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Split hand-foot malformation (SHFM) is a congenital limb defect characterized by median ray deficiencies and variable expressivity with incomplete penetrance. In a Brazilian cohort of five SHFM patients, one individual harbored a recurrent heterozygous variant in MAP3K20, presenting with split foot, hand syndactyly and ectodermal features, expanding the phenotypic spectrum of MAP3K20-related SHFM (1/5 probands) (PMID:39648035). No additional familial segregation or de novo confirmation was reported.
To date, no functional studies have evaluated the impact of MAP3K20 variants on limb development. Separate work on MAP3K20 (ZAK) loss-of-function demonstrates a recessive myofibrillar myopathy in homozygous individuals and animal models, indicating divergent mechanistic effects distinct from SHFM (PMID:37427997). This suggests haploinsufficiency or dominant-negative effects in SHFM remain uncharacterized.
Gene–Disease AssociationLimitedSingle heterozygous proband with MAP3K20 variant; no segregation; functional data lacking Genetic EvidenceLimitedOne proband with heterozygous MAP3K20 variant; no segregation or de novo confirmation Functional EvidenceLimitedAbsence of functional assays for limb development; MAP3K20 LoF linked to unrelated myopathy indicating divergent mechanisms |