Hypogonadotropic hypogonadism (GMS)

Gene: FGF8

Green List (high evidence)

Comment on mode of inheritance: There is a well established association between herterozygous FGF8 variants and Hypogonadotropic hypogonadism. There are also at 5 individuals reported in literature with biallelic FGF8 variants. However, three of them presented with holoprosencephaly, diabetes insipidus, and pituitary insufficiency, rather than hypogonadotropic hypogonadism. An individual with biallelic FGF8 variants and IHH, described in PMID: 18596921, harboured additional FGFR1 variants. Hence, there is little robust evidence for the association between biallelic FGF8 variants and HH, and the MOI should be changed to BIALLELIC, autosomal or pseudoautosomal on this panel.

Created: 7 Oct 2026, 2:14 p.m. | Last Modified: 7 Oct 2026, 2:16 p.m.

Panel Version: 5.4

PMID: 40508017 Chiarello et al., 2025
Congenital hypogonadotropic hypogonadism (CHH) cohort (14 patients). Seq method: NGS of 46 genes.
Pt5 - female, 42yrs; presented with hypogonadism, primary amenorrhea, and anosmia; brain MRI showed hypoplasia of olfactory bulbs; she harboured het variants in FGF8 (intronic variant chr10: g.103530393C>T) and IL17RD. Kallmann syndrome diagnosis.

PMID: 31748124 Men et al., 2020 - HET & HMZ
Study of a cohort of 145 Chinese IHH probands (125 men and 20 women). Seq method: WES + Sanger. Two novel mutations (p.E176K and p.R184C) reported in FGF8.
Proband 14, male, carried a de novo FGF8 p.E176K mutation, as well as an AXL variant inherited from an unaffected mother.
Proband 15 male, was homozygous for FGF8 p.R184C - consanguineous parents. He also had hearing loss and testicular calcification.

PMID: 29584859 Hong et al., 2018 - BIALLELIC
Cohort of 330 patients with holoprosencephaly, sequenced using a targeted capture panel of 150 developmental genes.
Patient 'BL11322' - homozygous for FGF8 p.T122M (consanguineous parents). Clinical features: seizures, dev delay, semilobar HPE, microcephaly, hypotelorism. Determined to be a hypomorph in a functional assay (zebrafish overexpression experiments).
Patient 'Anonymous' - hmz for FGF8 p.R178H (consanguineous parents). Clinical features: dev delay, semilobar HPE, diabetes insipidus, pituitary insufficiency.

PMID: 21832120 McCabe et al., 2011 - BIALLELIC
Study objective: screen for FGF8 mutations in patients with septo-optic dysplasia (n = 374) or holoprosencephaly (HPE)/midline clefts (n = 47). FGF8 analysed by PCR and direct sequencing. A homozygous p.R189H mutation was identified in a female patient of consanguineous parentage with semilobar HPE, diabetes insipidus, and TSH and ACTH insufficiency. 2 hets with this variant reported in gnomAD v4.

PMID: 20463092 Trarbach et al., 2010
2 het variants in FGF8 were identified in two unrelated IHH probands using targeted FGF8 seq.
F1 = 5 sibs with KS / normosmic IHH / delayed puberty, het for p.R127X. Cleft lip and palate and neurosensorial deafness were also noted.
F2 = proband is a 30-yr-old man with familial normosmic IHH and severe GnRH deficiency; het for FGF8 p.R129X.

PMID: 18596921 Falardeau et al., 2008
461 unrelated IHH probands screened. Study identified 6 missense mutations in FGF8 in IHH probands with variable olfactory phenotypes (candidate gene approach) - 3 familial and 3 sporadic cases.
Case 3 - homozygous for FGF8 p.Phe40Leu variant. Other cases had het FGF8 variants. Additional FGFR1 mutations were detected in cases 3 and 4.
Functional: mice homozygous for a hypomorphic Fgf8 allele lacked GnRH neurons in the hypothalamus, while heterozygous mice showed substantial decreases in the number of GnRH neurons and hypothalamic GnRH peptide concentration.

FGF8 is associated with AD Hypogonadotropic hypogonadism 6 with or without anosmia 612702 in OMIM (accessed 7th Oct 2026).
FGF8 variants account for <2% of persons with KS or normosmic isolated gonadotropin-releasing hormone deficiency (GeneReviews, PMID: 20301509).

Created: 7 Oct 2026, 1:31 p.m. | Last Modified: 7 Oct 2026, 2:07 p.m.

Panel Version: 5.4

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Hypogonadotropic hypogonadism 6 with or without anosmia, OMIM:612702

Publications

• 18596921
• 20463092
• 21832120
• 29584859
• 31748124
• 40508017

Green List (high evidence)

Green List (high evidence)