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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 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 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 v0.308 | 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. 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 v0.302 | 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 v0.299 | 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 v0.293 | 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 v0.291 | 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 v0.286 | 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 v0.281 | 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 v0.277 | 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 v0.274 | 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 v0.267 | 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 v0.239 | 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 v0.216 | COG6 |
Zornitza Stark gene: COG6 was added gene: COG6 was added to Differences of Sex Development. Sources: Literature Mode of inheritance for gene: COG6 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: COG6 were set to 33394555; 32683677 Phenotypes for gene: COG6 were set to Congenital disorder of glycosylation, type IIl, MIM# 614576 Review for gene: COG6 was set to AMBER Added comment: <20 families reported with this type of CDG; two families with multi-system features including significant DSD. Sources: Literature |
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| Differences of Sex Development v0.214 | CPE |
Zornitza Stark gene: CPE was added gene: CPE was added to Differences of Sex Development. Sources: Literature Mode of inheritance for gene: CPE was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CPE were set to 26120850; 32936766; 34383079 Phenotypes for gene: CPE were set to Intellectual developmental disorder and hypogonadotropic hypogonadism, MIM# 619326 Review for gene: CPE was set to GREEN Added comment: 8 individuals from 5 unrelated families reported. Sources: Literature |
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| Differences of Sex Development v0.208 | IGF2 |
Elena Savva gene: IGF2 was added gene: IGF2 was added to Differences of Sex Development. Sources: Literature Mode of inheritance for gene: IGF2 was set to MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed) Publications for gene: IGF2 were set to PMID: 31544945 Phenotypes for gene: IGF2 were set to Silver-Russell syndrome 3 MIM#616489 Review for gene: IGF2 was set to GREEN Added comment: PMID: 31544945 - 60% of patients reported some form of DSD including hypospadias, cryptochidism, abnormal scrotum etc. Sources: Literature |
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| 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 v0.185 | POR | Zornitza Stark Marked gene: POR as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences of Sex Development v0.185 | POR | Zornitza Stark Gene: por has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences of Sex Development v0.185 | POR | Zornitza Stark Phenotypes for gene: POR were changed from to Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis, MIM#201750; Disordered steroidogenesis due to cytochrome P450 oxidoreductase, MIM#613571 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences of Sex Development v0.184 | POR | Zornitza Stark Publications for gene: POR were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences of Sex Development v0.183 | POR | Zornitza Stark Mode of inheritance for gene: POR was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences of Sex Development v0.182 | POR | Zornitza Stark reviewed gene: POR: Rating: GREEN; Mode of pathogenicity: None; Publications: 27068427; Phenotypes: Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis, MIM#201750, Disordered steroidogenesis due to cytochrome P450 oxidoreductase, MIM#613571; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 v0.157 | 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 v0.155 | 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 v0.153 | 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 v0.151 | TACR3 |
Zornitza Stark gene: TACR3 was added gene: TACR3 was added to Disorders of Sex Differentiation. Sources: Expert list Mode of inheritance for gene: TACR3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TACR3 were set to 20332248; 19079066 Phenotypes for gene: TACR3 were set to Hypogonadotropic hypogonadism 11 with or without anosmia, MIM# 614840 Review for gene: TACR3 was set to GREEN Added comment: Multiple families reported. Sources: Expert list |
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| 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 | 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 v0.69 | 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 v0.66 | 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 v0.42 | 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 v0.29 | 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 v0.27 | KLB |
Zornitza Stark gene: KLB was added gene: KLB was added to Disorders of Sex Differentiation. Sources: Literature Mode of inheritance for gene: KLB was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: KLB were set to 28754744 Phenotypes for gene: KLB were set to Hypogonadotropic hypogonadism Review for gene: KLB was set to GREEN Added comment: Seven heterozygous loss‐of‐function KLB mutations in 13 individuals reported. In mice, lack of Klb led to delayed puberty, altered estrous cyclicity, and subfertility due to a hypothalamic defect associated with inability of GnRH neurons to release GnRH in response to FGF21. Functional analysis showed decreased activity in response to FGF21 and FGF8. KLB is an obligate coreceptor for FGF21 alongside FGFR1. Sources: Literature |
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| 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 v0.22 | 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 v0.8 | 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 v0.3 | 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 v0.0 | POR |
Zornitza Stark gene: POR was added gene: POR was added to Disorders of Sex Differentiation_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services Mode of inheritance for gene: POR was set to Unknown |
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