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Mendeliome v1.2628 OSM Bryony Thompson Marked gene: OSM as ready
Mendeliome v1.2628 OSM Bryony Thompson Gene: osm has been classified as Green List (High Evidence).
Mendeliome v1.2628 OSM Bryony Thompson Classified gene: OSM as Green List (high evidence)
Mendeliome v1.2628 OSM Bryony Thompson Gene: osm has been classified as Green List (High Evidence).
Mendeliome v1.2627 OSM Bryony Thompson gene: OSM was added
gene: OSM was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: OSM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OSM were set to 39847438; 40309776; 17118758
Phenotypes for gene: OSM were set to bone marrow failure syndrome MONDO:0000159
Review for gene: OSM was set to GREEN
Added comment: 6 individuals with with OSM deficiency and an inherited severe bone marrow failure syndrome from 3 consanguineous families with 2 different homozygous LoF variants. Supporting zebrafish and mouse models.
Sources: Literature
Mendeliome v1.2166 FGF8 Zornitza Stark edited their review of gene: FGF8: Added comment: Association with CHD: Two individuals reported but extensive functional data. MODERATE by ClinGen.; Changed publications: 32664970, 7768185, 32664970, 10603341, 19509466, 9462741, 10603341, 12223415; Changed phenotypes: Hypogonadotropic hypogonadism 6 with or without anosmia, MIM# 612702, Hypoplastic femurs and pelvis, MIM#619545, Congenital heart disease MONDO:0005453, FGF8-related
Mendeliome v1.1201 AXL Zornitza Stark Phenotypes for gene: AXL were changed from Kallman syndrome; normosmic idiopathic hypogonadotropic hypogonadism to Kallman syndrome, MONDO:0018800, AXL-related; normosmic idiopathic hypogonadotropic hypogonadism
Mendeliome v1.659 WDR11 Zornitza Stark Phenotypes for gene: WDR11 were changed from Intellectual disability; Hypogonadotropic hypogonadism 14 with or without anosmia MIM #614858 to Intellectual developmental disorder, autosomal recessive 78, MIM# 620237; Hypogonadotropic hypogonadism 14 with or without anosmia MIM #614858
Mendeliome v1.658 WDR11 Zornitza Stark edited their review of gene: WDR11: Changed phenotypes: Intellectual developmental disorder, autosomal recessive 78, MIM# 620237, Hypogonadotropic hypogonadism 14 with or without anosmia MIM #614858
Mendeliome v1.601 TRPC5 Hazel Phillimore gene: TRPC5 was added
gene: TRPC5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TRPC5 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: TRPC5 were set to PMID: 36323681; 24817631; 23033978; 33504798; 28191890
Phenotypes for gene: TRPC5 were set to Intellectual disability; autistic spectrum disorder
Review for gene: TRPC5 was set to AMBER
Added comment: PMID: 36323681; Leitão E. et al. (2022) Nat Commun.13(1):6570:
Missense variant NM_012471.2:c.523C>T, p.(Arg175Cys in three brothers with intellectual disability (ID) and autistic spectrum disorder (ASD), inherited from an asymptomatic mother and absent in the maternal grandparents.
Whole cell patch clamp studies of HEK293 created by site-directed mutagenesis showed increased current of this calcium channel (constitutively opened).
(This variant is absent in gnomAD v2.1.1).

Also, the nonsense variant, c.965G> A, p.(Trp322*) was found in a high functioning ASD male (maternally inherited), NMD-predicted.

Other papers and TRPC5 variants that were cited to associate this gene with X-linked ID and/or ASD include:
PMID: 24817631; Mignon-Ravix, C. et al. (2014) Am. J.Med. Genet. A 164A: 1991–1997: A hemizygous 47-kb deletion in Xq23 including exon 1 of the TRPC5 gene. He had macrocephaly, delayed psychomotor development, speech delay, behavioural problems, and autistic features. Maternally inherited, and a family history compatible with X-linked inheritance (i.e., maternal great uncle was also affected, although not tested).

In addition, PMID: 36323681; Leitão E. et al. (2022) cites papers with the variants p.(Pro667Thr), p.(Arg71Gln) and p.(Trp225*).
NB. p.(Pro667Thr) is absent in gnomAD (v2.1.1), p.(Arg71Gln) is also absent (the alternative variant p.(Arg71Trp) is present once as heterozygous only). p.(Trp225*) is absent, and it should be noted that PTCs / LoF variants are very rare (pLI = 1).

However, looking further into the three references, the evidence is not as clear or as accurate as was stated.

The missense variant c.1999C>A, p.(Pro667Thr), was stated as de novo, but was actually maternally inherited but was still considered a candidate for severe intellectual disability (shown in the Appendix, Patient 93, with severe speech delay, autism spectrum disorder and Gilles de la Tourette). This patient also has a de novo MTF1 variant. Reference: PMID: 23033978; de Ligt, J. et al. (2012) N. Engl. J. Med. 367: 1921–1929).

Missense variant (de novo): c.212G>A, p.(Arg71Gln), was found as part of the Deciphering Developmental Disorders (DDD) study and is shown in individual 164 in Supplementary Table 2 of PMID: 33504798; Martin, HC. et al. (2021) Nat. Commun.12: 627. Also displayed in DECIPHER (DDD research variant) with several phenotype traits, but ID and ASD are not specifically mentioned.

Nonsense variant: c.674G>A. p.(Trp225*) was stated as de novo but was inherited (reference PMID: 28191890; Kosmicki, JA. et al. (2017) Nat. Genet. 49: 504–510. Supplement Table 7). This was a study of severe intellectual delay, developmental delay / autism. (NB. The de novo p.(Arg71Gln) variant from the DDD study is also listed (subject DDD 342 in Supplement 4 / Table 2).
Sources: Literature
Mendeliome v1.335 NDNF Elena Savva Phenotypes for gene: NDNF were changed from Congenital hypogonadotropic hypogonadism (CHH) to Hypogonadotropic hypogonadism 25 with anosmia MIM#618841
Mendeliome v1.333 NDNF Elena Savva reviewed gene: NDNF: Rating: AMBER; Mode of pathogenicity: None; Publications: 31883645; Phenotypes: Hypogonadotropic hypogonadism 25 with anosmia MIM#618841; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.14650 ADD1 Chirag Patel gene: ADD1 was added
gene: ADD1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ADD1 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: ADD1 were set to PMID: 34906466
Phenotypes for gene: ADD1 were set to Intellectual disability, corpus callosum dysgenesis, and ventriculomegaly; no OMIM #
Review for gene: ADD1 was set to GREEN
Added comment: 4 unrelated individuals affected by ID and/or complete or partial agenesis of corpus callosum, and enlarged lateral ventricles. WES found loss-of-function variants - 1 recessive missense variant and 3 de novo variants. The recessive variant is associated with ACC and enlarged lateral ventricles, and the de novo variants were associated with complete or partial agenesis of corpus callosum, mild ID and attention deficit. Human variants impair ADD1 protein expression and/or dimerization with ADD2. Add1 knockout mice recapitulate corpus callosum dysgenesis and ventriculomegaly phenotypes. Three adducin genes (ADD1, ADD2, and ADD3) encode cytoskeleton proteins that are critical for osmotic rigidity and cell shape. ADD1, ADD2, and ADD3 form heterodimers (ADD1/ADD2, ADD1/ADD3), which further form heterotetramers. Adducins interconnect spectrin and actin filaments to form polygonal scaffolds beneath the cell membranes and form ring-like structures in neuronal axons. Adducins regulate mouse neural development, but their function in the human brain is unknown
Sources: Literature
Mendeliome v0.14167 FSHB Bryony Thompson Phenotypes for gene: FSHB were changed from to Hypogonadotropic hypogonadism 24 without anosmia MONDO:0009239
Mendeliome v0.14164 FSHB Bryony Thompson reviewed gene: FSHB: Rating: GREEN; Mode of pathogenicity: None; Publications: 8220432, 9280841, 9624193, 9806482, 9271483, 16630814; Phenotypes: Hypogonadotropic hypogonadism 24 without anosmia MONDO:0009239; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13809 DUSP6 Zornitza Stark Phenotypes for gene: DUSP6 were changed from to Hypogonadotropic hypogonadism 19 with or without anosmia - MIM#615269
Mendeliome v0.13682 DUSP6 Krithika Murali reviewed gene: DUSP6: Rating: RED; Mode of pathogenicity: None; Publications: 23643382; Phenotypes: Hypogonadotropic hypogonadism 19 with or without anosmia - MIM#615269; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.12992 PROK2 Zornitza Stark Phenotypes for gene: PROK2 were changed from to Hypogonadotropic hypogonadism 4 with or without anosmia, MIM# 610628
Mendeliome v0.12989 PROK2 Zornitza Stark reviewed gene: PROK2: Rating: GREEN; Mode of pathogenicity: None; Publications: 18559922, 17054399, 17959774, 18285834; Phenotypes: Hypogonadotropic hypogonadism 4 with or without anosmia, MIM# 610628; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.12250 OSMR Zornitza Stark Marked gene: OSMR as ready
Mendeliome v0.12250 OSMR Zornitza Stark Gene: osmr has been classified as Green List (High Evidence).
Mendeliome v0.12250 OSMR Zornitza Stark Phenotypes for gene: OSMR were changed from to Amyloidosis, primary localized cutaneous, 1 - MIM#105250
Mendeliome v0.12249 OSMR Zornitza Stark Publications for gene: OSMR were set to
Mendeliome v0.12248 OSMR Zornitza Stark Mode of inheritance for gene: OSMR was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.12224 OSMR Krithika Murali reviewed gene: OSMR: Rating: GREEN; Mode of pathogenicity: None; Publications: 19375894, 19528426, 25054142, 20507362, 19690585; Phenotypes: Amyloidosis, primary localized cutaneous, 1 - MIM#105250; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.12112 SEMA3A Zornitza Stark Phenotypes for gene: SEMA3A were changed from to Hypogonadotropic hypogonadism 16 with or without anosmia - MIM#614897; congenital heart disease; short stature
Mendeliome v0.12066 SEMA3A Samantha Ayres reviewed gene: SEMA3A: Rating: GREEN; Mode of pathogenicity: None; Publications: 28075028, 33369061, 20301509, 21059704, 24124006, 22927827; Phenotypes: Hypogonadotropic hypogonadism 16 with or without anosmia - MIM#614897, congenital heart disease, short stature; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.12064 LHB Alison Yeung Phenotypes for gene: LHB were changed from to Hypogonadotropic hypogonadism 23 with or without anosmia, MIM# 228300
Mendeliome v0.12062 LHB Alison Yeung reviewed gene: LHB: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hypogonadotropic hypogonadism 23 with or without anosmia, MIM# 228300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.11929 TACR3 Zornitza Stark Phenotypes for gene: TACR3 were changed from to Hypogonadotropic hypogonadism 11 with or without anosmia, MIM# 614840
Mendeliome v0.11926 TACR3 Zornitza Stark reviewed gene: TACR3: Rating: GREEN; Mode of pathogenicity: None; Publications: 20332248, 19079066; Phenotypes: Hypogonadotropic hypogonadism 11 with or without anosmia, MIM# 614840; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.11926 TAC3 Zornitza Stark Phenotypes for gene: TAC3 were changed from to Hypogonadotropic hypogonadism 10 with or without anosmia, MIM# 614839
Mendeliome v0.11923 TAC3 Zornitza Stark reviewed gene: TAC3: Rating: GREEN; Mode of pathogenicity: None; Publications: 19079066, 20332248, 23329188, 22031817; Phenotypes: Hypogonadotropic hypogonadism 10 with or without anosmia, MIM# 614839; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.11005 NHLH2 Zornitza Stark gene: NHLH2 was added
gene: NHLH2 was added to Mendeliome. Sources: Literature
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: Literature
Mendeliome v0.10966 FGF17 Zornitza Stark Phenotypes for gene: FGF17 were changed from to Hypogonadotropic hypogonadism 20 with or without anosmia MIM#615270
Mendeliome v0.10953 FGF17 Ain Roesley reviewed gene: FGF17: Rating: GREEN; Mode of pathogenicity: None; Publications: 31200363, 31748124, 23643382; Phenotypes: Hypogonadotropic hypogonadism 20 with or without anosmia MIM#615270; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.10790 TCF12 Zornitza Stark Phenotypes for gene: TCF12 were changed from Craniosynostosis 3, MIM# 615314; Kallman syndrome to Craniosynostosis 3, MIM# 615314; Hypogonadotropic hypogonadism 26 with or without anosmia, MIM# 619718; Kallman syndrome
Mendeliome v0.10789 TCF12 Zornitza Stark edited their review of gene: TCF12: Changed phenotypes: Craniosynostosis 3, MIM# 615314, Hypogonadotropic hypogonadism 26 with or without anosmia, MIM# 619718, Kallman syndrome
Mendeliome v0.10600 KISS1R Zornitza Stark Phenotypes for gene: KISS1R were changed from to Hypogonadotropic hypogonadism 8 with or without anosmia (MIM#614837)
Mendeliome v0.10597 KISS1R Zornitza Stark reviewed gene: KISS1R: Rating: GREEN; Mode of pathogenicity: None; Publications: 17164310, 31073722, 14573733; Phenotypes: Hypogonadotropic hypogonadism 8 with or without anosmia (MIM#614837); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9625 ANOS1 Zornitza Stark Phenotypes for gene: ANOS1 were changed from to Hypogonadotropic hypogonadism 1 with or without anosmia (Kallmann syndrome 1), MIM# 308700
Mendeliome v0.9622 ANOS1 Zornitza Stark reviewed gene: ANOS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 1594017, 8504298, 8989261; Phenotypes: Hypogonadotropic hypogonadism 1 with or without anosmia (Kallmann syndrome 1), MIM# 308700; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.9274 FGF8 Zornitza Stark Phenotypes for gene: FGF8 were changed from Hypogonadotropic hypogonadism 6 with or without anosmia, MIM# 612702; Femoral hypoplasia to Hypogonadotropic hypogonadism 6 with or without anosmia, MIM# 612702; Hypoplastic femurs and pelvis, MIM#619545
Mendeliome v0.9273 FGF8 Zornitza Stark edited their review of gene: FGF8: Changed phenotypes: Hypogonadotropic hypogonadism 6 with or without anosmia, MIM# 612702, Hypoplastic femurs and pelvis, MIM#619545
Mendeliome v0.9230 LRRK1 Zornitza Stark gene: LRRK1 was added
gene: LRRK1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: LRRK1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LRRK1 were set to 27829680; 27055475; 31571209; 32119750
Phenotypes for gene: LRRK1 were set to Osteosclerotic metaphyseal dysplasia (OSMD) (OMIM: 615198)
Review for gene: LRRK1 was set to GREEN
Added comment: At least 4 unrelated families reported.
Sources: Expert Review
Mendeliome v0.9088 FGF8 Zornitza Stark Phenotypes for gene: FGF8 were changed from to Hypogonadotropic hypogonadism 6 with or without anosmia, MIM# 612702; Femoral hypoplasia
Mendeliome v0.9085 FGF8 Zornitza Stark reviewed gene: FGF8: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hypogonadotropic hypogonadism 6 with or without anosmia, MIM# 612702; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8917 WDR11 Zornitza Stark Phenotypes for gene: WDR11 were changed from to Intellectual disability; Hypogonadotropic hypogonadism 14 with or without anosmia MIM #614858
Mendeliome v0.8914 WDR11 Zornitza Stark reviewed gene: WDR11: Rating: GREEN; Mode of pathogenicity: None; Publications: 34413497; Phenotypes: Intellectual disability, Hypogonadotropic hypogonadism 14 with or without anosmia MIM #614858; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7094 CHD7 Zornitza Stark Phenotypes for gene: CHD7 were changed from to Hypogonadotropic hypogonadism 5 with or without anosmia MIM#612370; CHARGE syndrome MIM#214800
Mendeliome v0.7091 CHD7 Elena Savva reviewed gene: CHD7: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 26411921; Phenotypes: Hypogonadotropic hypogonadism 5 with or without anosmia MIM#612370, CHARGE syndrome MIM#214800; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Mendeliome v0.6908 SMCHD1 Zornitza Stark edited their review of gene: SMCHD1: Added comment: Bosma arhinia microphthalmia syndrome (BAMS) is characterized by severe hypoplasia of the nose and eyes, palatal abnormalities, deficient taste and smell, inguinal hernias, hypogonadotropic hypogonadism with cryptorchidism, and normal intelligence. Choanal atresia is a feature. More than 30 unrelated individuals reported. Caused by gain of function missense variants with the extended ATPase domain.; Changed rating: GREEN; Changed mode of pathogenicity: Other; Changed publications: 28067909; Changed phenotypes: Bosma arhinia microphthalmia syndrome, MIM# 603457, Arhinia, choanal atresia, microphthalmia MONDO:0011323; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6908 SMCHD1 Zornitza Stark Phenotypes for gene: SMCHD1 were changed from Bosma arhinia microphthalmia syndrome, MIM 603457; Fascioscapulohumeral muscular dystrophy 2, digenic to Bosma arhinia microphthalmia syndrome, MIM 603457; Arhinia, choanal atresia, microphthalmia MONDO:0011323; Fascioscapulohumeral muscular dystrophy 2, digenic
Mendeliome v0.5628 CCDC141 Bryony Thompson gene: CCDC141 was added
gene: CCDC141 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CCDC141 was set to Unknown
Publications for gene: CCDC141 were set to 27014940; 28324054; 25192046
Phenotypes for gene: CCDC141 were set to Anosmic hypogonadotropic hypogonadism
Review for gene: CCDC141 was set to AMBER
Added comment: A consanguineous family had a homozygous nonsense variant, but also had a homozygous missense in FEZF1. 3 other families reported with heterozygous variants, but other variants in other genes present. In an olfactory mouse model, Ccdc141 is expressed in GnRH neurons and olfactory fibers and that knockdown of Ccdc141 reduces GnRH neuronal migration.
Sources: Literature
Mendeliome v0.5369 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; Jackson-Weiss syndrome 123150; Osteoglophonic dysplasia 166250; Pfeiffer syndrome 101600; Trigonocephaly 1 190440
Mendeliome v0.5357 FGFR1 Elena Savva reviewed gene: FGFR1: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 18034870, 23812909, 26942290; Phenotypes: Encephalocraniocutaneous lipomatosis, somatic mosaic 613001, Hartsfield syndrome 615465, Hypogonadotropic hypogonadism 2 with or without anosmia 147950, Jackson-Weiss syndrome 123150, Osteoglophonic dysplasia 166250, Pfeiffer syndrome 101600, Trigonocephaly 1 190440; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.5106 CNGA2 Zornitza Stark gene: CNGA2 was added
gene: CNGA2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CNGA2 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: CNGA2 were set to 28572688
Phenotypes for gene: CNGA2 were set to Congenital anosmia
Review for gene: CNGA2 was set to RED
Added comment: Single multiplex family with high-impact variant segregating with anosmia.
Sources: Literature
Mendeliome v0.3412 NSMF Zornitza Stark Phenotypes for gene: NSMF were changed from to Hypogonadotropic hypogonadism 9 with or without anosmia, MIM# 614838
Mendeliome v0.3408 NSMF Zornitza Stark reviewed gene: NSMF: Rating: RED; Mode of pathogenicity: None; Publications: 15362570, 17235395, 21700882; Phenotypes: Hypogonadotropic hypogonadism 9 with or without anosmia, MIM# 614838; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.3408 SPRY4 Zornitza Stark Phenotypes for gene: SPRY4 were changed from to Hypogonadotropic hypogonadism 17 with or without anosmia, MIM# 615266
Mendeliome v0.3404 SPRY4 Zornitza Stark reviewed gene: SPRY4: Rating: AMBER; Mode of pathogenicity: None; Publications: 23643382; Phenotypes: Hypogonadotropic hypogonadism 17 with or without anosmia, MIM# 615266; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.3404 KISS1 Zornitza Stark Phenotypes for gene: KISS1 were changed from to Hypogonadotropic hypogonadism 13 with or without anosmia, MIM# 614842
Mendeliome v0.3400 KISS1 Zornitza Stark reviewed gene: KISS1: Rating: AMBER; Mode of pathogenicity: None; Publications: 22335740, 25783047, 22766261, 17563351; Phenotypes: Hypogonadotropic hypogonadism 13 with or without anosmia, MIM# 614842; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3396 IL17RD Zornitza Stark Phenotypes for gene: IL17RD were changed from to Hypogonadotropic hypogonadism 18 with or without anosmia, MIM# 615267
Mendeliome v0.3392 IL17RD Zornitza Stark reviewed gene: IL17RD: Rating: AMBER; Mode of pathogenicity: None; Publications: 23643382, 32389901; Phenotypes: Hypogonadotropic hypogonadism 18 with or without anosmia, MIM# 615267; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.3391 HS6ST1 Zornitza Stark Phenotypes for gene: HS6ST1 were changed from to {Hypogonadotropic hypogonadism 15 with or without anosmia} 614880
Mendeliome v0.3387 HS6ST1 Zornitza Stark reviewed gene: HS6ST1: Rating: RED; Mode of pathogenicity: None; Publications: 21700882; Phenotypes: {Hypogonadotropic hypogonadism 15 with or without anosmia} 614880; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.3387 GNRH1 Zornitza Stark Phenotypes for gene: GNRH1 were changed from to Hypogonadotropic hypogonadism 12 with or without anosmia, MIM# 614841
Mendeliome v0.3384 GNRH1 Zornitza Stark reviewed gene: GNRH1: Rating: GREEN; Mode of pathogenicity: None; Publications: 19535795, 19567835, 32134721, 31200363, 26595427; Phenotypes: Hypogonadotropic hypogonadism 12 with or without anosmia, MIM# 614841; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3349 FEZF1 Zornitza Stark Phenotypes for gene: FEZF1 were changed from to Hypogonadotropic hypogonadism 22, with or without anosmia, MIM# 616030
Mendeliome v0.3331 FEZF1 Elena Savva reviewed gene: FEZF1: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 25192046, 32400067; Phenotypes: Hypogonadotropic hypogonadism 22, with or without anosmia 616030; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3215 FLRT3 Zornitza Stark Phenotypes for gene: FLRT3 were changed from to Hypogonadotropic hypogonadism 21 with anosmia (MIM# 615271)
Mendeliome v0.3211 FLRT3 Zornitza Stark reviewed gene: FLRT3: Rating: RED; Mode of pathogenicity: None; Publications: 23643382, 31200363; Phenotypes: Hypogonadotropic hypogonadism 21 with anosmia (MIM# 615271); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.3174 TSHZ1 Zornitza Stark changed review comment from: Two individuals reported with LoF variants, both with a phenotype of congenital aural atresia and hyposmia (PMID: 22152683). Temporal and spatial expression of Tshz1 mRNA during development of the middle ear is consistent with the phenotype (PMID: 17586487). Tsh2 null mouse model showed a middle ear malformation, and neonatal lethality. A conditional nervous system-specific Tshz1 knock out mouse model demonstrated hyposmia (PMIDs: 24487590; 17586487).; to: Two individuals reported with LoF variants, both with a phenotype of congenital aural atresia and hyposmia (PMID: 22152683). Temporal and spatial expression of Tshz1 mRNA during development of the middle ear is consistent with the phenotype (PMID: 17586487). Tsh2 null mouse model showed a middle ear malformation, and neonatal lethality. A conditional nervous system-specific Tshz1 knock out mouse model demonstrated hyposmia (PMIDs: 24487590; 17586487). Also note original report contains four individuals with deletions of this gene, further supporting gene-disease association.
Mendeliome v0.3173 TSHZ1 Zornitza Stark Phenotypes for gene: TSHZ1 were changed from to Aural atresia, congenital, MIM# 607842; Hyposmia
Mendeliome v0.3170 TSHZ1 Zornitza Stark reviewed gene: TSHZ1: Rating: GREEN; Mode of pathogenicity: None; Publications: 15834955, 22152683, 17586487, 24487590; Phenotypes: Aural atresia, congenital, MIM# 607842, Hyposmia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.3156 AXL Bryony Thompson gene: AXL was added
gene: AXL was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: AXL was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AXL were set to 18787040; 24476074
Phenotypes for gene: AXL were set to Kallman syndrome; normosmic idiopathic hypogonadotropic hypogonadism
Review for gene: AXL was set to AMBER
Added comment: Axl null mice had delayed first oestrus and persistently abnormal oestrous cyclicality compared with wild-type controls. Only a single study reported screening human cases. In a screen of 104 probands with KS or nIHH, four heterozygous AXL mutations were identified in two KS and two nIHH unrelated subjects (two males and two females). Three of the variants appear to be too common in gnomAD v2.1 given the reported prevalence of KS reported in GeneReviews (1:30,000 in males and 1:125,000 in females): c.587-6C>T (normal splicing in RNA studies, NFE AF 0.0001472), p.Q361P (NFE 0.002560), p.L50F (AJ 0.004405). The other variant p.S202C (4 hets, 1 female in gnomAD v2.1) is rare enough in gnomAD for a dominant disorder. In vitro functional assays were conducted and p.S202C had an significant effect on function, but so did the more common variant p.Q361P.
Sources: Literature
Mendeliome v0.2449 SMCHD1 Zornitza Stark Phenotypes for gene: SMCHD1 were changed from to Bosma arhinia microphthalmia syndrome, MIM 603457; Fascioscapulohumeral muscular dystrophy 2, digenic
Mendeliome v0.2377 SMCHD1 Teresa Zhao reviewed gene: SMCHD1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31600781; Phenotypes: Bosma arhinia microphthalmia syndrome, MIM 603457, Fascioscapulohumeral muscular dystrophy 2, digenic; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Mendeliome v0.2309 PROKR2 Zornitza Stark Phenotypes for gene: PROKR2 were changed from to Hypogonadotropic hypogonadism 3 with or without anosmia, MIM# 244200
Mendeliome v0.2305 PROKR2 Elena Savva reviewed gene: PROKR2: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID:18826963, 29161432; Phenotypes: Hypogonadotropic hypogonadism 3 with or without anosmia 244200; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.1630 GNRHR Zornitza Stark Phenotypes for gene: GNRHR were changed from to Hypogonadotropic hypogonadism 7 without anosmia, MIM#146110
Mendeliome v0.1627 GNRHR Kristin Rigbye reviewed gene: GNRHR: Rating: GREEN; Mode of pathogenicity: None; Publications: 28348023, 9371856; Phenotypes: Hypogonadotropic hypogonadism 7 without anosmia, 146110; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.0 OSMR Zornitza Stark gene: OSMR was added
gene: OSMR was added to Mendeliome_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: OSMR was set to Unknown