SPONDYLOCOSTAL DYSOSTOSIS

DLL3, MESP2, LFNG, HES7TBX6 AND RIPPLY2 GENE ANALYSIS IN SPONDYLOCOSTAL DYSOSTOSIS

The spondylocostal dysostoses (SCDs) are a group of disorders characterised by multiple vertebral segmentation defects, truncal shortening and rib abnormalities.  Disease-causing variants have been identified in the DLL3 (SCD type 1), MESP2 (SCD type 2), LFNG (SCD type 3), HES7 (SCD type 4) and TBX6 (SCD type 5) genes.

SCD type 1 is characterised by abnormal vertebral segmentation throughout the entire spine and misalignment of the ribs (Turnpenny et al. 2007 Dev Dyn. 236(6):1456-1474). Patients with SCD type 2 have abnormal vertebral segmentaton but the lumbar vertebrae are relatively mildly affected compared to those in the thoracic region.  SCD type 3 is characterised by severe shortening of the spine and non-progressive scoliosis of the cervical and thoracic spine (Sparrow et al. 2006 Am J Hum Genet 17:28-37). SCD type 4 is characterised by shortening of the spine, with multiple and contiguous vertebral segmentation defects involving all spinal regions, but mainly the thoracic spine. Ribs are irregularly aligned, with variable points of fusion along their length (Sparrow et al 2008 Hum Mol Genet 17(23):3761-3766).  SCD types 1, 2, 3 and 4 are inherited in an autosomal recessive manner.  Autosomal dominant SCD (SCD type 5) is caused by variants in the TBX6 gene (Sparrow et al 2013 Hum. Mol. Genet. 22: 1625-1631).

Segmentation defects of the vertebrae (SDV) are caused by aberrant somite formation during embryogenesis and result in irregular formation of the vertebrae and ribs.  ariants in the RIPPLY2 gene have been reported in patients with SDV  (McInerney-Leo et al 2015 Hum Mol Genet 24:1234-1242).

variants in the MESP2 gene have also been associated with spondylothoracic dysostosis (STD), characterised by shortening of the whole spine and a ‘crab-like’ appearance of the ribs as they fan out from their costovertebral origins (Cornier et al. 2008 Am J Hum Genet 82:1334-1341).

Clinical advice on genetic testing strategy can be obtained by emailing a spinal X-ray (or by sending a slide/CD/copy X-ray) to Dr Peter Turnpenny at the address below. 

Clinical Genetics Royal Devon & Exeter Hospital (Heavitree) Gladstone Road Exeter EX1 2ED UK Email. Peter.Turnpenny@nhs.net

The laboratory participates in the European Molecular Genetics Quality Network (EMQN) sequencing scheme.