Whole-genome sequencing identifies HOXD13 variants in syndactyly pedigrees.

BACKGROUND

Syndactyly demonstrates high genetic heterogeneity, with many cases lacking molecular diagnosis despite known HOXD13 involvement, suggesting conventional methods may miss a sub-class of variants.

RESULTS

Integrated whole-exome sequencing (WES) and whole-genome sequencing (WGS) analyses identified three novel HOXD13 variants: one 2-bp heterozygous deletion c.314_315del, p.(Lys105ArgfsTer131), and two heterozygous polyalanine expansions (PAE): c.186_212dup, p.(Ala63_Ala71dup) and c.203_204insAGCAGCGGCGGCTGCGGCGGCGGC, p.(Ala64_Ala71dup). WGS successfully identified cryptic variants undetectable by WES technology.

CONCLUSIONS

Our findings demonstrate the utility of WGS in identifying HOXD13 variants and support the genotype-phenotype correlation of polyalanine expansions in limb malformations, providing new insights for molecular diagnosis.