FGFR1 Tyrosine Kinase Domain Variant p.Val561Met in Caudal Dysraphism: A Case Report

Neural tube defects (NTDs) are complex congenital malformations with both environmental and genetic contributions. Monogenic causes of NTDs are increasingly recognized, particularly those involving genes that regulate key morphogenetic pathways. FGFR1, a receptor tyrosine kinase, is crucial for axial and neural development; however, its role in caudal dysraphism remains unclear.

We report a female fetus delivered at 25 weeks of gestation following prenatal diagnosis of severe lumbosacral spina bifida. Comprehensive postmortem and genetic investigations, including trio exome sequencing, were performed to identify potential causal variants.

Postmortem examination revealed Chiari II malformation, dysmorphic features, bilateral talipes, and a large caudal spinal defect. Trio exome sequencing identified a de novo heterozygous FGFR1 variant (c.1681G>A; p.Val561Met) affecting the conserved tyrosine kinase domain. This variant has been reported in somatic and developmental contexts, where it may modulate FGFR1 signaling, although evidence for constitutive activation remains limited and context-dependent. The variant has not been previously associated with NTD.

This single case raises the possibility that altered FGFR1 signaling may contribute to defective neurulation and warrants further investigation in larger cohorts. Our findings support considering FGFR1 in the differential diagnosis of complex or syndromic spinal dysraphism, though additional evidence is required before recommending its inclusion in routine panels for isolated cases.