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Hypogonadotropic hypogonadism (GMS) v4.7 FGFR1 Ida Ertmanska changed review comment from: PMID: 27055092 Mazen et al., 2016
Male patient with congenital heart disease (CHD) and ambiguous genitalia, referred at 15 months. Consanguineous parents, positive family history for CHD. Trio WES revealed a homozygous FGFR1 c.1418G>A variant (hg38: c.1424G>A, p.Arg475Gln - rs747333248, 34 total alleles in gnomAD v4.1.0, no homozygotes). Patient also homozygous for a STARD3 p.Ala247Val mutation, no disease association reported for this gene. Ambiguous genitalia highlighted as unusual presentation in FGFR1-related disease.

PMID: 25394172 Villanueva et al., 2015
7 individuals with Congenital hypogonadotropic hypogonadism (CHH), 3/7 with anosmia, and 7/7 with split hand/foot malformation. The patients harboured FGFR1 variants - 6 heterozygous and 1 homozygous.
P1: male, homozygous for c.1286T>A, p.V429E. Heterozygous sister and parents. Sister has hyposmia, otherwise no phenotype reported in heterozygous family members.
In the 6 heterozygous pedigrees, CHH was an autosomal dominant trait with incomplete penetrance.

PMID: 23812909 Simonis et al., 2013
6 patients with Hartsfield syndrome and 1 female fetus with similar symptoms. FGFR1 variants were detected in the extracellular binding domain (two patients with homozygous mutations) or the intracellular tyrosine kinase domain (four heterozygous de novo variants). Patients presented with holoprosencephaly 7/7 (lobar, alobar, or semilobar), corpus callosum agenesis 5/7 (full or partial), ectrodactyly 7/7 (hands and/or feet affected), growth retardation 6/6, genital anomalies 3/6 (micropenis, cryptorchidism), DD/ID 6/6 (mild to severe). P1 was homozygous for L165S, heterozygous parents unaffected. P2 was homozygous for L191S, parents not available for testing.

PMID: 23154428 Jarzabek et al., 2012
5 Kallmann syndrome (KS) patients who carry FGFR1 mutations (Gly270Asp, Gly97Ser, Met161Thr, Ser685Phe and Ala167Ser/Ala167Ser). Patients 1-4 harboured de novo heterozygous FGFR1 mutations, while P5 was homozygous for the c.499G>T, p.Ala167Ser variant - his parents are sister are heterozygous and unaffected. All 5 patients had absent puberty, as well as hyposmia or anosmia. 3/5 patients presented with skeletal abnormalities and lip/palate malformations.
P5 (previously described in PMID: 12627230) had KS, cleft palate, corpus callosum agenesis, vertebral anomalies, unilateral fusion of fourth and fifth metacarpal bones, and bilateral oligodactyly of feet (four digits).

FGFR1 is associated with multiple dominant conditions in OMIM, including AD Hypogonadotropic hypogonadism 2 with or without anosmia, OMIM:147950 and AD Hartsfield syndrome, OMIM:615465.; to: PMID: 27055092 Mazen et al., 2016
Male patient with congenital heart disease (CHD) and ambiguous genitalia, referred at 15 months. Consanguineous parents, positive family history for CHD. Trio WES revealed a homozygous FGFR1 c.1418G>A variant (hg38: c.1424G>A, p.Arg475Gln - rs747333248, 34 total alleles in gnomAD v4.1.0, no homozygotes). Patient also homozygous for a STARD3 p.Ala247Val mutation, no disease association reported for this gene. Ambiguous genitalia highlighted as unusual presentation in FGFR1-related disease.

PMID: 25394172 Villanueva et al., 2015
7 individuals with Congenital hypogonadotropic hypogonadism (CHH), 3/7 with anosmia, and 7/7 with split hand/foot malformation. The patients harboured FGFR1 variants - 6 heterozygous and 1 homozygous.
P1: male, homozygous for c.1286T>A, p.V429E. Heterozygous sister and parents. Sister has hyposmia, otherwise no phenotype reported in heterozygous family members.
In the 6 heterozygous pedigrees, CHH was an autosomal dominant trait with incomplete penetrance.

PMID: 23812909 Simonis et al., 2013
6 patients with Hartsfield syndrome and 1 female fetus with similar symptoms. FGFR1 variants were detected in the extracellular binding domain (two patients with homozygous mutations) or the intracellular tyrosine kinase domain (four heterozygous de novo variants). Patients presented with holoprosencephaly 7/7 (lobar, alobar, or semilobar), corpus callosum agenesis 5/7 (full or partial), ectrodactyly 7/7 (hands and/or feet affected), growth retardation 6/6, genital anomalies 3/6 (micropenis, cryptorchidism), DD/ID 6/6 (mild to severe). P1 was homozygous for L165S, heterozygous parents unaffected. P2 was homozygous for L191S, parents not available for testing.

PMID: 23154428 Jarzabek et al., 2012
5 Kallmann syndrome (KS) patients who carry FGFR1 mutations (Gly270Asp, Gly97Ser, Met161Thr, Ser685Phe and Ala167Ser/Ala167Ser). Patients 1-4 harboured de novo heterozygous FGFR1 mutations, while P5 was homozygous for the c.499G>T, p.Ala167Ser variant - his parents are sister are heterozygous and unaffected. All 5 patients had absent puberty, as well as hyposmia or anosmia. 3/5 patients presented with skeletal abnormalities and lip/palate malformations.
P5 (previously described in PMID: 12627230) had KS, cleft palate, corpus callosum agenesis, vertebral anomalies, unilateral fusion of fourth and fifth metacarpal bones, and bilateral oligodactyly of feet (four digits).

FGFR1 is associated with multiple dominant conditions in OMIM, including AD Hypogonadotropic hypogonadism 2 with or without anosmia, OMIM:147950 and AD Hartsfield syndrome, OMIM:615465 (accessed 27th Feb 2026).
Hypogonadotropic hypogonadism (GMS) v4.7 FGFR1 Ida Ertmanska Phenotypes for gene: FGFR1 were changed from Hypogonadotropic hypogonadism type 2(OMIM 147950) to Hypogonadotropic hypogonadism 2 with or without anosmia, OMIM:147950; Hartsfield syndrome, OMIM:615465
Hypogonadotropic hypogonadism (GMS) v4.6 FGFR1 Ida Ertmanska Publications for gene: FGFR1 were set to
Hypogonadotropic hypogonadism (GMS) v4.5 FGFR1 Ida Ertmanska Tag Q1_26_MOI tag was added to gene: FGFR1.
Hypogonadotropic hypogonadism (GMS) v4.5 FGFR1 Ida Ertmanska commented on gene: FGFR1: Comment on mode of inheritance: There are more than 3 unrelated cases reported for both dominant and recessive FGFR1-related hypogonadotropic hypogonadism. The condition is usually caused by heterozygous kinase domain variants or homozygous extracellular domain mutations, but there are exceptions to this genotype-phenotype pattern (e.g. PMID: 27790375). Based on available evidence, the MOI for Hypogonadotropic hypogonadism (GMS) should be changed to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.
Hypogonadotropic hypogonadism (GMS) v4.5 FGFR1 Ida Ertmanska reviewed gene: FGFR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23154428, 23812909, 25394172, 27055092; Phenotypes: Hypogonadotropic hypogonadism 2 with or without anosmia, OMIM:147950, Hartsfield syndrome, OMIM:615465; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
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.
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.
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.
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)."
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
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