WNT10B and split hand-foot malformation 6

Split hand-foot malformation 6 (SHFM6) is an autosomal recessive limb disorder characterized by median clefts of the hands and feet, severe digital hypoplasia, polydactyly and flexion contractures. Biallelic loss-of-function variants in WNT10B underlie split hand-foot malformation 6, which to date has been reported in only three unrelated pedigrees (PMID:31421290).

In a case series of three autosomal recessive families, the index of family 1 was homozygous for c.676C>T (p.Arg226Ter) causing a premature stop codon; family 2 harbored a homozygous splice acceptor variant c.338-1G>C; and family 3 presented a compound heterozygous genotype combining the nonsense c.676C>T (p.Arg226Ter) and a missense p.Gln86Pro (PMID:31421290).

Segregation analysis showed that unaffected parents and siblings were heterozygous carriers, consistent with autosomal recessive inheritance; no additional affected relatives beyond the index cases were reported.

Clinically, affected individuals exhibit more severe foot malformations than hand defects and variably present with polydactyly (HP:0010442), severe flexion digital contractures, and phalangeal dysplasia.

The pathogenic mechanism is presumed loss-of-function through nonsense-mediated decay or aberrant splicing of WNT10B, a key morphogen in limb bud patterning; no dedicated functional assays for SHFM6 have been reported.

Collectively, these data support a Moderate clinical validity for the WNT10B–SHFM6 relationship. Genetic testing for WNT10B should be considered in patients with split hand-foot malformation consistent with recessive inheritance.

References

• European journal of medical genetics • 2020 • A classification system for split-hand/ foot malformation (SHFM): A proposal based on 3 pedigrees with WNT10B mutations. PMID:31421290

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