Mesoaxial Synostotic Syndactyly with Phalangeal Reduction (MSSD) via the BHLHA9 Gene

Mesoaxial synostotic syndactyly with phalangeal reduction (MSSD) (syndactyly type IX) is a rare nonsyndromic digit anomaly. The clinical features include mesoaxial osseous synostosis at the metacarpal level, reduction of one or more phalanges, hypoplasia of distal phalanges of preaxial and postaxial digits, clinodactyly of fifth fingers, and preaxial fusion of toes (Malik et al. 2014).

MSSD is an autosomal recessive disorder. It is caused by pathogenic variants in the BHLHA9 gene on chromosome17p13. The BHLHA9 gene contains a single exon coding for a class II basic helix-loop-helix transcription factor which regulate embryo development. All pathogenic variants reported to date for MSSD are missense variants. A homozygous pathogenic variant in BHLHA9 also causes complex camptosynpolydactyly (CCSPD) (Phadke et al. 2016). In addition, telomeric duplications of 17p13 involving BHLHA9 are associated with a form of split-hand/foot malformation with long bone deficiency (SHFLD3) (Klopocki et al. 2012).

There have only been three pathogenic variants reported to date for Mesoaxial Synostotic Syndactyly with Phalangeal reduction (Malik et al. 2014).

This test provides full coverage of all coding exons of the BHLHA9 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).