Holoprosencephaly

Gene: FGF8

Green List (high evidence)

Comment on mode of inheritance: There is a well established association between herterozygous FGF8 variants and Holoprosencephaly. There are also at least 5 individuals reported in literature with biallelic FGF8 variants. Two probands had hypogonadotropic hypogonadism and three others presented with holoprosencephaly and pituitary insufficiency. However, the evidence for the 3 HPE families is confounded by consanguinity and limited segregation evidence. Hence, the MOI should be remain as 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted', until more evidence emerges. A watchlist_moi tag was added.

Created: 7 Oct 2026, 2:59 p.m. | Last Modified: 19 Oct 2026, 7:28 a.m.

Panel Version: 6.6

BIALLELIC CASE REPORTS:
PMID: 29584859 Hong et al., 2018
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
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: 31748124 - IHH Proband 15, male, was homozygous for FGF8 p.R184C - consanguineous parents. He also had hearing loss and testicular calcification.
PMID: 18596921 - Case 3 - IHH proband homozygous for FGF8 p.Phe40Leu variant. Additional FGFR1 mutations were also detected.

MONOALLELIC CASES:
PMID: 27363716 Dubourg et al., 2016
Study screened a cohort of 257 HPE patients. 2.3% of patients had a FGF8 variant.
- Fetus with semilobar HPE had a het FGF8 p.Thr199Met variant, along with a FGFR1 splice variant.
- 4yo boy with semilobar HPE was het for FGF8 p.Ala106Glu (de novo)
- 2 unrelated families with a het FGF8 p.Arg129* variant and alobar HPE / syntelencephaly.
- 2 unrelated families with a het FGF8 p.Arg206Gln variant and lobar HPE, or microfom in the second family (where the variant cosegregated with another mutation in DLL1).
No pituitary deficiency reported for these patients.

PMID: 21045958 Arauz et al., 2010
Study screened 360 probands with HPE for sequence variations in FGF8.
Described a family with HPE and a heterozygous (putative hypomorphic) FGF8 variant c.686C>T, p.T229M. Twins affected - one with semilobar HPE, microcephaly, cleft palate, seizures, diabetes insipidus (DI), and severe neurological impairment; the other twin had only single maxillary central incisor and hypotelorism. Mother was het for the same variant but only noted to have mild hypotelorism. No coding mutations found in SHH, ZIC2, SIX3, or TGIF.
The same variant was reported in an IHH patient in PMID: 18596921.

FGF8 is associated with AD Hypogonadotropic hypogonadism 6 with or without anosmia 612702 in OMIM (accessed 7th Oct 2026).

Created: 7 Oct 2026, 2:20 p.m. | Last Modified: 7 Oct 2026, 3:03 p.m.

Panel Version: 6.4

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
hypogonadotropic hypogonadism 6 with or without anosmia, MONDO:0012988; Hypogonadotropic hypogonadism 6 with or without anosmia, OMIM:612702

Publications

• 18596921
• 21045958
• 21832120
• 27363716
• 29584859
• 31748124

As discussed with the GMS Neurology Specialist Test Group webex call 11th July 2019: The Specialist Test Group all agreed that there is enough evidence to rate this gene Green

Created: 29 Jul 2019, 2:13 p.m. | Last Modified: 29 Jul 2019, 2:13 p.m.

Panel Version: 1.20

Comment when marking as ready: 4 cases in PMID 27363716. Considered sufficient evidence

Created: 30 May 2017, 3:42 p.m.

Comment on list classification: 4 unrelated cases in PMID 27363716 with holoprosencephaly. 3 missense, 1 nonsense.

Created: 30 May 2017, 3:41 p.m.

I don't know

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
612702

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
612702

Publications

• 27363716