FGF16 – Syndactyly Type 8

FGF16 (fibroblast growth factor 16) has been implicated in X-linked recessive fusion of the fourth and fifth metacarpals (MF4; syndactyly type 8) based on truncating variants identified in multiple male probands. FGF16 and Syndactyly Type 8 have been linked through clinical and experimental studies.

Genetic Evidence: In a sporadic male patient with MF4 and generalized joint laxity, Sanger sequencing revealed a novel frameshift variant c.474_477del (p.Glu158AspfsTer25) in exon 3; his clinically unaffected mother was heterozygous, consistent with X-linked recessive inheritance (PMID:24706454). Three additional unrelated families were identified by whole-exome sequencing, each harboring distinct nonsense mutations in exons 1–3, expanding the allelic series to three C-terminal truncating variants that likely escape nonsense-mediated decay (PMID:25333065).

Inheritance is X-linked recessive, with no additional affected relatives reported beyond the four male probands. All reported variants are loss-of-function (truncating) and cluster in the last exon of FGF16, suggesting a common pathogenic mechanism.

Functional studies: Morpholino-mediated suppression of fgf16 in zebrafish embryos recapitulated metacarpal 4–5 fusion and digital hypoplasia, corroborating haploinsufficiency as the disease mechanism and supporting the human genotype–phenotype correlation (PMID:25333065).

No conflicting evidence has been reported. Collectively, truncating FGF16 variants in four unrelated male probands with supportive zebrafish phenocopy provide moderate clinical validity for FGF16 in syndactyly type 8.

Key Take-home: Truncating FGF16 mutations cause X-linked syndactyly type 8 (MF4), informing molecular diagnosis and genetic counseling.

References

• Birth defects research. Part A, Clinical and molecular teratology • 2014 • Further evidence for FGF16 truncating mutations as the cause of X-linked recessive fusion of metacarpals 4 / 5. PMID:24706454
• Molecular genetics & genomic medicine • 2014 • Identification of three novel FGF16 mutations in X-linked recessive fusion of the fourth and fifth metacarpals and possible correlation with heart disease. PMID:25333065

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