A Novel Heterozygous c.1024A>G Variant in BMPR1B Causes Either Isolated Brachydactyly Type A4 With Variable...

BDA4 and BDD are rare autosomal dominant conditions characterized by distinct hand/foot malformations, including middle phalangeal shortening in the second and fifth digits and short, broad thumb terminal phalanges. While variations in BMPR1B have been implicated in the pathogenesis of BDA1 and BDA2, the genetic basis underlying BDA4 and BDD remains unclear. Clinical and radiographic phenotyping were performed to assess and diagnose the affected pedigree. Whole-exome sequencing and Sanger sequencing were employed to identify and validate the genetic variation. Bioinformatics analyses were conducted to evaluate the potential pathogenicity of the variant. Functional validation was carried out by assessing SMAD4 localization in BMP4-stimulated 293T transfectants. We present the first report of a rare Chinese Han pedigree exhibiting two distinct phenotypes: isolated BDA4 and incomplete BDA4 overlapping BDD, which were observed across two branches. All affected individuals harbored a novel heterozygous c.1024A>G (p.K342E) variant in BMPR1B, with bioinformatics analyses suggesting its pathogenic potential. Structural analyses indicated a conformational change within the kinase domain. Functional assays revealed a marked reduction in nuclear SMAD4 accumulation in transfectants expressing the mutant BMPR1B compared to the wild-type counterpart. This study provides the first evidence implicating BMPR1B as a pathogenic gene for both isolated BDA4 and incomplete BDA4 with BDD overlap. The BMPR1B c.1024A>G (p.K342E) variant disrupts kinase activity and impairs SMAD1/5/8 phosphorylation, which in turn suppresses downstream IHH expression and interferes with BMP-mediated skeletal patterning. We propose that the variant, in combination with genetic background and environmental factors, leads to the observed variable expressivity in this pedigree. Our findings expand the mutational spectrum of brachydactyly and underscore BMPR1B as a candidate gene for further investigation in brachydactyly pathogenesis.