FGFR1 – Holoprosencephaly

Holoprosencephaly (HPE) is the most common forebrain cleavage defect, characterized by incomplete separation of the cerebral hemispheres and midline facial anomalies. Etiology is highly heterogeneous, encompassing chromosomal abnormalities and single-gene defects. FGFR1 has emerged as a monogenic cause of HPE, with heterozygous variants detected by prenatal and postnatal sequencing. Studies combining large HPE cohorts and functional assays support its role in midline brain development.

In a multi-patient study of over 200 HPE probands, nine distinct heterozygous FGFR1 variants were identified by next-generation sequencing, with five kinase-domain mutations demonstrating dominant-negative activity in zebrafish over-expression assays (PMID:26931467). A targeted NGS screen of 257 HPE patients found FGFR1 among the minor HPE genes, alongside FGF8, SHH, ZIC2, SIX3 and GLI2 (PMID:27363716). More recently, prenatal exome sequencing discovered a maternal c.296A>G (p.Tyr99Cys) FGFR1 variant segregating with recurrent HPE spectrum malformations in two consecutive pregnancies (PMID:38679587).

Genetic segregation is limited: the c.296A>G (p.Tyr99Cys) allele was transmitted from an asymptomatic mother to two affected fetuses, supporting pathogenicity but indicating incomplete penetrance. No additional multi-generation pedigrees have been reported to date.

The FGFR1 variant spectrum in HPE includes missense substitutions in the extracellular and kinase domains (e.g., c.1379T>C (p.Val460Ala), c.1468G>A (p.Gly490Arg)), and splice-site mutations (c.1977+1G>A). Missense alleles predominate, with no clear founder variants identified.

Functional assays demonstrate that five FGFR1 kinase-domain mutations act dominantly to disrupt FGF signaling, producing HPE-like midline defects in zebrafish models. One family exemplifies gene:gene interaction, where a deleterious FGFR1 allele synergizes with an FGF8 loss-of-function allele to cause HPE in human embryos.

Pathogenic FGFR1 variants exert a dominant-negative mechanism on receptor tyrosine kinase activity, impairing downstream MAPK and PI3K signaling essential for ventral forebrain cleavage. Concordant zebrafish rescue studies bolster the causative link.

Some FGFR1 variants identified in HPE cohorts behave like wild-type in rescue assays, reflecting allelic heterogeneity and variable expressivity. Asymptomatic carriers highlight incomplete penetrance and complicate risk prediction.

Overall, genetic data from large HPE series and concordant functional studies support a Moderate clinical validity for FGFR1 in HPE. Continued identification of familial segregation and additional functional characterization will strengthen the association. Key take-home: FGFR1 should be included in HPE gene panels to enhance prenatal diagnosis and genetic counseling.

References

• Human molecular genetics • 2016 • Dominant-negative kinase domain mutations in FGFR1 can explain the clinical severity of Hartsfield syndrome. PMID:26931467
• Human mutation • 2016 • Mutational Spectrum in Holoprosencephaly Shows That FGF is a New Major Signaling Pathway. PMID:27363716
• The journal of maternal-fetal & neonatal medicine • 2024 • Prenatal identification of a pathogenic maternal FGFR1 variant in two consecutive pregnancies with fetal forebrain malformations. PMID:38679587

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