A Confirmatory Case of Severe Spondylocostal Dysostosis Caused by Biallelic Loss-of-Function of DMRT2

Spondylocostal dysostosis (SCDO) is a rare genetic disorder characterized by abnormal development of the axial skeleton, resulting in malformations of the vertebrae and ribs that often impair lung development and lead to significant respiratory morbidity. SCDO is thought to arise from defects in the paraxial presomitic mesoderm, an embryonic tissue that forms the vertebral column and ribs. Pathogenic variants in DLL3, MESP2, LFNG, HES7, TBX6, and RIPPLY2 have been identified in various SCDO subtypes. In addition, a single case of a lethal SCDO-like phenotype caused by a homozygous start-loss variant in DMRT2 has been reported. DMRT2 encodes a transcription factor expressed in the dermomyotome during early somite formation in mice. Here, we describe a newborn with severe costovertebral malformations and dysmorphic features, in whom exome sequencing identified a homozygous loss-of-function variant in DMRT2. The phenotype strikingly overlaps the previous report, further supporting the role of biallelic pathogenic DMRT2 variants in a severe SCDO-like disorder. Notably, our patient also exhibited thymic aplasia and immunodeficiency. A review of the exome sequencing data did not reveal any variant that could account for the immunodeficiency. These features have not been previously associated with SCDO, suggesting a potential phenotypic expansion.