BHLHA9 – mesoaxial synostotic syndactyly with phalangeal reduction

Mesoaxial synostotic syndactyly with phalangeal reduction (MSSD) is an extremely rare autosomal recessive limb malformation characterized by fusion of the third and fourth digits with axial phalangeal reduction. Pathogenic variants in BHLHA9, a basic helix–loop–helix transcription factor, have been reported in multiple consanguineous and nonconsanguineous families, establishing it as the causative gene for MSSD.

To date, four unrelated families comprising eight affected individuals have been described. A consanguineous Pakistani pedigree segregating MSSD in an autosomal recessive manner yielded five homozygous missense cases (c.311T>C (p.Ile104Thr)) (PMID:29263794). Subsequent studies reported a homozygous insertion–deletion (c.252_270delinsGCA; p.Phe85GlufsTer108) (PMID:30107244) and a homozygous frameshift (c.409delC; p.His137ThrfsTer61) (PMID:31152918). A nonconsanguineous singleton presented compound heterozygous loss-of-function alleles (c.226A>T (p.Lys76Ter) and c.269G>C (p.Arg90Pro)) (PMID:31912643), confirming autosomal recessive inheritance.

Variants span missense, frameshift, and in-frame indels affecting the bHLH domain critical for DNA binding. The recurrent missense variant c.311T>C (p.Ile104Thr) is located in a conserved helix and alters a hydrophobic residue essential for dimerization.

The phenotypic spectrum includes central syndactyly with phalangeal reduction, occasionally accompanied by fifth-finger clinodactyly (HP:0004209) and postaxial polydactyly (HP:0100259) (PMID:31152918). No extracutaneous or syndromic features have been observed.

Functional knockout of Bhlha9 in mice produces limb syndactyly and aberrant apical ectodermal ridge formation, with dysregulated expression of AER genes including Trp63 (PMID:28324176). In vitro assays confirm Bhlha9’s regulatory role on TP63, consistent with a loss-of-function mechanism.

Collectively, robust segregation in four families, diverse biallelic variant classes, and concordant functional data support a Strong gene–disease association for BHLHA9 and mesoaxial synostotic syndactyly with phalangeal reduction. Genetic testing for BHLHA9 should be incorporated into diagnostic workflows for congenital syndactylies.

References

• Human Genome Variation • 2017 • A novel homozygous missense mutation in BHLHA9 causes mesoaxial synostotic syndactyly with phalangeal reduction in a Pakistani family. PMID:29263794
• European Journal of Medical Genetics • 2019 • A novel insertion and deletion mutation in the BHLHA9 underlies polydactyly and mesoaxial synostotic syndactyly with phalangeal reduction. PMID:30107244
• European Journal of Medical Genetics • 2019 • A novel frameshift variant in BHLHA9 underlies mesoaxial synostotic syndactyly associated with postaxial polydactyly. PMID:31152918
• American Journal of Medical Genetics Part A • 2020 • First case of compound heterozygous BHLHA9 variants in mesoaxial synostotic syndactyly with phalangeal reduction. PMID:31912643
• Journal of Bone and Mineral Metabolism • 2018 • Bhlha9 regulates apical ectodermal ridge formation during limb development. PMID:28324176

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