Split-hand/foot malformation - molecular cause and implications in genetic counseling

Area of Science:

• Genetics
• Developmental Biology
• Clinical Medicine

Background:

• Split-hand/foot malformation (SHFM) is a congenital limb malformation affecting the central rays of the autopod.
• It can occur as an isolated trait or part of a complex syndrome, with predominantly sporadic occurrences and variable inheritance patterns.

Purpose of the Study:

• To review the known molecular basis of isolated SHFM.
• To provide clinical and molecular information on SHFM abnormalities and discuss pathogenic pathways.
• To propose a diagnostic flowchart and address genetic counseling challenges.

Main Methods:

• Literature review of genetic loci and mutations associated with isolated SHFM.
• Analysis of clinical and molecular data for different SHFM types.
• Discussion of genetic pathways and diagnostic strategies.

Main Results:

• Seven chromosomal loci (SHFM1-6, SHFM/SHFLD) and three genes (TP63, WNT10B, DLX5) are implicated in isolated SHFM.
• Chromosomal rearrangements (deletions/duplications) are common, alongside point mutations.
• Current understanding identifies causative genetic changes in approximately 50% of SHFM patients.

Conclusions:

• Understanding SHFM pathogenesis is advancing, enabling genetic diagnosis in about half of affected individuals.
• A diagnostic flowchart is proposed to guide molecular genetic testing for SHFM.
• Genetic counseling for SHFM, particularly sporadic cases, remains complex.