FGF8 – Holoprosencephaly

Holoprosencephaly (HPE) is the most common malformation of the human forebrain, characterized by failed or incomplete cleavage of the cerebral hemispheres. Fibroblast Growth Factor 8 (FGF8), a member of the FGF family, is expressed at the anterior neural ridge and is critical for prosencephalic patterning. Although FGF8 variants have been implicated in facial clefting and hypogonadotropic hypogonadism, their role in HPE was not established until recent studies integrated genetic and experimental data.

In a cohort of 360 HPE probands screened by high-resolution melting and direct sequencing, eight rare FGF8 sequence variants were identified, including a heterozygous missense mutation c.686C>T (p.Thr229Met) that segregated with variable classic HPE in three affected family members (PMID:21045958). A separate aCGH study of 136 individuals with HPE-related deletions reported one patient with a deletion encompassing the FGF8 locus who presented with frank HPE (PMID:20066439).

Targeted next-generation sequencing of 257 HPE cases confirmed FGF8 as a minor but recurrent HPE gene, detecting a deleterious c.617G>A (p.Arg206Gln) variant among pathogenic hits (PMID:27363716). In a focused ophthalmologic cohort of 10 HPE patients with mutations in SHH, SIX3, ZIC2, or FGF8, nine exhibited at least two eye anomalies, underscoring phenotypic variability in FGF8-associated HPE (PMID:21976454).

FGF8-related HPE follows an autosomal dominant inheritance pattern with variable expressivity. Segregation of the c.686C>T (p.Thr229Met) variant in a three-member pedigree provides segregation evidence for haploinsufficiency. Additional cases of de novo or familial FGF8 loss-of-function alleles further support dominant inheritance.

Functional assays in zebrafish demonstrate that human FGF8 loss-of--function variants impair midline forebrain development, recapitulating HPE phenotypes and confirming a haploinsufficiency mechanism (PMID:29584859). Studies of FGFR1–FGF8 digenic interactions reveal synergistic dominant-negative effects that exacerbate HPE in both human families and zebrafish models (PMID:26931467).

No convincing reports refute the FGF8–HPE association, although incomplete penetrance and oligogenic contributions may account for variable expressivity. The integration of segregation, case-control screening, and animal model data yields a ClinGen Moderate validity classification for FGF8 in HPE.

Key Take-home: Heterozygous loss-of-function variants in FGF8 cause autosomal dominant holoprosencephaly via haploinsufficiency and should be included in diagnostic gene panels.

References

• Molecular syndromology • 2010 • A Hypomorphic Allele in the FGF8 Gene Contributes to Holoprosencephaly and Is Allelic to Gonadotropin-Releasing Hormone Deficiency in Humans. PMID:21045958
• Human genetics • 2010 • Clinical characterization of individuals with deletions of genes in holoprosencephaly pathways by aCGH refines the phenotypic spectrum of HPE. PMID:20066439
• Human mutation • 2016 • Mutational Spectrum in Holoprosencephaly Shows That FGF is a New Major Signaling Pathway. PMID:27363716
• American journal of medical genetics. Part A • 2011 • A broad range of ophthalmologic anomalies is part of the holoprosencephaly spectrum. PMID:21976454
• Human molecular genetics • 2018 • Loss-of-function mutations in FGF8 can be independent risk factors for holoprosencephaly. PMID:29584859
• Human molecular genetics • 2016 • Dominant-negative kinase domain mutations in FGFR1 can explain the clinical severity of Hartsfield syndrome. PMID:26931467

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