Spondylocostal Dysostosis and Spondylothoracic Dysostosis via the MESP2 Gene

Spondylocostal Dysostosis (SCD) is characterized by abnormal segmentation of the vertebral column. Spondylothoracic Dysostosis (STD) (also referred as Jarcho-Levin syndrome) is a form of SCD (Turnpenny et al. 2003). Patients have short trunks with multiple vertebral defects and rib anomalies (Turnpenny et al. 2003). Four autosomal recessive forms (Types 1-4) and at least one autosomal dominant form of SCD are known. Pathogenic variants in the genes involved in the Notch signal pathway (MESP2, DLL3, LFNG and HES7) are associated with autosomal recessive SCD, and pathogenic variants in the TBX6 gene are responsible for autosomal dominant SCD. TBX6 is a regulator for Notch signal pathway and a member of the T-box DNA-binding domain family (Takemoto et al. 2011).

SCD Type 2 is an autosomal recessive condition caused by pathogenic variants in the MESP2 gene. MESP2 pathogenic variants have been reported in a number of Puerto Rican families with STD (Cornier et al. 2004; Cornier et al. 2008) as well as one Lebanese family with SCD (Whittock et al. 2004). Most of patients with Puerto Rican origin carry a homozygous nonsense variant p.Glu103*, likely indicating a founder effect. Affected children from the reported Lebanese family were homozygous for a frameshift variant (c.500_503dupACCG). At PreventionGenetics, we identified a homozygous whole MESP2 gene deletion in one SCD patient.

Pathogenic MESP2 variants were found in all studied 14 Puerto Rican spondylocostal dysostosis (SCD) families (Cornier et al. 2008). The percent of spondylothoracic dysostosis caused by pathogenic variants in MESP2 may vary by ethnic background. Probably <5% of SCD patients have causative variants in MESP2 (Sparrow et al. 2006).

At PreventionGenetics, we identified a homozygous whole MESP2 gene deletion in one SCD patient.

This test provides full coverage of all coding exons of the MESP2 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).