Spondylocostal dysostosis (SCDO) is a rare genetic disease defined by vertebral and rib deformities, shortened thorax, spinal deformity, and respiratory issues due to pulmonary hypoplasia. It arises from aberrant maturation of the paraxial presomitic mesoderm. SCDO shows locus heterogeneity with six described subtypes (SCDO1–6) related to DLL3, MESP2, LFNG, HES7, TBX6, and RIPPLY2, respectively.
Exome sequencing (ES) was performed on the proband’s DNA. FASTQ files were processed through the Geneyx Analysis software, where alignment and variant calling were performed using Illumina DRAGEN, and the resulting VCFs were thoroughly annotated with the Geneyx Analysis platform for filtering and interpretation. Immunological evaluation included flow cytometry of peripheral blood mononuclear cells.
The proband was a male infant, firstborn to related non-Ashkenazi Jewish parents, delivered at 36+6 weeks. At birth, he was presented with respiratory distress necessitating intubation and was found to have multiple skeletal deviations, alongside dysmorphic features, inguinal hernias, thymic aplasia, cardiac defects, and bilateral duplicated kidneys. Laboratory tests confirmed substantial lymphopenia. He developed serious cytomegalovirus pneumonitis and bacterial infections, leading to demise at 3 months of age. The ES found a homozygous DMRT2 frameshift change (c.129delC, p.Asp43fs*75), absent from population databases and predicted to cause biallelic loss of function, classified as likely pathogenic per ACMG guidelines. Notably, the ES revealed no alternative explanation for the skeletal findings.
The DMRT2 gene codes a transcription factor essential for vertebral and rib development, with studies in animal models demonstrating its critical role in somitogenesis and skeletal morphogenesis. While only one case of a homozygous start-loss change in DMRT2 had previously been reported, associated with lethal spondylocostal dysostosis, the authors reported a second case involving a male neonate with similar severe skeletal malformations. The identified biallelic frameshift variant and the close phenotypic overlap with the prior case strongly support the pathogenicity of DMRT2 deficiency in humans. Furthermore, the patient was also presented with profound immunodeficiency because of thymic aplasia, a feature not previously linked to DMRT2, suggesting a possible expansion of the phenotype. As no alternative genetic explanation was identified, the authors propose that thymic defects may represent an underrecognized effect of DMRT2 loss. These findings strengthen the genotype-phenotype association and highlight the importance of including DMRT2 in exome-based skeletal dysplasia panels.
