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| Differences of Sex Development v1.35 | PLXNA1 |
Lucy Spencer gene: PLXNA1 was added gene: PLXNA1 was added to Differences of Sex Development. Sources: Literature Mode of inheritance for gene: PLXNA1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: PLXNA1 were set to 28334861; 30467832; 34636164 Phenotypes for gene: PLXNA1 were set to Hypogonadotropic hypogonadism MONDO:0018555, PLXNA1-related Review for gene: PLXNA1 was set to AMBER Added comment: reported phenotype expansion for monoallelic Kallman syndrome: PMIDs 28334861 13 families with Kallman syndrome, however only 3 of these variants (His684Tyr Lys1618Thr Cys1744Phe) are absent from gnomad, the rest have at least 6 hets and most have over 20 hets. in transfected cells His684Tyr, Lys1618Thr and some of the common missense variants were shown to result in reduced total amounts of protein. In a minigene assay Cys1744Phe which is at the last base of an exon was shown to cause intron 28 retention which would be out of frame. No variants in this study were noted to be de novo. PMID: 30467832 10 missense variants identified in patients with hypogonadotropic hypogonadism. Again some of the reported missense have over 20 hets in gnomad but 5 of the variants are rare or absent Lys1451Arg, Ser1850Arg, Ile1701Val, Pro485Leu and Val536Ile. All of these variants were either inherited from a parent or inheritance was unknown, and 1 individual had a better diagnosis with a nonsense in FGFR1 while other patients had variants in other genes amber for HH. No variants in this study were noted to be de novo. PMID: 34636164 another 10 missense variants identified in 11 families with hypogonadotropic hypogonadism. However, only 3 were not common in gnomad; Pro848Arg, Ala1106Val, and Ser1709Leu. Ala1106Val and Ser1709Leu were both inherited from unaffected mothers, and most patients in this study also had variants of interest in other genes. No variants in this study were noted to be de novo. So at least 10 reports of variants that are rare/absent in gnomad with Kallman syndrome, all missense variants, most without segregation information or inherited from unaffected/unknown if affected parents. Some with a bit of functional work. Many patients also have variants of interest in other genes amber or green for the same phenotype. borderline amber/green Sources: Literature |
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| Differences of Sex Development v0.360 | FGFR1 | Zornitza Stark Marked gene: FGFR1 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences of Sex Development v0.360 | FGFR1 | Zornitza Stark Gene: fgfr1 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 v0.359 | FGFR1 | Zornitza Stark Publications for gene: FGFR1 were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences of Sex Development v0.358 | FGFR1 | Zornitza Stark Mode of inheritance for gene: FGFR1 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 v0.284 | 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 v0.27 | 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 v0.0 | FGFR1 |
Zornitza Stark gene: FGFR1 was added gene: FGFR1 was added to Disorders of Sex Differentiation_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services Mode of inheritance for gene: FGFR1 was set to Unknown |
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