Mesoaxial synostotic syndactyly with phalangeal reduction caused by same homozygous BHLHA9 variant in a non-consanguineous Indian couple

BHLHA9 gene encodes Basic helix-loop-helix (bHLH) proteins which are transcription factors that regulate embryonic development specifically the limbs by regulating the apical ectodermal ridge. Pathogenic variants in this gene are associated with Mesoaxial synostotic syndactyly with phalangeal reduction (MSSD), Complex camptosynpolydactyly and Split-hand/foot malformation with long bone deficiency-3 (SHFLD3). Purpose To present a rare case of Mesoaxial synostotic syndactyly with phalangeal reduction (MSSD) associated with a same homozygous BHLHA9 variant in a non-consanguineous couple, highlighting the phenotypic spectrum of the disorder, emphasizing the importance of genetic testing in clarifying inheritance patterns in rare limb malformations and underscoring the role of exome sequencing in diagnosis. Methods We evaluated a non-consanguineous couple, both of whom presented with syndactyly and oligodactyly. Detailed clinical examination and radiographic assessment were performed to document limb abnormalities. Whole-exome sequencing was carried out, and variant interpretation was performed according to ACMG/AMP guidelines. Results Exome sequencing identified a homozygous likely pathogenic variant, c.252_270delinsGCA (p.Phe85Glufs*108) in BHLHA9 gene [NM_001164405.2] associated with MSSD. This frameshift variant is predicted to disrupt the normal protein function. The variant has previously been described in two affected individuals from a consanguineous Pakistani family. Conclusions This report describes a rare occurrence of MSSD associated with the same homozygous BHLHA9 variant in a non-consanguineous Indian couple, with recurrence in the offspring and variable phenotypic expressivity.