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Hypogonadotropic hypogonadism (GMS) v3.14 | NSMF | Arina Puzriakova Added comment: Comment on mode of inheritance: Updated from biallelic to monoallelic as only heterozygous variants in this gene have been reported in association with IHH, even though this is only partially explains the phenotype due to possible oligogenic variants in other genes such as FGFR1 and HS6ST1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Hypogonadotropic hypogonadism (GMS) v1.42 | DUSP6 |
Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM but not in Gene2Phenotype. PMID: 23643382 - 5 cases with variants in DUSP6 (3 of these cases have variants in other genes FGFR1 and SPRY4). PMID: 32389901 - 6 cases with variants in DUSP6 (1 case also has variants in CCDC141). Based on the available evidence this gene has been given an Amber rating and will be reviewed by the GMS specialist group. |
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Hypogonadotropic hypogonadism (GMS) v1.41 | FGF17 |
Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM but not in Gene2Phenotype. PMID: 23643382 identfied 3 cases with variants in the FGF17 gene. However, 1 of these cases have variants in other genes as well (FLRT3, HS6ST1 and FGFR1). Based on the available evidence variants in this gene contribute to disease with variable penetrance. This gene has been given an Amber rating until further evidence is available. |
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Hypogonadotropic hypogonadism (GMS) v1.30 | KLB |
Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. This gene is not associated with a phenotype in OMIM or Gene2Phenotype. This gene is Green on the Hypogonadotropic hypogonadism (Version 1.29) panel and have the following review: "Rachel Jones (GSTT) Green List (high evidence) Publication by Pitteloud et al: "Genetic screening of 334 CHH patients identified seven heterozygous loss‐of‐function KLB mutations in 13 patients (4%). Most patients with KLB mutations (9/13) exhibited metabolic defects. 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." They also included functional analysis and showed decreased activity in response to FGF21 and FGF8 KLB is an obligate coreceptor for FGF21 alongside FGFR1 Created: 10 Mar 2020, 10:55 a.m. | Last Modified: 10 Mar 2020, 10:55 a.m. Panel Version: 1.27 Mode of inheritance MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes hypogonadotrophic hypogonadism Publications PMID: 28754744 Created: 10 Mar 2020, 10:55 a.m. Last Modified: 10 Mar 2020, 10:55 a.m. Panel version: 1.27" There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review. |
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Hypogonadotropic hypogonadism (GMS) v1.15 | CCDC141 |
Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. 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. After discussing with the Genomics England Clinical Team, it was decided that this gene should have an Amber rating as variants. Helen Brittain (Genomics England): "...variants in this gene may be seen as a risk allele (either with other known contributory genetic factors, or unexplained variable penetrance)." |
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Hypogonadotropic hypogonadism (GMS) v1.8 | DUSP6 |
Zornitza Stark gene: DUSP6 was added gene: DUSP6 was added to Hypogonadotropic hypogonadism idiopathic. Sources: Expert list Mode of inheritance for gene: DUSP6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: DUSP6 were set to 23643382; 32389901 Phenotypes for gene: DUSP6 were set to Hypogonadotropic hypogonadism 19 with or without anosmia, MIM# 615269 Review for gene: DUSP6 was set to GREEN gene: DUSP6 was marked as current diagnostic Added comment: PMID: 23643382 - 5 individuals with congenital hypogonadotrophic hypogonadism (CHH) (3 carry additional variants in FGFR1, SPRY4) PMID: 32389901 - 6 individuals with isolated HH, 3 also had cryptorchidism. Sources: Expert list |
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Hypogonadotropic hypogonadism (GMS) v0.11 | FGFR1 | Ivone Leong Classified gene: FGFR1 as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Hypogonadotropic hypogonadism (GMS) v0.11 | FGFR1 | Ivone Leong Gene: fgfr1 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Hypogonadotropic hypogonadism (GMS) v0.7 | FGFR1 | Simon Thomas reviewed gene: FGFR1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Hypogonadotropic hypogonadism (GMS) v0.6 | FGFR1 | Ivone Leong Source Wessex and West Midlands GLH was added to FGFR1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Hypogonadotropic hypogonadism (GMS) v0.5 | FGFR1 | Martina Owens reviewed gene: FGFR1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Hypogonadotropic hypogonadism (GMS) v0.4 | FGFR1 | Ivone Leong Added phenotypes Hypogonadotropic hypogonadism type 2(OMIM 147950) for gene: FGFR1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Hypogonadotropic hypogonadism (GMS) v0.3 | FGFR1 |
Ivone Leong gene: FGFR1 was added gene: FGFR1 was added to Hypogonadotropic hypogonadism idiopathic. Sources: South West GLH,NHS GMS Mode of inheritance for gene: FGFR1 was set to BIALLELIC, autosomal or pseudoautosomal |