorders, and/or genital anomalies (35%). Loss of function is the expected mechanism of disease with functional experiments in C. elegans and in vitro ubiquitination assays. Sources: Literature |
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Differences of Sex Development v0.380 | TWNK | Zornitza Stark Marked gene: TWNK as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.378 | POLR1C | Zornitza Stark Marked gene: POLR1C as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.375 | AXL | Zornitza Stark Marked gene: AXL as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.375 | SOX2 | Zornitza Stark Marked gene: SOX2 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.375 | POLR3B | Zornitza Stark Marked gene: POLR3B as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.374 | POLR3A | Zornitza Stark Marked gene: POLR3A as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.373 | MARS2 | Zornitza Stark Marked gene: MARS2 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.373 | MARS2 | Zornitza Stark Gene: mars2 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.373 | MARS2 | Zornitza Stark Publications for gene: MARS2 were set to PMID: 27650058, 21464306, 27087618 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.372 | LARS2 | Zornitza Stark Marked gene: LARS2 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.372 | LARS2 | Zornitza Stark Gene: lars2 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.372 | LARS2 | Zornitza Stark Phenotypes for gene: LARS2 were changed from Perrault syndrome 4; MIM# 615300 to Perrault syndrome 4, MIM# 615300 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.371 | LARS2 | Zornitza Stark Publications for gene: LARS2 were set to PMID: 32423379, 29205794, 23541342, 30737337, 26657938, | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.370 | IRF6 | Zornitza Stark Marked gene: IRF6 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.370 | HHAT | Zornitza Stark Marked gene: HHAT as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.369 | HARS2 | Zornitza Stark Marked gene: HARS2 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.369 | HARS2 | Zornitza Stark Gene: hars2 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.369 | HARS2 | Zornitza Stark Publications for gene: HARS2 were set to PMID: 27650058, 21464306, 27087618 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.368 | FREM2 | Zornitza Stark Marked gene: FREM2 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.367 | WT1 | Zornitza Stark Marked gene: WT1 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.365 | SRY | Zornitza Stark Marked gene: SRY as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.362 | SOX9 | Zornitza Stark Marked gene: SOX9 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.360 | FGFR1 | Zornitza Stark Marked gene: FGFR1 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.360 | FGFR1 | Zornitza Stark Phenotypes for gene: FGFR1 were changed from to Encephalocraniocutaneous lipomatosis, somatic mosaic 613001; Hartsfield syndrome 615465; Hypogonadotropic hypogonadism 2 with or without anosmia 147950; Osteoglophonic dysplasia 166250 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.357 | FGFR2 | Zornitza Stark Marked gene: FGFR2 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.357 | FGFR2 | Zornitza Stark Phenotypes for gene: FGFR2 were changed from to Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis,MIM# 207410, Apert syndrome, MIM# 101200, Beare-Stevenson cutis gyrata syndrome, MIM# 123790, Bent bone dysplasia syndrome, MIM# 614592 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.354 | FSHB | Zornitza Stark Marked gene: FSHB as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.351 | FSHR | Zornitza Stark Phenotypes for gene: FSHR were changed from to Ovarian dysgenesis 1 MONDO:0024463; Ovarian hyperstimulation syndrome MONDO:0011972 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.350 | FSHR | Zornitza Stark Marked gene: FSHR as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.348 | FSHR | Chirag Patel reviewed gene: FSHR: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 16630814, 7553856, 9020851, 9769327, 20087398, 9854118, 12930928, 12930927, 17721928, 26911863; Phenotypes: Ovarian dysgenesis 1 MONDO:0024463, Ovarian hyperstimulation syndrome MONDO:0011972; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.348 | FGFR2 | Chirag Patel reviewed gene: FGFR2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 29848297, 32879300; Phenotypes: Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis,MIM# 207410, Apert syndrome, MIM# 101200, Beare-Stevenson cutis gyrata syndrome, MIM# 123790, Bent bone dysplasia syndrome, MIM# 614592; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.348 | FGFR1 | Chirag Patel reviewed gene: FGFR1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 18034870, 23812909, 26942290; Phenotypes: Encephalocraniocutaneous lipomatosis, somatic mosaic 613001, Hartsfield syndrome 615465, Hypogonadotropic hypogonadism 2 with or without anosmia 147950, Osteoglophonic dysplasia 166250; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.348 | FRAS1 | Zornitza Stark Marked gene: FRAS1 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.347 | FGF8 | Zornitza Stark Marked gene: FGF8 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.344 | DHCR7 | Zornitza Stark Marked gene: DHCR7 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.342 | CTU2 | Zornitza Stark Marked gene: CTU2 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.341 | CHD7 | Zornitza Stark Marked gene: CHD7 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.341 | CHD7 | Zornitza Stark Phenotypes for gene: CHD7 were changed from to Hypogonadotropic hypogonadism 5 with or without anosmia MIM#612370; CHARGE syndrome MIM#214800 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.338 | CHD7 | Zornitza Stark reviewed gene: CHD7: Rating: GREEN; Mode of pathogenicity: None; Publications: 26411921; Phenotypes: Hypogonadotropic hypogonadism 5 with or without anosmia MIM#612370, CHARGE syndrome MIM#214800; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.338 | CHD4 | Zornitza Stark Marked gene: CHD4 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.337 | ATRX | Zornitza Stark Marked gene: ATRX as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.335 | ARX | Zornitza Stark Marked gene: ARX as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.335 | ARX | Zornitza Stark Gene: arx has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.335 | ARX | Zornitza Stark Phenotypes for gene: ARX were changed from to X-linked lissencephaly with abnormal genitalia, MONDO:0010268 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.334 | ARX | Zornitza Stark Publications for gene: ARX were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.333 | ARX | Zornitza Stark Mode of inheritance for gene: ARX was changed from Unknown to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.332 | ARX | Zornitza Stark reviewed gene: ARX: Rating: GREEN; Mode of pathogenicity: None; Publications: 14722918; Phenotypes: X-linked lissencephaly with abnormal genitalia, MONDO:0010268; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.332 | AR | Zornitza Stark Marked gene: AR as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.332 | AR | Zornitza Stark Gene: ar has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.332 | AR | Zornitza Stark Phenotypes for gene: AR were changed from to Hypospadias 1, X-linked MIM#30063; Androgen insensitivity MIM#300068; Androgen insensitivity, partial, with or without breast cancer MIM#312300 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.331 | AR | Zornitza Stark Publications for gene: AR were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.330 | AR | Zornitza Stark Mode of inheritance for gene: AR was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.329 | AR | Zornitza Stark reviewed gene: AR: Rating: GREEN; Mode of pathogenicity: None; Publications: 22334387; Phenotypes: Hypospadias 1, X-linked MIM#30063, Androgen insensitivity MIM#300068, Androgen insensitivity, partial, with or without breast cancer MIM#312300; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.329 | AMHR2 | Zornitza Stark Marked gene: AMHR2 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.325 | Chirag Patel Panel types changed to Victorian Clinical Genetics Services; Genetic Health Queensland; Royal Melbourne Hospital; Rare Disease | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.322 | FRAS1 |
Chirag Patel gene: FRAS1 was added gene: FRAS1 was added to Differences of Sex Development. Sources: Literature Mode of inheritance for gene: FRAS1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FRAS1 were set to PMID: 12766769, 18671281, 18000968 Phenotypes for gene: FRAS1 were set to Fraser syndrome 1, MIM#219000 Review for gene: FRAS1 was set to GREEN Added comment: Fraser syndrome is an autosomal recessive malformation disorder. Major criteria include syndactyly, cryptophthalmos spectrum, urinary tract abnormalities, ambiguous genitalia, laryngeal and tracheal anomalies, and positive family history. Minor criteria include anorectal defects, dysplastic ears, skull ossification defects, umbilical abnormalities, and nasal anomalies. Established gene-disease association. Sources: Literature |
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Differences of Sex Development v0.321 | FREM2 |
Chirag Patel gene: FREM2 was added gene: FREM2 was added to Differences of Sex Development. Sources: Literature Mode of inheritance for gene: FREM2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FREM2 were set to PMID: 15838507, 29688405, 18203166, 18671281, 18000968 Phenotypes for gene: FREM2 were set to Fraser syndrome 2, MIM#617666 Review for gene: FREM2 was set to GREEN Added comment: Fraser syndrome is an autosomal recessive malformation disorder. Major criteria include syndactyly, cryptophthalmos spectrum, urinary tract abnormalities, ambiguous genitalia, laryngeal and tracheal anomalies, and positive family history. Minor criteria include anorectal defects, dysplastic ears, skull ossification defects, umbilical abnormalities, and nasal anomalies. Established gene-disease association. Sources: Literature |
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Differences of Sex Development v0.319 | SOX2 |
Chirag Patel gene: SOX2 was added gene: SOX2 was added to Differences of Sex Development. Sources: Literature Mode of inheritance for gene: SOX2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SOX2 were set to PMID: 20301477 Phenotypes for gene: SOX2 were set to Anophthalmia/microphthalmia-esophageal atresia syndrome MONDO:0008799; Microphthalmia, syndromic 3, MIM# 206900; Optic nerve hypoplasia and abnormalities of the central nervous system, MIM# 206900 Review for gene: SOX2 was set to GREEN Added comment: SOX2 disorder includes anophthalmia and/or microphthalmia, brain malformations, developmental delay / intellectual disability, oesophageal atresia, pituitary hypoplasia, postnatal growth delay, hypotonia, seizures, and spastic or dystonic movements, and hypogonadotropic hypogonadism (manifest as cryptorchidism and micropenis in males, gonadal dysgenesis infrequently in females, and delayed puberty in both sexes). Established gene-disease association. Sources: Literature |
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Differences of Sex Development v0.315 | CHD4 |
Chirag Patel gene: CHD4 was added gene: CHD4 was added to Differences of Sex Development. Sources: Literature Mode of inheritance for gene: CHD4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CHD4 were set to PMID: 31388190, 32881470 Phenotypes for gene: CHD4 were set to Sifrim-Hitz-Weiss syndrome, MIM #617159 Review for gene: CHD4 was set to GREEN Added comment: Sifrim-Hitz-Weiss syndrome is an autosomal dominant intellectual developmental disorder with variable congenital defects affecting other systems, including cardiac, skeletal, and urogenital. Some patients may have short stature, enlarged head circumference, hearing loss, and nonspecific dysmorphic facial features. Established gene-disease association. Hypogonadism is common in males (cryptorchidism and/or microphallus), with hormonal profile consistent with hypogonadotropic hypogonadism. Sources: Literature |
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Differences of Sex Development v0.314 | POLR1C |
Chirag Patel gene: POLR1C was added gene: POLR1C was added to Differences of Sex Development. Sources: Literature Mode of inheritance for gene: POLR1C was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: POLR1C were set to PMID: 26151409, 32042905, 33005949 Phenotypes for gene: POLR1C were set to Leukodystrophy, hypomyelinating, 11, OMIM#616494 Review for gene: POLR1C was set to RED Added comment: Hypomyelinating leukodystrophy-11 (HLD11) is an autosomal recessive neurologic disorder characterized by delayed psychomotor development and other neurologic features associated with hypomyelination on brain imaging. Some patients may have additional nonneurologic features, particularly dental abnormalities and possibly hypogonadotropic hypogonadism. Thiffault et al. (2015) reported 8 unrelated patients with hypomyelinating leukodystrophy and 13 homozygous or compound heterozygous mutations in the POLR1C gene. All had neurologic abnormalities, including delayed psychomotor development, loss or lack of independent ambulation, abnormal cognition, tremor, ataxia, spasticity, and cerebellar findings. Three had myopia and 3 had dental abnormalities. Six patients were too young to be assessed for hypogonadotropic hypogonadism, and 2 did not have hypogonadism. Gauquelin et al. (2019) reported 23 patients with hypomyelinating leukodystrophy and 29 different variants (homozygous or compound heterozygous) in the POLR1C gene. Patients too young to comment on hypogonadotropic hypogonadism. Sources: Literature |
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Differences of Sex Development v0.314 | POLR1C |
Chirag Patel gene: POLR1C was added gene: POLR1C was added to Differences of Sex Development. Sources: Literature Mode of inheritance for gene: POLR1C was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: POLR1C were set to PMID: 26151409, 32042905, 33005949 Phenotypes for gene: POLR1C were set to Leukodystrophy, hypomyelinating, 11, OMIM#616494 Review for gene: POLR1C was set to RED Added comment: Hypomyelinating leukodystrophy-11 (HLD11) is an autosomal recessive neurologic disorder characterized by delayed psychomotor development and other neurologic features associated with hypomyelination on brain imaging. Some patients may have additional nonneurologic features, particularly dental abnormalities and possibly hypogonadotropic hypogonadism. Thiffault et al. (2015) reported 8 unrelated patients with hypomyelinating leukodystrophy and 13 homozygous or compound heterozygous mutations in the POLR1C gene. All had neurologic abnormalities, including delayed psychomotor development, loss or lack of independent ambulation, abnormal cognition, tremor, ataxia, spasticity, and cerebellar findings. Three had myopia and 3 had dental abnormalities. Six patients were too young to be assessed for hypogonadotropic hypogonadism, and 2 did not have hypogonadism. Gauquelin et al. (2019) reported 23 patients with hypomyelinating leukodystrophy and 29 different variants (homozygous or compound heterozygous) in the POLR1C gene. Patients too young to comment on hypogonadotropic hypogonadism. Sources: Literature |
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Differences of Sex Development v0.314 | POLR1C |
Chirag Patel gene: POLR1C was added gene: POLR1C was added to Differences of Sex Development. Sources: Literature Mode of inheritance for gene: POLR1C was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: POLR1C were set to PMID: 26151409, 32042905, 33005949, ............22855961 Phenotypes for gene: POLR1C were set to Leukodystrophy, hypomyelinating, 11, OMIM#616494 Review for gene: POLR1C was set to RED Added comment: Hypomyelinating leukodystrophy-11 (HLD11) is an autosomal recessive neurologic disorder characterized by delayed psychomotor development and other neurologic features associated with hypomyelination on brain imaging. Some patients may have additional nonneurologic features, particularly dental abnormalities and possibly hypogonadotropic hypogonadism. Thiffault et al. (2015) reported 8 unrelated patients with hypomyelinating leukodystrophy and 13 homozygous or compound heterozygous mutations in the POLR1C gene. All had neurologic abnormalities, including delayed psychomotor development, loss or lack of independent ambulation, abnormal cognition, tremor, ataxia, spasticity, and cerebellar findings. Three had myopia and 3 had dental abnormalities. Six patients were too young to be assessed for hypogonadotropic hypogonadism, and 2 did not have hypogonadism. Gauquelin et al. (2019) reported 23 patients with hypomyelinating leukodystrophy and 29 different variants (homozygous or compound heterozygous) in the POLR1C gene. Patients too young to comment on hypogonadotropic hypogonadism. Sources: Literature |
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Differences of Sex Development v0.312 | POLR3B |
Chirag Patel gene: POLR3B was added gene: POLR3B was added to Differences of Sex Development. Sources: Literature Mode of inheritance for gene: POLR3B was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: POLR3B were set to PubMed: 27512013, 23355746, 22036171, 22036172, 25339210, 33005949, 22855961 Phenotypes for gene: POLR3B were set to Leukodystrophy, hypomyelinating, 8, with or without oligodontia and/or hypogonadotropic hypogonadism; OMIM #614381 Review for gene: POLR3B was set to GREEN Added comment: Hypomyelinating leukodystrophy-8 (HLD8) is an autosomal recessive neurologic disorder characterized by early childhood onset of cerebellar ataxia and mild intellectual disabilities associated with diffuse hypomyelination apparent on brain MRI. Variable features include oligodontia and/or hypogonadotropic hypogonadism. There is considerable inter- and intrafamilial variability. Multiples families reported with compound heterozygous mutations in POL3RB gene. Wolf et al. (2014) performed a cross-sectional observational study of 105 patients with 4H syndrome, including 43 with mutations in the POLR3A gene and 62 with mutations in the POLR3B gene. Delayed puberty/HH, in those old enough to assess, occurred in 81% of patients with POLR3A mutations and in 69% of those with POLR3B mutations. Sources: Literature |
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Differences of Sex Development v0.311 | POLR3A |
Chirag Patel gene: POLR3A was added gene: POLR3A was added to Differences of Sex Development. Sources: Literature Mode of inheritance for gene: POLR3A was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: POLR3A were set to PubMed: 21855841, 25339210, 33005949, 22855961 Phenotypes for gene: POLR3A were set to Leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism, OMIM#607694 Review for gene: POLR3A was set to GREEN Added comment: Hypomyelinating leukodystrophy-7 (HLD7) is an autosomal recessive neurodegenerative disorder characterized by childhood onset of progressive motor decline manifest as spasticity, ataxia, tremor, and cerebellar signs, as well as mild cognitive regression. Other common features may include hypodontia or oligodontia and hypogonadotropic hypogonadism. There is considerable inter- and intrafamilial variability. Bernard et al. (2011) identified 14 different mutations in the POLR3A gene (homozygous or compound heterozygous state), in 19 patients from 12 families. The mutations were spread throughout the gene, and there were no obvious genotype/phenotype correlations. Immunoblot analysis showed decreased levels of POLR3A protein in fibroblasts from 4 affected individuals, and decreased levels in the cortex and cerebral white matter of another patient, suggesting that loss of function is responsible for the disorder. Wolf et al. (2014) performed a cross-sectional observational study of 105 patients with 4H syndrome, including 43 with mutations in the POLR3A gene and 62 with mutations in the POLR3B gene. Delayed puberty/HH, in those old enough to assess, occurred in 81% of patients with POLR3A mutations and in 69% of those with POLR3B mutations. Sources: Literature |
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Differences of Sex Development v0.310 | HARS2 | Chirag Patel Classified gene: HARS2 as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.310 | HARS2 | Chirag Patel Gene: hars2 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.308 | HHAT |
Chirag Patel gene: HHAT was added gene: HHAT was added to Differences of Sex Development. Sources: Expert list Mode of inheritance for gene: HHAT was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: HHAT were set to PMID: 24784881, 33749989, 35045414 Phenotypes for gene: HHAT were set to Nivelon-Nivelon-Mabille syndrome, OMIM:600092 Review for gene: HHAT was set to GREEN Added comment: 3 individuals from 3 families with 46, XY karyotype and sex reversal, with supportive mouse model reported in 24784881. PMID:24784881 - Callier et al 2014 - report a family with 2 siblings with Disorder of Sex Development (DSD) and chondrodysplasia (Nivelon-Nivelon-Mabille syndrome). The first sibling (46,XY karyotype) displayed severe dwarfism with generalized chondrodysplasia, a narrow, bell-shaped thorax, micromelia, brachydactyly, severe microcephaly (-7.5 SD at age 16 (PMID:15578577) with cerebellar vermis hypoplasia, facial anomalies, hypoplastic irides, and coloboma of both optic discs. Complete gonadal dysgenesis ( including normal external female genitalia, lack of pubertal development, primary amenorrhea, and hypergonadotrophic hypogonadism) and intellectual disability is also noted. The second sibling (46,XX karyotype) had histologically normal ovaries and similar phenotypic abnormalities including severe dwarfism and generalized chondrodysplasia. Using WES a homozygous missense variant was found NM_001122834:c.860G>T:p.(Gly287Val) in HHAT in the first sibling which is in the conserved MBOAT domain. The parents were heterozygous. They also found that mice lacking functional Hhat show a similar phenotype as the syndromic 46,XY DSD patient including testicular dysgenesis and skeletal defects. PMID: 33749989 - Pande et al 2021 - report multiple malformations in three pregnancies with a novel biallelic in-frame deletion, c.365_367del; (p.Thr122del), in exon 5 of HHAT in the living proband. She shows severe microphthalmia, microcephaly (−8 SD head circumference at age 7), skeletal dysplasia (narrow bell-shaped thorax, short and angel-shaped epiphyses of hands and feet) and midface retrusion, short columella with a groove at the base, prominent ears, long philtrum, depressed nasal bridge, everted lower lip, and a single central incisor. She also has complete sex reversal (karyotype of 46, XY, normal internal organs including uterus and ovaries.) PMID: 35045414 - Mazen et al 2022 - report an Egyptian patient with 46,XY DSD (ambiguous genitalia and microcephaly) and a homozygous missense variant in HHAT, which segregated with the phenotype in the family. Sources: Expert list |
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Differences of Sex Development v0.307 | CTU2 |
Chirag Patel changed review comment from: DREAM-PL syndrome presents with dysmorphic facies, renal agenesis, ambiguous genitalia, microcephaly, polydactyly, and lissencephaly. Other anomalies include corpus callosum agenesis or dysgenesis, septal defects, PDA, hypoplastic right ventricle and joint contractures. PMID:26633546. Affected members of all 3 families have microcephaly, facial dysmorphia and unilateral renal agenesis. 2/3 families have ambiguous genitalia; however, only 1 family had karyotyping done, which showed normal male karyotype (46 XY). 2/3 had congenital heart disease. PMID: 27480277. Same variant as PMID:26633546. Affected individuals in this extended family have similar phenotype as PMID:26633546. Patient 1: in addition to microcephaly also has renal anomalies (small kidneys) and possible ambiguous genitalia with normal XY karyotype. Patient 2: cousin of patient 1. In addition to microcephaly did not have renal anomalies and nor ambiguous genitalia. Both patients have congenital heart disease. PMID: 31301155. 5 new cases, all with microcephaly. 4/5 with renal anomalies, 2/5 with ambiguous genitalia, 4/5 congenital heart disease. Functional characterization using patient-derived cells for each of these alleles, as well as the original founder allele; revealed a specific impairment of wobble uridine thiolation in all known thiol-containing tRNAs. Sources: Literature; to: DREAM-PL syndrome presents with dysmorphic facies, renal agenesis, ambiguous genitalia, microcephaly, polydactyly, and lissencephaly. PMID:26633546. Affected members of all 3 families have microcephaly, facial dysmorphia and unilateral renal agenesis. 2/3 families have ambiguous genitalia; however, only 1 family had karyotyping done, which showed normal male karyotype (46 XY). 2/3 had congenital heart disease. PMID: 27480277. Same variant as PMID:26633546. Affected individuals in this extended family have similar phenotype as PMID:26633546. Patient 1: in addition to microcephaly also has renal anomalies (small kidneys) and possible ambiguous genitalia with normal XY karyotype. Patient 2: cousin of patient 1. In addition to microcephaly did not have renal anomalies and nor ambiguous genitalia. Both patients have congenital heart disease. PMID: 31301155. 5 new cases, all with microcephaly. 4/5 with renal anomalies, 2/5 with ambiguous genitalia, 4/5 congenital heart disease. Functional characterization using patient-derived cells for each of these alleles, as well as the original founder allele; revealed a specific impairment of wobble uridine thiolation in all known thiol-containing tRNAs. Sources: Literature |
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Differences of Sex Development v0.307 | CTU2 |
Chirag Patel changed review comment from: DREAM-PL syndrome presents with dysmorphic facies, renal agenesis, ambiguous genitalia, microcephaly, polydactyly, and lissencephaly. Other anomalies include corpus callosum agenesis or dysgenesis, septal defects, PDA, hypoplastic right ventricle and joint contractures. More than 6 families reported, four had the same founder variant. Functional characterization using patient-derived cells for each of these alleles, as well as the original founder allele; revealed a specific impairment of wobble uridine thiolation in all known thiol-containing tRNAs Sources: Literature; to: DREAM-PL syndrome presents with dysmorphic facies, renal agenesis, ambiguous genitalia, microcephaly, polydactyly, and lissencephaly. Other anomalies include corpus callosum agenesis or dysgenesis, septal defects, PDA, hypoplastic right ventricle and joint contractures. PMID:26633546. Affected members of all 3 families have microcephaly, facial dysmorphia and unilateral renal agenesis. 2/3 families have ambiguous genitalia; however, only 1 family had karyotyping done, which showed normal male karyotype (46 XY). 2/3 had congenital heart disease. PMID: 27480277. Same variant as PMID:26633546. Affected individuals in this extended family have similar phenotype as PMID:26633546. Patient 1: in addition to microcephaly also has renal anomalies (small kidneys) and possible ambiguous genitalia with normal XY karyotype. Patient 2: cousin of patient 1. In addition to microcephaly did not have renal anomalies and nor ambiguous genitalia. Both patients have congenital heart disease. PMID: 31301155. 5 new cases, all with microcephaly. 4/5 with renal anomalies, 2/5 with ambiguous genitalia, 4/5 congenital heart disease. Functional characterization using patient-derived cells for each of these alleles, as well as the original founder allele; revealed a specific impairment of wobble uridine thiolation in all known thiol-containing tRNAs. Sources: Literature |
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Differences of Sex Development v0.306 | CTU2 |
Chirag Patel gene: CTU2 was added gene: CTU2 was added to Differences of Sex Development. Sources: Literature Mode of inheritance for gene: CTU2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CTU2 were set to PMID: 27480277, 26633546, 31301155, 38348206 Phenotypes for gene: CTU2 were set to DREAM-PL syndrome (Microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome), MIM#618142 Review for gene: CTU2 was set to GREEN Added comment: DREAM-PL syndrome presents with dysmorphic facies, renal agenesis, ambiguous genitalia, microcephaly, polydactyly, and lissencephaly. Other anomalies include corpus callosum agenesis or dysgenesis, septal defects, PDA, hypoplastic right ventricle and joint contractures. More than 6 families reported, four had the same founder variant. Functional characterization using patient-derived cells for each of these alleles, as well as the original founder allele; revealed a specific impairment of wobble uridine thiolation in all known thiol-containing tRNAs Sources: Literature |
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Differences of Sex Development v0.304 | TWNK |
Chirag Patel gene: TWNK was added gene: TWNK was added to Differences of Sex Development. Sources: Literature Mode of inheritance for gene: TWNK was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TWNK were set to PMID: 25355836, 31852434, 31455392 Phenotypes for gene: TWNK were set to Perrault syndrome 5; MIM# 616138 Review for gene: TWNK was set to GREEN Added comment: Perrault syndrome-5 (PRLTS5) is an autosomal recessive disorder characterized by progressive ataxia, axonal neuropathy, hyporeflexia, and abnormal eye movements, accompanied by progressive hearing loss and ovarian dysgenesis. PMID: 25355836: 4 women from 2 unrelated families with Perrault syndrome-5. 2 sisters in each family presented with primary amenorrhea, lack of secondary sexual characteristics, and gonadal dysgenesis; 2 sisters in 1 family showed streak ovaries. Three of the 4 girls had onset of sensorineural hearing loss at 7 to 8 years of age; the fourth had onset of hearing loss at age 13. All 4 patients developed neurologic involvement in the second or third decades, with features including ataxia, nystagmus, hyporeflexia, and sensory axonal neuropathy with distal sensory impairment. WES identified compound heterozygous variants in each family, but functional studies of the variants were not performed. PMID: 31852434: female with severe bilateral hypoacusis, severe ataxia, polyneuropathy, lower limb spastic paraparesis with pyramidal signs, and gonadal dysgenesis, and compound heterozygous variants in TWNK gene (but functional studies of the variants were not performed). PMID: 31455392: 3 siblings from one family with childhood-onset bilateral sensorineural hearing impairment, neurological signs (spinocerebellar ataxia, polyneuropathy), and gonadal dysfunction with early cessation of menses in the 2 females. WES identified compound heterozygous pathogenic mutations in the TWNK gene, which segregated with disease. , Sources: Literature |
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Differences of Sex Development v0.303 | MARS2 | Chirag Patel Classified gene: MARS2 as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.303 | MARS2 | Chirag Patel Gene: mars2 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.302 | MARS2 |
Chirag Patel gene: MARS2 was added gene: MARS2 was added to Differences of Sex Development. Sources: Expert Review Mode of inheritance for gene: MARS2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MARS2 were set to PMID: 27650058, 21464306, 27087618 Phenotypes for gene: MARS2 were set to Perrault syndrome 2, MIM# 614926 Review for gene: MARS2 was set to GREEN Added comment: Perrault syndrome-2 (PRLTS2) is an autosomal recessive disorder characterized by sensorineural deafness in both males and females. Affected females have primary amenorrhea, streak gonads (ovarian dysgenesis), and infertility, whereas affected males show normal pubertal development and are fertile. No neurological abnormalities reported. PMID: 21464306: five affected siblings from one family with three females with ovarian dysgenesis with primary amenorrhea and streak gonads along with sensorineural hearing loss (two males had normal fertility) had two variants in HARS2 with confirmed biparental inheritance. Functional studies showed that the mutations resulted in decreased enzyme activity, and knockdown of the HARS2 homolog in C. elegans caused severe gonadal defects and infertility. PMID: 27650058: two unrelated probands with Perrault syndrome with profound deafness and secondary amenorrhoea with gonadal dysgenesis were found to have a homozygous variant in HARS2. These probands were not related but were from the same region in Morocco. PMID: 27087618: 2 siblings in Turkish family with Perrault syndrome (female sibling had with secondary amenorrhea and gonadal dysgenesis) were found to have a homozygous variant in HARS2. No functional work. Sources: Expert Review |
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Differences of Sex Development v0.301 | HARS2 |
Chirag Patel gene: HARS2 was added gene: HARS2 was added to Differences of Sex Development. Sources: Literature Mode of inheritance for gene: HARS2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: HARS2 were set to PMID: 27650058, 21464306, 27087618 Phenotypes for gene: HARS2 were set to Perrault syndrome 2, MIM# 614926 Review for gene: HARS2 was set to GREEN Added comment: Perrault syndrome-2 (PRLTS2) is an autosomal recessive disorder characterized by sensorineural deafness in both males and females. Affected females have primary amenorrhea, streak gonads (ovarian dysgenesis), and infertility, whereas affected males show normal pubertal development and are fertile. No neurological abnormalities reported. PMID: 21464306: five affected siblings from one family with three females with ovarian dysgenesis with primary amenorrhea and streak gonads along with sensorineural hearing loss (two males had normal fertility) had two variants in HARS2 with confirmed biparental inheritance. Functional studies showed that the mutations resulted in decreased enzyme activity, and knockdown of the HARS2 homolog in C. elegans caused severe gonadal defects and infertility. PMID: 27650058: two unrelated probands with Perrault syndrome with profound deafness and secondary amenorrhoea with gonadal dysgenesis were found to have a homozygous variant in HARS2. These probands were not related but were from the same region in Morocco. PMID: 27087618: 2 siblings in Turkish family with Perrault syndrome (female sibling had with secondary amenorrhea and gonadal dysgenesis) were found to have a homozygous variant in HARS2. No functional work. Sources: Literature |
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Differences of Sex Development v0.300 | LARS2 | Chirag Patel Classified gene: LARS2 as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.300 | LARS2 | Chirag Patel Gene: lars2 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.299 | LARS2 |
Chirag Patel gene: LARS2 was added gene: LARS2 was added to Differences of Sex Development. Sources: Literature Mode of inheritance for gene: LARS2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: LARS2 were set to PMID: 32423379, 29205794, 23541342, 30737337, 26657938, Phenotypes for gene: LARS2 were set to Perrault syndrome 4; MIM# 615300 Review for gene: LARS2 was set to GREEN Added comment: Perrault syndrome-4 (PRLTS4) is an autosomal recessive disorder primarily characterized by early-onset sensorineural hearing loss in both males and females, and premature ovarian failure (POF) due to ovarian dysgenesis in females. Affected individuals may also develop neurologic involvement, including developmental delay or learning difficulties in childhood or onset of progressive movement abnormalities, such as spasticity, in adulthood. Brain imaging may show progressive leukodystrophy. At least 6 families with affected females reported with biallelic variants in LARS2 (mostly missense), which segregated in family. Patient-derived mitochondria showed decreased LARS2 aminoacylation activity (about 50% of controls) in one study. Sources: Literature |
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Differences of Sex Development v0.297 | RNF216 | Zornitza Stark Marked gene: RNF216 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.296 | RNF216 |
Zornitza Stark gene: RNF216 was added gene: RNF216 was added to Differences of Sex Development. Sources: Expert list Mode of inheritance for gene: RNF216 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RNF216 were set to 25841028; 23656588 Phenotypes for gene: RNF216 were set to Cerebellar ataxia and hypogonadotropic hypogonadism, MIM# 212840 Review for gene: RNF216 was set to GREEN Added comment: Gordon Holmes syndrome is an autosomal recessive adult-onset neurodegenerative disorder characterized by progressive cognitive decline, dementia, and variable movement disorders, such as ataxia and chorea. The neurologic phenotype is associated with hypogonadotropic hypogonadism, which can present with amenorrhoea in females. Sources: Expert list |
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Differences of Sex Development v0.294 | FKBP4 | Bryony Thompson Marked gene: FKBP4 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.293 | FKBP4 |
Mark Cleghorn gene: FKBP4 was added gene: FKBP4 was added to Differences of Sex Development. Sources: Other Mode of inheritance for gene: FKBP4 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: FKBP4 were set to complex neurodevelopmental disorder MONDO:0100038 Penetrance for gene: FKBP4 were set to unknown Review for gene: FKBP4 was set to AMBER Added comment: Rebecca Yarwood, University of Manchester ESHG presentation 4/6/24, unpublished Bilalleic FKBP4 w NDD + DSD Protein has functions in hormone receptor trafficking FKPB4 highly expressed in stem cell and progenitor cells in gonad and neuronal degeneration Index case Severe GDD abN external genitalia CV AbN FBBP4 p.E196* Via GeneMatcher 7 families (12 individuals) 12/12 severe GDD/ID 9/10 microcephaly 11/12 external genital abnormalities (details not provided) All w homozygous pLoF variants (mixture of canonical splice, frameshift, nonsense) Sources: Other |
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Differences of Sex Development v0.293 | RXFP2 |
Katie Ayers edited their review of gene: RXFP2: Added comment: One individual with bilateral cryptorchidism and infertility had homozygous c.1406delT in RXFP2 (NM_130806.5), leading to a frameshift p.(Phe469Serfs*8). From consanguinous family. Two affected brothers with homozygous missense variant c.1015A>G in RXFP2 (NM_130806.5) resulting in an amino acid substitution p.(Asn339Asp) with bilateral cryptorchidism.; Changed publications: 37208861; Changed phenotypes: Infertility, cryptorchidism, non-obstructive azoospermia |
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Differences of Sex Development v0.293 | RXFP2 | Katie Ayers edited their review of gene: RXFP2: Added comment: Homozygous non-canonical splicing variant by whole-exome sequencing and Sanger sequencing . NM_130806: c.1376-12A > G; Changed rating: GREEN; Changed mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Changed publications: 38430325; Changed phenotypes: cryptorchidism and non-obstructive azoospermia; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.293 | AXL |
Zornitza Stark gene: AXL was added gene: AXL was added to Differences of Sex Development. Sources: Expert Review Mode of inheritance for gene: AXL was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: AXL were set to 24476074 Phenotypes for gene: AXL were set to Hypogonadotropic hypogonadism, MONDO:0018555, AXL-related Review for gene: AXL was set to RED Added comment: Four variants reported in individuals with KS/IHH. One is non-canonical splice site variant (c.586-6 C>T) but authors demonstrate no abnormal splicing occurs. Remainder are missense. Segregation in one family only: inherited from phenotypically normal parent. Axl null mice demonstrated delay in first estrus and the interval between vaginal opening and first estrus Sources: Expert Review |
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Differences of Sex Development v0.292 | SEMA3A | Zornitza Stark Marked gene: SEMA3A as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.291 | SEMA3A |
Zornitza Stark gene: SEMA3A was added gene: SEMA3A was added to Differences of Sex Development. Sources: Expert Review Mode of inheritance for gene: SEMA3A was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal Publications for gene: SEMA3A were set to 28075028; 33369061; 20301509; 21059704; 24124006; 22927827 Phenotypes for gene: SEMA3A were set to Hypogonadotropic hypogonadism 16 with or without anosmia - MIM#614897 Review for gene: SEMA3A was set to GREEN Added comment: Heterozygous variants associated with isolated GnRH deficiency with or without anosmia (Kallman syndrome like). More severe phenotype with biallelic SEMA3A variants including postnatal short stature and congenital heart defects in 3/3 published, unrelated individuals. PMID 33369061 Gileta et al 2021 - report x1 patient. Female proband was compound heterozygote for a nonsense variant and a multiexonic deletion of SEMA3A. Presents with postnatal short stature, congenital cardiac anomalies, dysmorphic features, hypogonadotrophic hypogonadism and anosmia. PMID 28075028 Baumann et al 2017 - report x1 patient. Homozygous LoF variants identified in a proband from a consanguineous Turkish family. Noted at birth to have a high-positioned scapulae, deformed ribs and a lateral clavicular hook. The patient also had upper/lower limb contractures and aberrant right subclavian artery. Mild facial dysmorphism, micropenis and hypogonadotrophic hypogonadism also noted in the first week of life. Postnatal short stature (length 50cm at term birth) PMID 24124006 Hofmann et al 2013 - first reported biallelic variants in a proband with postnatal short stature, skeletal anomalies of the thorax, congenital heart defect and camptodactyly Sources: Expert Review |
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Differences of Sex Development v0.289 | DCAF17 | Zornitza Stark Marked gene: DCAF17 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.287 | CLPP | Zornitza Stark Marked gene: CLPP as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.286 | CLPP |
Zornitza Stark gene: CLPP was added gene: CLPP was added to Differences of Sex Development. Sources: Expert Review Mode of inheritance for gene: CLPP was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CLPP were set to 23541340; 25956234; 26970254; 27087618; 27650058; 27650058; 27899912 Phenotypes for gene: CLPP were set to Perrault syndrome 3, MIM# 614129 Review for gene: CLPP was set to AMBER Added comment: Multiple families with Perrault syndrome, HH is an inconsistent feature. PMID: 23541340, describes 3 consanguineous Pakistani families (PDF1, PKDF291 and DEM4395), all affected individuals had sensorineural hearing loss. Family PDF1: 3 affected sisters, 1/3 had delayed puberty, streak ovaries and hormone levels consistant with hypogonadotropic hypogonadism, 2/3 had incipient POF and 1/3 had white matter phenotype. All three had epilepsy, short stature, microcephaly (< 3 percentile), moderate learning difficulties and ataxia. Family PKDF291: 4 affected females with primary amenorrhea and hypogonadotropic hypogonadism. 3/4 had rudimentary uterus and small ovaries, 1/4 had small uterus and normal sized ovaries. No learning disabilities, microcephaly, short stature, epilepsy or neurological deficiet in all affected females. Family DEM4395: 1 affected male and 2 affected females. All females had normal periods but their hormone profiles were not investigated. Aside from hearing loss there were no other self reported medical problems. PMID: 25956234. Consanguineous Saudi family with 1 affected male and 1 affected female. Both patients have hearing loss, growth retardation and mental retardation, spastic diplegia and mild-severe white matter loss. No seizures were described in the patients. There is a third sibling (8 months) with the same variant; however, he did not show any of the phenotypes seen in his siblings but he is under regular checkups from a clinical team. PMID:26970254. Consanguineous family of Arabic descent. Proband with 4 unaffected siblings and parents. Proband has hearing loss, azoospermia, no neurological symptoms other than the foot drop (neurophysiology revealed a sensory-motor demyelinative axonal peripheral neuropathy of the lower limbs). Father has cerebellar ataxia (cause unknown). PMID: 27087618. Non-consanguineous Turkish family; however, parents are from the same village. 2 affected siblings (1 male, 1 female). Sister has secondary amenorrhea, hearing loss, no ovaries detected, hypogonadotropic hypogonadism, no neurological problems. Brother has hearing loss but no other problems. PMID: 27650058. Consanguineous Algerian family with 2 affected females. Both have hearing loss and secondary amenorrhea, but no other neurological symptoms. PMID: 27899912. 3 affected families, with 5 affected individuals (all males). All had congenital deafness, psychomotor retardation, white matter phenotype and short stature. Patients were not tested for infertility. Sources: Expert Review |
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Differences of Sex Development v0.285 | CCDC141 | Zornitza Stark Marked gene: CCDC141 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.284 | CCDC141 |
Zornitza Stark gene: CCDC141 was added gene: CCDC141 was added to Differences of Sex Development. Sources: Expert Review Mode of inheritance for gene: CCDC141 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: CCDC141 were set to 251920460; 28324054; 32520725; 27014940 Phenotypes for gene: CCDC141 were set to congenital hypogonadotropic hypogonadism, MONDO:0015770, CCDC141-related Review for gene: CCDC141 was set to AMBER Added comment: PMID: 251920460 describes 2 affected siblings from a consanguineous family with anosmic HH, who had homozygous variant in FEZF1 (Amber gene on this panel) and also homozyous for variant in CCDC141. PMID: 28324054 describes the above case and also 3 new cases (all had normal sense of smell and HH). Family 2: compound het for CCDC141 and heterozygous for DMXL2 variant. Family 3: heterozygous for CCDC141 variant and heterozygous for variants in 3 other genes (NR5A2, FSHB - Green on HH panel, IGSF10). Family 4: affected patient was heterozygous for CCDC141 variant, which the father also carried but father was unaffected. PMID: 32520725 describes a large Chinese cohort with congenital HH looking at the contribution of CCDC141 to the disease. 12 probands had variants CCDC141 and 9 of these probands had variants in other HH-related genes (inluding PCSK1, ANOS1, PROKR2, AXL, SOX10, HS6ST1, PNPLA6 and FGFR1). The authors concluded that CCDC141 variants alone is not sufficient to cause HH. PMID: 27014940 talks about a ccdc141 knockdown mouse model reduces GnRH neuronal migration. Overall, insufficient evidence for gene-disease association; may be a modifier. Sources: Expert Review |
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Differences of Sex Development v0.283 | NR2F2 | Zornitza Stark Phenotypes for gene: NR2F2 were changed from 46,XX disorder of sex development (DSD) and congenital heart defects to 46XX sex reversal 5, MIM# 618901 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.282 | SOX11 | Zornitza Stark Marked gene: SOX11 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.281 | SOX11 |
Zornitza Stark gene: SOX11 was added gene: SOX11 was added to Differences of Sex Development. Sources: Expert Review Mode of inheritance for gene: SOX11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SOX11 were set to 29459093; 24886874; 33086258; 33785884; 35642566; 35341651 Phenotypes for gene: SOX11 were set to Intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism, MIM# 615866 Review for gene: SOX11 was set to GREEN Added comment: Over 40 individuals reported, e.g. PMID 35341651. The phenotype that has emerged over time is distinct from patients with mutations in ARID1B (614556) and Coffin-Siris syndrome-1 (135900). Patients with IDDMOH tend to be microcephalic and have ocular motor apraxia, abnormal eye morphology, or hypogonadotropic hypogonadism. Sources: Expert Review |
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Differences of Sex Development v0.280 | SLC20A1 | Zornitza Stark Marked gene: SLC20A1 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.279 | PTCH1 | Zornitza Stark Marked gene: PTCH1 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.277 | SLC20A1 |
Chirag Patel gene: SLC20A1 was added gene: SLC20A1 was added to Differences of Sex Development. Sources: Literature Mode of inheritance for gene: SLC20A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SLC20A1 were set to PMID: 32850778, 27013921 Phenotypes for gene: SLC20A1 were set to Bladder-Exstrophy-Epispadias Complex (BEEC) Review for gene: SLC20A1 was set to GREEN gene: SLC20A1 was marked as current diagnostic Added comment: Three individuals with BEEC and animal model supporting role of this gene in urinary tract and urorectal development. Sources: Literature |
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Differences of Sex Development v0.276 | PTCH1 |
Chirag Patel gene: PTCH1 was added gene: PTCH1 was added to Differences of Sex Development. Sources: Other Mode of inheritance for gene: PTCH1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: PTCH1 were set to Bladder exstrophy and epispadias complex (BEEC) Review for gene: PTCH1 was set to AMBER Added comment: ESHG 2023: 9 individuals with BEEC (WES/Sanger) with 9 x rare HTZ variants in PTCH1 (2 de novo, 7 inherited unaffected parent). No clinical features of Gorlin syndrome and variants not seen in Gorlin syndrome. Zebrafish models: a) knock out and knock in (1 missense variant) models showed no phenotype b) co-injection of WT and missense variant led to altered cloaca on D5. Proposed mechanism is dominant negative effect. Sources: Other |
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Differences of Sex Development v0.276 | PTCH1 |
Chirag Patel gene: PTCH1 was added gene: PTCH1 was added to Differences of Sex Development. Sources: Other Mode of inheritance for gene: PTCH1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: PTCH1 were set to Bladder exstrophy and epispadias complex (BEEC) Review for gene: PTCH1 was set to AMBER Added comment: ESHG 2023: 9 individuals with BEEC (WES/Sanger) with 9 x rare HTZ variants in PTCH1 (2 de novo, 7 inherited unaffected parent). No clinical features of Gorlin syndrome and variants not seen in Gorlin syndrome. Zebrafish models: a) knock out and knock in (1 missense variant) models showed no phenotype b) co-injection of WT and missense variant led to altered cloaca on D5. Proposed mechanism is dominant negative effect. Sources: Other |
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Differences of Sex Development v0.275 | SART3 | Krithika Murali Classified gene: SART3 as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.275 | SART3 | Krithika Murali Gene: sart3 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.274 | SART3 | Krithika Murali Marked gene: SART3 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.274 | SART3 | Krithika Murali Gene: sart3 has been removed from the panel. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.274 | SART3 |
Daniel Flanagan gene: SART3 was added gene: SART3 was added to Differences of Sex Development. Sources: Expert list Mode of inheritance for gene: SART3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SART3 were set to PMID: 37296101 Phenotypes for gene: SART3 were set to Neurodevelopmental disorder (MONDO#0700092), SART3-related; 46,XY disorder of sex development (MONDO:0020040), SART3-related Review for gene: SART3 was set to GREEN Added comment: Nine individuals from six families presenting with intellectual disability, global developmental delay, a subset of brain anomalies, together with gonadal dysgenesis in 46,XY individuals. Additionally, two individuals had seizures and two had epileptiform activity reported on EEG. Human induced pluripotent stem cells carrying patient variants in SART3 show disruption to multiple signalling pathways, upregulation of spliceosome components and demonstrate aberrant gonadal and neuronal differentiation in vitro. Sources: Expert list |
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Differences of Sex Development v0.274 | DAAM2 | Zornitza Stark Marked gene: DAAM2 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.272 | ARHGAP35 | Zornitza Stark Marked gene: ARHGAP35 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.272 | ARHGAP35 | Zornitza Stark Gene: arhgap35 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.272 | ARHGAP35 | Zornitza Stark Phenotypes for gene: ARHGAP35 were changed from Idiopathic hypogonadotropic hypogonadism, no OMIM # to Hypogonadotropic hypogonadism, MONDO:0015770, ARHGAP35-related | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.271 | ARHGAP35 | Zornitza Stark reviewed gene: ARHGAP35: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hypogonadotropic hypogonadism, MONDO:0015770, ARHGAP35-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.271 | ARHGAP35 | Chirag Patel Classified gene: ARHGAP35 as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.271 | ARHGAP35 | Chirag Patel Gene: arhgap35 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.270 | ARHGAP35 |
Chirag Patel gene: ARHGAP35 was added gene: ARHGAP35 was added to Differences of Sex Development. Sources: Literature Mode of inheritance for gene: ARHGAP35 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ARHGAP35 were set to PMID: 36178483 Phenotypes for gene: ARHGAP35 were set to Idiopathic hypogonadotropic hypogonadism, no OMIM # Review for gene: ARHGAP35 was set to GREEN Added comment: 12 patients with idiopathic hypogonadotropic hypogonadism. Rare protein-truncating variants (n = 5) and missense variants (n = 7) found in the RhoGAP domain of ARHGAP35 gene. Zebrafish modeling using gnrh3:egfp phenotype assessment showed that mutant larvae with deficient arhgap35a (predominant ARHGAP35 paralog in zebrafish brain), displayed decreased GnRH3-GFP+ neuronal area, a readout for IHH. In vitro GAP activity studies showed that 1 rare missense variant (Arg1284Trp) had decreased GAP activity. Sources: Literature |
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Differences of Sex Development v0.268 | KCNK3 | Zornitza Stark Marked gene: KCNK3 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.267 | KCNK3 |
Krithika Murali gene: KCNK3 was added gene: KCNK3 was added to Differences of Sex Development. Sources: Literature Mode of inheritance for gene: KCNK3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: KCNK3 were set to 36195757 Phenotypes for gene: KCNK3 were set to Neurodevelopmental disorder, MONDO:0700092, KCNK3-related; developmental delay with sleep apnoea (DDSA) Review for gene: KCNK3 was set to GREEN Added comment: PMID 36195757 Sörmann et al 2022 report 9 unrelated individuals with de novo heterozygous KCNK3 missense variants (21 weeks to 25 years old). All 8 living probands (3-25 years) had hypotonia, global developmental delay, central and/or obstructive sleep apnoea and feeding difficulties. 7/9 probands had additional anomalies including microcephaly (at least 3/9), arthrogryposis/flexion contractures/foot deformities (7/9), scoliosis, cleft palate (2/9), and ambiguous genitalia/undescended testes (5/6) and dysmorphism. IUGR reported in 3/9 probands and polyhdramnios in 2/9. KCNK3 encodes the TASK-1 K2P channel expressed throughout the central nervous system. All identified variants clustered near the X-gate and are involved in inter- or intra-subunit interaction likely to hold the X-gate closed. Individuals with variants located in the M2 transmembrane helix had a more severe phenotype than those with variants in the M4 helix. Functional studies support a gain of function disease mechanism with increased channel activation. TASK-1 K+ channel inhibitors (some in clinical use) have been raised as a possible therapeutic strategy. ---- Heterozygous LoF variants associated with a different disorder - primary pulmonary arterial hypertension Sources: Literature |
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Differences of Sex Development v0.265 | PBX1 | Bryony Thompson Phenotypes for gene: PBX1 were changed from 46, XY gonadal dysgenesis to 46, XY gonadal dysgenesis; congenital anomalies of kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay MONDO:0060549 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.262 | PBX1 | Bryony Thompson reviewed gene: PBX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 35451537, 31302614, 31058389, 32141698; Phenotypes: congenital anomalies of kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay MONDO:0060549; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.262 | PRDM13 | Zornitza Stark Phenotypes for gene: PRDM13 were changed from congenital hypogonadotropic hypogonadism, MONDO:0015770 to Cerebellar dysfunction, impaired intellectual development, and hypogonadotropic hypogonadism, MIM# 619761 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.261 | PRDM13 | Zornitza Stark reviewed gene: PRDM13: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Cerebellar dysfunction, impaired intellectual development, and hypogonadotropic hypogonadism, MIM# 619761; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.261 | MAP3K1 | Zornitza Stark Marked gene: MAP3K1 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.258 | DUSP6 | Zornitza Stark Marked gene: DUSP6 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.254 | HSD3B2 | Zornitza Stark Marked gene: HSD3B2 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.251 | RSPO1 | Zornitza Stark Marked gene: RSPO1 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.251 | RSPO1 | Zornitza Stark Phenotypes for gene: RSPO1 were changed from to Palmoplantar hyperkeratosis with squamous cell carcinoma of skin and sex reversal MIM#610644; Palmoplantar hyperkeratosis and true hermaphroditism MIM#610644 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.248 | RSPO1 | Belinda Chong reviewed gene: RSPO1: Rating: GREEN; Mode of pathogenicity: None; Publications: 17041600, 18085567, 18250098, 18250097; Phenotypes: Palmoplantar hyperkeratosis with squamous cell carcinoma of skin and sex reversal MIM#610644, Palmoplantar hyperkeratosis and true hermaphroditism MIM#610644; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.248 | SRD5A2 | Zornitza Stark Marked gene: SRD5A2 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.245 | STAR | Zornitza Stark Marked gene: STAR as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.245 | STAR | Zornitza Stark Gene: star has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.245 | STAR | Zornitza Stark Phenotypes for gene: STAR were changed from to Lipoid adrenal hyperplasia (MIM#201710) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.244 | STAR | Zornitza Stark Publications for gene: STAR were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.243 | STAR | Zornitza Stark Mode of inheritance for gene: STAR was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.242 | STAR | Zornitza Stark reviewed gene: STAR: Rating: GREEN; Mode of pathogenicity: None; Publications: 7892608, 8634702; Phenotypes: Lipoid adrenal hyperplasia (MIM#201710); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.242 | PPP2R3C | Zornitza Stark Marked gene: PPP2R3C as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.240 | PPP2R3C |
Chirag Patel gene: PPP2R3C was added gene: PPP2R3C was added to Differences of Sex Development. Sources: Literature Mode of inheritance for gene: PPP2R3C was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PPP2R3C were set to PMID: 30893644, 34714774, 34750818 Phenotypes for gene: PPP2R3C were set to Gonadal dysgenesis, dysmorphic facies, retinal dystrophy, and myopathy, OMIM # 618419 Review for gene: PPP2R3C was set to GREEN Added comment: Gonadal dysgenesis, dysmorphic facies, retinal dystrophy, and myopathy (GDRM) is characterized by 46,XY complete gonadal dysgenesis in association with extragonadal anomalies, low birth weight, typical facial gestalt, rod and cone dystrophy, sensorineural hearing loss, omphalocele, anal atresia, renal agenesis, skeletal abnormalities, dry and scaly skin, severe myopathy, and neuromotor delay. 11 unrelated families with syndromic complete gonadal dysgenesis. 9 families had 46,XY females with complete gonadal dysgenesis, but 2 families had 46,XX patients with hypergonadotropic hypogonadism, nonvisualized gonads, primary amenorrhea, and absence of secondary sexual characteristics. Variants segregated with disease in each family and were not found in ethnically matched controls or in public variant databases. The heterozygous fathers exhibited morphologic abnormalities of spermatozoa and reduced fertility. Sources: Literature |
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Differences of Sex Development v0.239 | NHLH2 | Zornitza Stark Marked gene: NHLH2 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.239 | NHLH2 |
Zornitza Stark gene: NHLH2 was added gene: NHLH2 was added to Differences of Sex Development. Sources: Expert Review Mode of inheritance for gene: NHLH2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NHLH2 were set to 35066646 Phenotypes for gene: NHLH2 were set to Hypogonadotropic hypogonadism 27 without anosmia , MIM# 619755 Review for gene: NHLH2 was set to RED Added comment: Single individual reported homozygous for a missense variant in this gene. Two other individuals heterozygous for missense variants identified as part of this cohort; however, had alternative diagnoses. Sources: Expert Review |
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Differences of Sex Development v0.237 | MAMLD1 | Zornitza Stark Marked gene: MAMLD1 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.234 | PRDM13 | Seb Lunke Marked gene: PRDM13 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.233 | PRDM13 |
Seb Lunke gene: PRDM13 was added gene: PRDM13 was added to Differences of Sex Development. Sources: Literature Mode of inheritance for gene: PRDM13 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PRDM13 were set to 34730112 Phenotypes for gene: PRDM13 were set to congenital hypogonadotropic hypogonadism, MONDO:0015770 Review for gene: PRDM13 was set to AMBER Added comment: Recessive disease causing ID and DSD described in three supposedly unrelated families (2 consanguine), but all are from Malta, and all share the same 13bp deletion spanning an exon-intron boundary. Mouse KO is embryonically lethal, and tissue specific KO failed to replicate many of the patients phenotypes, other than hypoplasia of the cerebellar vermis and hemispheres at P21. Sources: Literature |
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Differences of Sex Development v0.232 | CYP17A1 | Zornitza Stark Marked gene: CYP17A1 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.229 | CYP11B1 | Zornitza Stark Marked gene: CYP11B1 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.226 | CYP11A1 | Zornitza Stark Marked gene: CYP11A1 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.226 | CYP11A1 | Zornitza Stark Phenotypes for gene: CYP11A1 were changed from to Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete, MIM# 613743 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.223 | CYP11A1 | Zornitza Stark reviewed gene: CYP11A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 12161514, 16705068, 18182448, 28425981; Phenotypes: Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete, MIM# 613743; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.223 | HSD17B3 | Zornitza Stark Marked gene: HSD17B3 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.220 | ANOS1 | Zornitza Stark Marked gene: ANOS1 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.217 | COG6 | Zornitza Stark Marked gene: COG6 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.215 | CPE | Zornitza Stark Marked gene: CPE as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.213 | CDKN1C | Zornitza Stark Marked gene: CDKN1C as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.211 | CDKN1C | Zornitza Stark Mode of pathogenicity for gene: CDKN1C was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.209 | CDKN1C | Zornitza Stark reviewed gene: CDKN1C: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 22634751, 33076988, 31976094, 31497289; Phenotypes: IMAGe syndrome, MIM# 614732; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.209 | IGF2 | Zornitza Stark Marked gene: IGF2 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.208 | SEMA3F | Zornitza Stark Marked gene: SEMA3F as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.208 | PLXNA3 | Zornitza Stark Marked gene: PLXNA3 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.207 | SEMA3F |
Chirag Patel gene: SEMA3F was added gene: SEMA3F was added to Differences of Sex Development. Sources: Literature Mode of inheritance for gene: SEMA3F was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SEMA3F were set to PMID: 33495532 Phenotypes for gene: SEMA3F were set to Hypogonadotropic hypogonadism Review for gene: SEMA3F was set to GREEN Added comment: Screened 216 patients with Idiopathic hypogonadotropic hypogonadism by exome sequencing. Identified 10 individuals from 7 families with heterozygous SEMA3F missense variants. In 4 of the kindreds, there was at least one more gene known to be associated with IHH (oligogenecity). Provide unequivocal human embryonic data showing the expression of SEMA3F along the developing human GnRH migratory pathway. SEMA3Fs harboring the P452T, T29M, and T724M missense variants showed impaired SEMA3F secretion in whole cell lysates. Sources: Literature |
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Differences of Sex Development v0.207 | PLXNA3 |
Chirag Patel gene: PLXNA3 was added gene: PLXNA3 was added to Differences of Sex Development. Sources: Literature Mode of inheritance for gene: PLXNA3 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: PLXNA3 were set to PMID: 33495532 Phenotypes for gene: PLXNA3 were set to Hypogonadotropic hypogonadism Added comment: Screened 216 patients with Idiopathic hypogonadotropic hypogonadism by exome sequencing. Identified 7 individuals from 5 families with hemizygous PLXNA3 missense variants. In 2 of the kindreds, there was at least one more gene known to be associated with IHH (oligogenecity). Data provided with evidence that PLXNA3, a key component of the SEMA3F holoreceptor complex,31 is expressed by the human GnRH and olfactory/vomeronasal systems. S646P variant showed PLXNA3 localization exclusively in the ER, indicating that the variant S646P disrupts cell surface localization of PLXNA3. Sources: Literature |
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Differences of Sex Development v0.206 | LHCGR | Zornitza Stark Marked gene: LHCGR as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.203 | Bryony Thompson Panel types changed to Victorian Clinical Genetics Services; Royal Melbourne Hospital; Rare Disease | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.200 | DLK1 | Zornitza Stark Marked gene: DLK1 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.197 | MKRN3 | Natasha Brown Marked gene: MKRN3 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.197 | MKRN3 |
Natasha Brown changed review comment from: PMID: 31687022 4 novel missense, c.1138G > A (p.Glu380Lys), c.1420T > A (p.Leu474Met), c.673C > G (p.Leu225Val), and c.1071C > G (p.Ile357Met) in two sporadic cases and three familial cases. ACMG: (p.Glu380Lys and p.Ile357Met) = LP, but (p.Leu474Met) (p.Leu225Val) are VUS. PMID: 31636607 3 novel promotor variants found in 6 unrelated females; significant reduction of MKRN3 promoter activity using luciferase assays. PMID: 32480405 - 2 females with whole gene deletions of MKRN3 PMID: 31041429 systematic review/meta analysis: "Patients with MKRN3 mutations presented with signs and symptoms of early reactivation of the hypothalamic-pituitary-gonadal axis, represented by precocious development of sexual characteristics, BA advancement, and pubertal levels of basal or poststimulated LH" Sources: Literature; to: PMID: 23738509: four (3fs; 1missense) novel heterozygous mutations in MKRN3, in 5 of the 15 families; both sexes were affected; mouse model confirms low expression. PMID: 31687022 4 novel missense, c.1138G > A (p.Glu380Lys), c.1420T > A (p.Leu474Met), c.673C > G (p.Leu225Val), and c.1071C > G (p.Ile357Met) in two sporadic cases and three familial cases. ACMG: (p.Glu380Lys and p.Ile357Met) = LP, but (p.Leu474Met) (p.Leu225Val) are VUS. PMID: 31636607 3 novel promotor variants found in 6 unrelated females; significant reduction of MKRN3 promoter activity using luciferase assays. PMID: 32480405 - 2 females with whole gene deletions of MKRN3 PMID: 31041429 systematic review/meta analysis: "Patients with MKRN3 mutations presented with signs and symptoms of early reactivation of the hypothalamic-pituitary-gonadal axis, represented by precocious development of sexual characteristics, BA advancement, and pubertal levels of basal or poststimulated LH" Sources: Literature |
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Differences of Sex Development v0.197 | MKRN3 |
Natasha Brown gene: MKRN3 was added gene: MKRN3 was added to Differences of Sex Development. Sources: Literature Mode of inheritance for gene: MKRN3 was set to MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed) Publications for gene: MKRN3 were set to PMID: 31687022; 31041429; 31636607; 32480405 Phenotypes for gene: MKRN3 were set to central precocious puberty Penetrance for gene: MKRN3 were set to unknown Review for gene: MKRN3 was set to GREEN Added comment: PMID: 31687022 4 novel missense, c.1138G > A (p.Glu380Lys), c.1420T > A (p.Leu474Met), c.673C > G (p.Leu225Val), and c.1071C > G (p.Ile357Met) in two sporadic cases and three familial cases. ACMG: (p.Glu380Lys and p.Ile357Met) = LP, but (p.Leu474Met) (p.Leu225Val) are VUS. PMID: 31636607 3 novel promotor variants found in 6 unrelated females; significant reduction of MKRN3 promoter activity using luciferase assays. PMID: 32480405 - 2 females with whole gene deletions of MKRN3 PMID: 31041429 systematic review/meta analysis: "Patients with MKRN3 mutations presented with signs and symptoms of early reactivation of the hypothalamic-pituitary-gonadal axis, represented by precocious development of sexual characteristics, BA advancement, and pubertal levels of basal or poststimulated LH" Sources: Literature |
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Differences of Sex Development v0.195 | CYP19A1 | Zornitza Stark Marked gene: CYP19A1 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.195 | CYP19A1 | Zornitza Stark Phenotypes for gene: CYP19A1 were changed from to Aromatase deficiency (MIM#613546), AR; Aromatase excess syndrome (MIM#139300), AD | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.192 | CYP19A1 | Teresa Zhao reviewed gene: CYP19A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 17164303, 25264451; Phenotypes: Aromatase deficiency (MIM#613546), AR, Aromatase excess syndrome (MIM#139300), AD; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.192 | AMH | Seb Lunke Marked gene: AMH as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.192 | AMH | Seb Lunke Added comment: Comment when marking as ready: 64 different alleles have been discovered in 79 families. There is a common 27-bp deletion in the kinase domain in caucasians. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.189 | PAX8 | Zornitza Stark Marked gene: PAX8 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.188 | PAX8 |
Zornitza Stark gene: PAX8 was added gene: PAX8 was added to Differences of Sex Development. Sources: Literature Mode of inheritance for gene: PAX8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PAX8 were set to 33434492 Phenotypes for gene: PAX8 were set to Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) Review for gene: PAX8 was set to AMBER Added comment: 5 individuals identified in large cohorts with MRKHS and likely deleterious variants in PAX8. At least one of the individuals had congenital hypothyroidism together with features of MRKHS. Variants in this gene are associated with congenital hypothyroidism. Sources: Literature |
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Differences of Sex Development v0.187 | BMP7 | Zornitza Stark Marked gene: BMP7 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.187 | BMP7 |
Zornitza Stark gene: BMP7 was added gene: BMP7 was added to Differences of Sex Development. Sources: Literature Mode of inheritance for gene: BMP7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: BMP7 were set to 33434492 Phenotypes for gene: BMP7 were set to Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) Review for gene: BMP7 was set to RED Added comment: Two individuals with likely deleterious variants identified in a cohort of individuals with MRKHS. Sources: Literature |
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Differences of Sex Development v0.185 | POR | Zornitza Stark Marked gene: POR as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.182 | BMP15 | Zornitza Stark Marked gene: BMP15 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.182 | BMP15 | Zornitza Stark Phenotypes for gene: BMP15 were changed from to Ovarian dysgenesis 2, MIM# 300510; Premature ovarian failure 4, MIM# 300510 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.179 | BMP15 | Zornitza Stark reviewed gene: BMP15: Rating: GREEN; Mode of pathogenicity: None; Publications: 15136966, 16508750, 16464940; Phenotypes: Ovarian dysgenesis 2, MIM# 300510, Premature ovarian failure 4, MIM# 300510; Mode of inheritance: Other | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.179 | GATA4 | Zornitza Stark Marked gene: GATA4 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.179 | GATA4 | Zornitza Stark Phenotypes for gene: GATA4 were changed from to Testicular anomalies with or without congenital heart disease, MIM# 615542 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.175 | GATA4 | Michelle Torres reviewed gene: GATA4: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 21220346, 30455927, 29735817, 27899157, 26490186, 29670578, 32992319; Phenotypes: ?Testicular anomalies with or without congenital heart disease 615542 AD, Atrial septal defect 2 607941 AD, Atrioventricular septal defect 4 614430 AD, Tetralogy of Fallot 187500 AD, Ventricular septal defect 1 614429 AD; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.175 | NR5A1 | Zornitza Stark Marked gene: NR5A1 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.175 | NR5A1 | Zornitza Stark Phenotypes for gene: NR5A1 were changed from to Adrenocortical insufficiency, (MIM#612964); 46, XX sex reversal 4, (MIM# 617480); Premature ovarian failure 7, (MIM#612964); Spermatogenic failure 8, (MIM#613957); 46XY sex reversal 3, (MIM#612965) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.172 | NR5A1 | Ain Roesley edited their review of gene: NR5A1: Added comment: 188 variants from 238 cases. No genotype-phenotype correlation establised; Changed phenotypes: Adrenocortical insufficiency, (MIM#612964), 46, XX sex reversal 4, (MIM# 617480), Premature ovarian failure 7, (MIM#612964), Spermatogenic failure 8, (MIM#613957), 46XY sex reversal 3, (MIM#612965) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.172 | NR5A1 | Ain Roesley reviewed gene: NR5A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31513305; Phenotypes: Adrenocortical insufficiency, (MIM#612964), 46, XX sex reversal 4, (MIM# 617480), Premature ovarian failure 7, (MIM#612964), Spermatogenic failure 8, (MIM#613957), 46XY sex reversal 3, (MIM#612965), Autosomal dominant; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.171 | IGSF10 | Zornitza Stark Marked gene: IGSF10 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.170 | IGSF10 |
Zornitza Stark gene: IGSF10 was added gene: IGSF10 was added to Disorders of Sex Differentiation. Sources: Expert list Mode of inheritance for gene: IGSF10 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: IGSF10 were set to 27137492; 31042289 Phenotypes for gene: IGSF10 were set to delayed puberty; hypogonadotropic hypogonadism; primary ovary insufficiency Added comment: PMID: 27137492 - 4 Finnish families segregating p.Glu161Lys, but Finnish MAF in ExAC is 2%. Another six additional families with a possible missense, but variants are seen in ExAC suggesting incomplete penetrance. Supporting in vitro functional assays and zebrafish model. PMID: 31042289 - 2 unrelated consanguineous families with homozygous variants and family with a heterozygous frameshift and apparent incomplete penetrance. Sources: Expert list |
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Differences of Sex Development v0.169 | TCF12 | Zornitza Stark Marked gene: TCF12 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.168 | TCF12 |
Zornitza Stark gene: TCF12 was added gene: TCF12 was added to Disorders of Sex Differentiation. Sources: Literature Mode of inheritance for gene: TCF12 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: TCF12 were set to 32620954 Phenotypes for gene: TCF12 were set to Kallmann syndrome Review for gene: TCF12 was set to GREEN Added comment: Note monoallelic variants in this gene are a well-established cause of craniosynostosis. ------------------------------------------------------------------------------------------------------------------------ - PMID: 32620954 (2020) - 13 unrelated kindreds (11 de novo, 1 AD and 1 AR) comprising 14 affected individuals with an anosmic form of isolated GnRH deficiency (IGD) (Kallman syndrome) due to different LoF variants in TCF12. Clinical manifestation included anosmia and pubertal failure (with reproductive phenotypes such as micropenis, bilateral cryptorchidism, hypospadias). Two unrelated individuals within the cohort additionally exhibited craniosynostosis, and a further two pedigrees had a family history of craniosynostosis (that did not affect the index case). Multiplex cases typically presented incomplete penetrance. Loss of tcf12 in a mutant zebrafish model perturbed GnRH neuronal patterning, with concomitant expression attenuation of tcf3a/b and stub1 (latter mutated in other syndromic forms of IGD). Furthermore, restored STUB1 expression rescued loss of tcf12 in vivo. Green for mono-allelic variants, caution with bi-allelic variants. Sources: Literature |
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Differences of Sex Development v0.167 | NR0B1 | Zornitza Stark Marked gene: NR0B1 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.161 | HOXA13 | Zornitza Stark Marked gene: HOXA13 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.161 | PROKR2 | Zornitza Stark Marked gene: PROKR2 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.157 | NSMF | Zornitza Stark Marked gene: NSMF as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.157 | NSMF |
Zornitza Stark gene: NSMF was added gene: NSMF was added to Disorders of Sex Differentiation. Sources: Expert list Mode of inheritance for gene: NSMF was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: NSMF were set to 15362570; 17235395; 21700882 Phenotypes for gene: NSMF were set to Hypogonadotropic hypogonadism 9 with or without anosmia, MIM# 614838 Review for gene: NSMF was set to RED Added comment: Rare variants reported in individuals with IHH; however, variants in other IHH genes also present, and at least one of the variants has a very high population frequency in gnomad (intronic 8-bp deletion ending 14 bp before exon 10 (1159-14_-22del), present in 258 individuals). Sources: Expert list |
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Differences of Sex Development v0.156 | SPRY4 | Zornitza Stark Marked gene: SPRY4 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.155 | SPRY4 |
Zornitza Stark gene: SPRY4 was added gene: SPRY4 was added to Disorders of Sex Differentiation. Sources: Expert list Mode of inheritance for gene: SPRY4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SPRY4 were set to 23643382 Phenotypes for gene: SPRY4 were set to Hypogonadotropic hypogonadism 17 with or without anosmia, MIM# 615266 Review for gene: SPRY4 was set to AMBER Added comment: 14 unrelated individuals reported originally. Three of these had variants in other IHH genes. The p.Lys177Arg variant is present in 454 individuals in gnomad, p.Ser241Tyr is present in 1279 individuals including 6 homozygotes, p.Val304Ile is present in 457 individuals. These population frequencies cast doubt on the gene-disease relationship. Sources: Expert list |
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Differences of Sex Development v0.154 | KISS1 | Zornitza Stark Marked gene: KISS1 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.153 | KISS1 |
Zornitza Stark gene: KISS1 was added gene: KISS1 was added to Disorders of Sex Differentiation. Sources: Expert list Mode of inheritance for gene: KISS1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: KISS1 were set to 22335740; 25783047; 22766261; 17563351 Phenotypes for gene: KISS1 were set to Hypogonadotropic hypogonadism 13 with or without anosmia, MIM# 614842 Review for gene: KISS1 was set to AMBER Added comment: Reported in Turkish families, supportive mouse model, but no variants identified in other cohorts. Role of KISS1 receptor much more established. Sources: Expert list |
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Differences of Sex Development v0.152 | TACR3 | Zornitza Stark Marked gene: TACR3 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.150 | INSL3 | Zornitza Stark Marked gene: INSL3 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.146 | IL17RD | Zornitza Stark Marked gene: IL17RD as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.142 | HSD17B4 | Zornitza Stark Marked gene: HSD17B4 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.139 | HS6ST1 | Zornitza Stark Marked gene: HS6ST1 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.132 | HESX1 | Zornitza Stark Marked gene: HESX1 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.132 | HESX1 | Zornitza Stark Phenotypes for gene: HESX1 were changed from to Pituitary hormone deficiency, combined, 5, MIM# 182230 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.130 | HESX1 | Zornitza Stark reviewed gene: HESX1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Pituitary hormone deficiency, combined, 5, MIM# 182230; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.130 | GNRH1 | Zornitza Stark Marked gene: GNRH1 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.127 | Zornitza Stark Panel types changed to Victorian Clinical Genetics Services; Rare Disease | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.125 | TSPYL1 | Zornitza Stark Marked gene: TSPYL1 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.121 | WDR11 | Zornitza Stark Marked gene: WDR11 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.118 | KISS1R | Zornitza Stark Marked gene: KISS1R as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.115 | LEP | Zornitza Stark Marked gene: LEP as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.112 | LEPR | Zornitza Stark Marked gene: LEPR as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.109 | FGF17 | Zornitza Stark Marked gene: FGF17 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.109 | FGF17 | Zornitza Stark Added comment: Comment when marking as ready: Borderline Green/Amber: contribution may not be monogenic. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.107 | LHB | Zornitza Stark Marked gene: LHB as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.104 | FEZF1 | Zornitza Stark Marked gene: FEZF1 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.100 | ESR2 | Zornitza Stark Marked gene: ESR2 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.100 | ESR2 | Zornitza Stark Phenotypes for gene: ESR2 were changed from 46,XY Disorders of Sex Development to 46,XY Disorders of Sex Development; Ovarian dysgenesis 8, MIM# 618187 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.97 | ESR2 | Zornitza Stark reviewed gene: ESR2: Rating: AMBER; Mode of pathogenicity: None; Publications: 30113650; Phenotypes: Ovarian dysgenesis 8, MIM# 618187; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.97 | ERAL1 | Zornitza Stark Marked gene: ERAL1 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.96 | MKKS | Zornitza Stark reviewed gene: MKKS: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Bardet-Biedl syndrome 6 (MIM#605231), McKusick-Kaufman syndrome (MIM#236700); Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.96 | MKKS | Zornitza Stark Marked gene: MKKS as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.96 | MKKS | Zornitza Stark Phenotypes for gene: MKKS were changed from to Bardet-Biedl syndrome 6 (MIM#605231); McKusick-Kaufman syndrome (MIM#236700) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.92 | DMRT1 | Zornitza Stark Marked gene: DMRT1 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.91 | DHCR24 | Zornitza Stark Marked gene: DHCR24 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.87 | CYB5A | Zornitza Stark Marked gene: CYB5A as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.85 | LHX3 | Zornitza Stark Marked gene: LHX3 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.84 | LHX3 | Zornitza Stark Phenotypes for gene: LHX3 were changed from to Pituitary hormone deficiency, combined, 3 (MIM#221750) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.82 | CUL4B | Zornitza Stark Marked gene: CUL4B as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.80 | CBX2 | Zornitza Stark Marked gene: CBX2 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.76 | MCM5 | Zornitza Stark Marked gene: MCM5 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.73 | ATF3 | Zornitza Stark Marked gene: ATF3 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.72 | ERAL1 |
Elena Savva gene: ERAL1 was added gene: ERAL1 was added to Disorders of Sex Differentiation. Sources: Expert list Mode of inheritance for gene: ERAL1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ERAL1 were set to PMID: 28449065 Phenotypes for gene: ERAL1 were set to Perrault syndrome 6 617565 Review for gene: ERAL1 was set to AMBER Added comment: PMID: 28449065 - 3 unrelated patient with perrault syndrome with the same founder missense (p.Asn236Ile). Symptoms included hearing loss, premature ovarian failure, primary amenorrhea Supported by functional analysis on patient cells, and transfected yeast reciprocating the phenotype. Sources: Expert list |
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Differences of Sex Development v0.72 | DMRT1 |
Elena Savva gene: DMRT1 was added gene: DMRT1 was added to Disorders of Sex Differentiation. Sources: Expert list Mode of inheritance for gene: DMRT1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: DMRT1 were set to PMID: 31479588; 24934491; 29527098 Phenotypes for gene: DMRT1 were set to Azoospermia Review for gene: DMRT1 was set to RED Added comment: PMID: 31479588 - 1 patient with azoospermia and XY genotype. Also carries an additional variant in KLHL10 PMID: 24934491 - 6 patients with male infertility, however the 4 identified variants were also found in 2 controls and have a high frequency in the population (gnomAD). No functional studies. PMID: 23555275 - Identifies CNVs in azoospermia patients, calls the gene a risk factor Sources: Expert list |
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Differences of Sex Development v0.72 | CYB5A |
Elena Savva gene: CYB5A was added gene: CYB5A was added to Disorders of Sex Differentiation. Sources: Expert list Mode of inheritance for gene: CYB5A was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CYB5A were set to PMID: 22170710; 32051920 Phenotypes for gene: CYB5A were set to Methemoglobinemia and ambiguous genitalia 250790 Review for gene: CYB5A was set to GREEN Added comment: PMID: 22170710 - 3 siblings with 46,XY DSD, sex steroid deficiency, female genitalia and a homozygous missense variant. Supported by LOF functional studies. Mineralocorticoids and glucocorticoids were normal. PMID: 32051920 - 1 female with a homozygous missense, no DSD but methemoglobinemia. All female genitalia are normal and she has had a normal female child. Paper reviews prior reports and notes an additional 2 unrelated homozygous reports of 46 XY DSD patients with normal Methemoglobin. All variants were rare/absent (gnomAD) and PTCs. Sources: Expert list |
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Differences of Sex Development v0.72 | LHX3 | Crystle Lee reviewed gene: LHX3: Rating: GREEN; Mode of pathogenicity: None; Publications: 28302169, 17327381, 30262920; Phenotypes: Pituitary hormone deficiency, combined, 3 (MIM#221750); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.72 | CUL4B |
Elena Savva gene: CUL4B was added gene: CUL4B was added to Disorders of Sex Differentiation. Sources: Expert list Mode of inheritance for gene: CUL4B was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal Publications for gene: CUL4B were set to PMID: 25385192 Phenotypes for gene: CUL4B were set to Mental retardation, X-linked, syndromic 15 (Cabezas type) 300354 Review for gene: CUL4B was set to GREEN Added comment: PMID: 25385192 - 25 patients (11 families) with syndromic features including hypogonadism (85%) and gynecomastia (33%) Sources: Expert list |
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Differences of Sex Development v0.72 | NR3C1 | Zornitza Stark Marked gene: NR3C1 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.69 | MCM5 |
Crystle Lee gene: MCM5 was added gene: MCM5 was added to Disorders of Sex Differentiation. Sources: Expert Review Mode of inheritance for gene: MCM5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MCM5 were set to 28198391 Phenotypes for gene: MCM5 were set to ?Meier-Gorlin syndrome 8 (MIM#617564) Review for gene: MCM5 was set to RED Added comment: Only single patient reported in 2017. Patient presented with microstomia, thick lips, micrognathia, bilateral microtia, low set ears and bilateral cryptorchidism. Sources: Expert Review |
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Differences of Sex Development v0.69 | MKKS | Crystle Lee reviewed gene: MKKS: Rating: AMBER; Mode of pathogenicity: None; Publications: 10973251, 26900326, 10973238; Phenotypes: Bardet-Biedl syndrome 6 (MIM#605231), McKusick-Kaufman syndrome (MIM#236700); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.69 | PCSK1 | Zornitza Stark Marked gene: PCSK1 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.66 | PROK2 | Zornitza Stark Marked gene: PROK2 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.66 | PROK2 | Zornitza Stark Added comment: Comment when marking as ready: Evidence supporting association between bi-allelic variants causing IHH is stronger than for mono-allelic disease. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.63 | PROP1 | Zornitza Stark Marked gene: PROP1 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.63 | PROP1 | Zornitza Stark Phenotypes for gene: PROP1 were changed from to Pituitary hormone deficiency, combined, 2 (MIM#262600) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.60 | RPL10 | Zornitza Stark Marked gene: RPL10 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.59 | SAMD9 | Zornitza Stark Marked gene: SAMD9 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.58 | SEMA3E | Zornitza Stark Marked gene: SEMA3E as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.57 | SGPL1 | Zornitza Stark Marked gene: SGPL1 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.56 | SOX10 | Zornitza Stark Marked gene: SOX10 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.56 | SOX10 | Zornitza Stark Phenotypes for gene: SOX10 were changed from PCWH syndrome (MIM#609136); Waardenburg syndrome, type 2E, with or without neurologic involvement (MIM#611584); Waardenburg syndrome, type 4C (MIM#613266) to Kallman syndrome; PCWH syndrome (MIM#609136); Waardenburg syndrome, type 2E, with or without neurologic involvement (MIM#611584); Waardenburg syndrome, type 4C (MIM#613266) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.54 | TAC3 | Zornitza Stark Marked gene: TAC3 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.51 | TOE1 | Zornitza Stark Marked gene: TOE1 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.50 | PROP1 | Crystle Lee reviewed gene: PROP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 15941866, 11549703; Phenotypes: Pituitary hormone deficiency, combined, 2 (MIM#262600); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.50 | AKR1C4 | Zornitza Stark Marked gene: AKR1C4 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.46 | AKR1C2 | Zornitza Stark Marked gene: AKR1C2 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.42 | RPL10 |
Crystle Lee gene: RPL10 was added gene: RPL10 was added to Disorders of Sex Differentiation. Sources: Expert Review Mode of inheritance for gene: RPL10 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: RPL10 were set to 25316788; 26290468; 25846674; 29066376 Phenotypes for gene: RPL10 were set to Mental retardation, X-linked, syndromic, 35 (MIM#300998) Review for gene: RPL10 was set to GREEN Added comment: At least 3 variants have been reported. Urogenital anomalies are a feature of the associated condition. PMID: 25316788: Variant reported in 3 members of a family. Genitourinary abnormalities (ie cryptorchidism) reported in all 3 affected individuals. PMID: 26290468: Reported in a family with two affected cousins presenting with X-linked ID, cerebellar hypoplasia, and spondylo-epiphyseal dysplasia. Only one of the affected males presented with cryptorchidism. PMID: 25846674: 3 of 4 affected males in the family presented with urogenital anomalies Sources: Expert Review |
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Differences of Sex Development v0.42 | SAMD9 |
Crystle Lee gene: SAMD9 was added gene: SAMD9 was added to Disorders of Sex Differentiation. Sources: Expert Review Mode of inheritance for gene: SAMD9 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: SAMD9 were set to 27182967 Phenotypes for gene: SAMD9 were set to MIRAGE syndrome (MIM#617053) Review for gene: SAMD9 was set to GREEN Added comment: At least 10 families ( 8 diff variants) reported in one publication. External genital abnormalities observed in all 46, XY patients. Sources: Expert Review |
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Differences of Sex Development v0.42 | SEMA3E |
Crystle Lee gene: SEMA3E was added gene: SEMA3E was added to Disorders of Sex Differentiation. Sources: Expert Review Mode of inheritance for gene: SEMA3E was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SEMA3E were set to 25985275 Phenotypes for gene: SEMA3E were set to ?CHARGE syndrome (MIM#214800) Review for gene: SEMA3E was set to RED Added comment: Only one variant reported in 2 sibling with Kallman syndrome. Mouse model supports involvement of this gene with the phenotype. Variant not present in gnomad in homozygosity. Sources: Expert Review |
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Differences of Sex Development v0.42 | SGPL1 |
Crystle Lee gene: SGPL1 was added gene: SGPL1 was added to Disorders of Sex Differentiation. Sources: Expert Review Mode of inheritance for gene: SGPL1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SGPL1 were set to 28165339; 28165343; 28181337 Phenotypes for gene: SGPL1 were set to Nephrotic syndrome, type 14 (MIM#617575) Review for gene: SGPL1 was set to GREEN Added comment: >5 families reported. Cryptorchidism and hypogonadism are features of the associated phenotype. Sources: Expert Review |
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Differences of Sex Development v0.42 | SOX10 |
Crystle Lee gene: SOX10 was added gene: SOX10 was added to Disorders of Sex Differentiation. Sources: Expert Review Mode of inheritance for gene: SOX10 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: SOX10 were set to 23643381; 15004559 Phenotypes for gene: SOX10 were set to PCWH syndrome (MIM#609136); Waardenburg syndrome, type 2E, with or without neurologic involvement (MIM#611584); Waardenburg syndrome, type 4C (MIM#613266) Mode of pathogenicity for gene: SOX10 was set to Other Review for gene: SOX10 was set to GREEN Added comment: Well reported gene disease association. Cryptorchidism and hypogonadism is a feature of Kallman Syndrome and WS4C PMID: 23643381: Reported 6 variants in individuals with Kallman syndrome which is associated with hypogonadotropic hypogonadism. Functional studies performed. PMID: 15004559: PCWH is caused by dominant-negative mutations (truncating variants) whereas NMD and thus haploinsufficiency results in WS4C Sources: Expert Review |
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Differences of Sex Development v0.42 | TOE1 |
Crystle Lee gene: TOE1 was added gene: TOE1 was added to Disorders of Sex Differentiation. Sources: Expert Review Mode of inheritance for gene: TOE1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TOE1 were set to 28092684 Phenotypes for gene: TOE1 were set to Pontocerebellar hypoplasia, type 7 (MIM#614969) Review for gene: TOE1 was set to GREEN Added comment: >10 families with pontocerebellar hypoplasia type 7 (PCH7) reported with biallelic variants.MRI showed reduced cerebellar volume in these families. Ambiguous genitalia is a feature of this condition. Sources: Expert Review |
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Differences of Sex Development v0.42 | WNT4 | Zornitza Stark Marked gene: WNT4 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.38 | ZFPM2 | Zornitza Stark Marked gene: ZFPM2 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.34 | FLRT3 | Zornitza Stark Marked gene: FLRT3 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.34 | FLRT3 | Zornitza Stark Added comment: Comment when marking as ready: Oligogenic inheritance postulated. I also note one of the variants, Gln69Lys is present in 7 individuals in gnomad. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.34 | FLRT3 | Zornitza Stark Marked gene: FLRT3 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.31 | ESR2 |
Bryony Thompson gene: ESR2 was added gene: ESR2 was added to Disorders of Sex Differentiation. Sources: Literature Mode of inheritance for gene: ESR2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: ESR2 were set to 29261182; 9861029 Phenotypes for gene: ESR2 were set to 46,XY Disorders of Sex Development Review for gene: ESR2 was set to AMBER Added comment: A homozygous indel (Asn181del) was identified in a syndromic case with 46,XY DSD, and 2 heterozygous missense variants were identified in 2 non-syndromic cases with 46,XY DSD. Asn181del and Leu426Arg were found to have significantly increased transcriptional activation in in vitro luciferase assays. Esrb null male mice showed no overt abnormalities and reproduced normally. Older mutant males displayed signs of prostate and bladder hyperplasia. Sources: Literature |
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Differences of Sex Development v0.30 | NR2F2 | Zornitza Stark Marked gene: NR2F2 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.29 | NR2F2 |
Zornitza Stark gene: NR2F2 was added gene: NR2F2 was added to Disorders of Sex Differentiation. Sources: Expert list Mode of inheritance for gene: NR2F2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: NR2F2 were set to 29478779; 31687637 Phenotypes for gene: NR2F2 were set to 46,XX disorder of sex development (DSD) and congenital heart defects Review for gene: NR2F2 was set to GREEN Added comment: Four unrelated individuals reported. Note two had the same 7bp deletion, c.97_103delCCGCCCG, NM_021005.3, and the third individual had an adjacent deletion, c.103_109delGGCGCCC, NM_021005.3. All three were of very different ancestries, making founder effect unlikely. Fourth individual had a larger deletion encompassing this gene. Gene is also linked with isolated CHD (Congenital heart defects, multiple types, 4, MIM# 615779) Sources: Expert list |
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Differences of Sex Development v0.28 | KLB | Zornitza Stark Marked gene: KLB as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.26 | NDNF | Zornitza Stark Marked gene: NDNF as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.25 | NDNF |
Zornitza Stark gene: NDNF was added gene: NDNF was added to Disorders of Sex Differentiation. Sources: Literature Mode of inheritance for gene: NDNF was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: NDNF were set to 31883645 Phenotypes for gene: NDNF were set to Congenital hypogonadotropic hypogonadism (CHH) Review for gene: NDNF was set to GREEN Added comment: Three heterozygous protein-truncating variants and one heterozygous missense variant identified in a cohort of 240 unrelated IHH patients. The authors also provided supporting evidence from animal models. Sources: Literature |
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Differences of Sex Development v0.24 | MYRF | Zornitza Stark Marked gene: MYRF as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.23 | DHX37 | Zornitza Stark Marked gene: DHX37 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.22 | DHX37 |
Zornitza Stark gene: DHX37 was added gene: DHX37 was added to Disorders of Sex Differentiation. Sources: Literature Mode of inheritance for gene: DHX37 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: DHX37 were set to 31337883; 31745530 Phenotypes for gene: DHX37 were set to 46,XY gonadal dysgenesis; testicular regression syndrome (TRS) Review for gene: DHX37 was set to GREEN Added comment: Seventeen individuals reported in two studies. Sources: Literature |
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Differences of Sex Development v0.21 | MYRF |
Ain Roesley gene: MYRF was added gene: MYRF was added to Disorders of Sex Differentiation. Sources: Literature Mode of inheritance for gene: MYRF was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: MYRF were set to PMID: 30985895 Phenotypes for gene: MYRF were set to disorders of sex development Review for gene: MYRF was set to GREEN Added comment: PMID: 30985895; 4 unrelated families with de novo variants. 1 family includes monozygotic twins Sources: Literature |
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Differences of Sex Development v0.21 | RXFP2 | Zornitza Stark Marked gene: RXFP2 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.17 | DHH | Zornitza Stark Marked gene: DHH as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.17 | DHH | Zornitza Stark Phenotypes for gene: DHH were changed from to 46XY partial gonadal dysgenesis, with minifascicular neuropathy, MIM# 607080 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.14 | DHH | Naomi Baker reviewed gene: DHH: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31018998, 29471294, 11017805.; Phenotypes: gonadal dysgenesis, minifascicular neuropathy.; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.14 | GNRHR | Zornitza Stark Marked gene: GNRHR as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.11 | CYP21A2 | Zornitza Stark Marked gene: CYP21A2 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.9 | SOX3 | Zornitza Stark Marked gene: SOX3 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.8 | SOX3 |
Zornitza Stark gene: SOX3 was added gene: SOX3 was added to Disorders of Sex Differentiation. Sources: Expert Review SV/CNV tags were added to gene: SOX3. Mode of inheritance for gene: SOX3 was set to Other Publications for gene: SOX3 were set to 21183788; 22678921; 25781358; 31523625 Phenotypes for gene: SOX3 were set to XX male sex reversal Mode of pathogenicity for gene: SOX3 was set to Other Review for gene: SOX3 was set to AMBER Added comment: Multiple individuals reported; animal model: association is with structural variants, primarily duplications. Sources: Expert Review |
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Differences of Sex Development v0.5 | PPP1R12A | Zornitza Stark Marked gene: PPP1R12A as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.5 | PPP1R12A | Zornitza Stark Added comment: Comment when marking as ready: Now published; 12 individuals, upgraded to Green. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.4 | PBX1 | Zornitza Stark Marked gene: PBX1 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.3 | PBX1 |
Zornitza Stark gene: PBX1 was added gene: PBX1 was added to Disorders of Sex Differentiation_VCGS. Sources: Literature Mode of inheritance for gene: PBX1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PBX1 were set to 31302614; 31058389 Phenotypes for gene: PBX1 were set to 46, XY gonadal dysgenesis Review for gene: PBX1 was set to AMBER Added comment: Two individuals reported with mono allelic variants in this gene and 46,XY gonadal dysgenesis. Sources: Literature |
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Differences of Sex Development v0.2 | PPP1R12A | Zornitza Stark Marked gene: PPP1R12A as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differences of Sex Development v0.0 | STAR |
Zornitza Stark gene: STAR was added gene: STAR was added to Disorders of Sex Differentiation_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services Mode of inheritance for gene: STAR was set to Unknown |
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Differences of Sex Development v0.0 | ARX |
Zornitza Stark gene: ARX was added gene: ARX was added to Disorders of Sex Differentiation_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services Mode of inheritance for gene: ARX was set to Unknown |
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Differences of Sex Development v0.0 | AR |
Zornitza Stark gene: AR was added gene: AR was added to Disorders of Sex Differentiation_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services Mode of inheritance for gene: AR was set to Unknown |