Spondylocostal Dysostosis Panel

Congenital vertebral malformation (CVM) is a birth defect of the vertebral column with an estimated prevalence of 0.13-0.51 per 1000 live births (Giampietro et al. 2009. PubMed ID: 19154516). It can be further divided into several groups such as Klippel-Feil syndrome and Spondylocostal Dysostosis. Fetal ultrasound can detect vertebrae defects as early as 13 weeks gestation (Turnpenny et al. 2017. PubMed ID: 20301771).

Spondylocostal Dysostosis (SCD) involves segmentation defect(s) of the vertebrae. Patients with SCD have short trunks with multiple vertebral defects and rib anomalies (Turnpenny et al. 2017. PubMed ID: 20301771). SCD is further divided into six sub-groups caused by pathogenic variants in the DLL3, MESP2, LFNG, HES7, TBX6, and RIPPLY2 genes, respectively.

Molecular genetic testing is advantageous to establish a proper diagnosis for individuals with CVM or SCD.

Pathogenic variants in the genes involved in the Notch signal pathway (MESP2, DLL3, LFNG, HES7 and RIPPLY2) are associated with autosomal recessive SCD, and pathogenic variants in the TBX6 gene are responsible for autosomal dominant SCD. TBX6 is a regulator for the Notch signal pathway and a member of the T-box DNA-binding domain family (Takemoto et al. 2011. PubMed ID: 21331042).

About 5 unique pathogenic variants in the MESP2 gene have been reported. They are: missense (1), nonsense (2), and frameshift (1) (Whittock et al. 2004. PubMed ID: 15122512; Cornier et al. 2008. PubMed ID: 18485326; Human Gene Mutation Database). The MESP2 c.307G>T (p.Glu103*) variant was identified in 12 out of 14 studied Puerto Rican families (Cornier et al. 2008. PubMed ID: 18485326). At PreventionGenetics, we identified a homozygous whole MESP2 gene deletion in one SCD patient.

Almost 20 unique DLL3 pathogenic variants have been reported. They are: truncating (85%) and missense (15%), respectively. No large deletions/duplications have been reported (Turnpenny et al. 2003. PubMed ID: 12746394).

Only 1 missense causative variant was reported in the LFNG gene (Sparrow et al. 2006. PubMed ID: 16385447). In addition, a large de novo duplication involving LFNG and other 8 genes was reported in a patient with Asperger Syndrome (Vulto-van Silfhout et al. 2012. PubMed ID: 22822384).

About 5 unique pathogenic variants in the HES7 gene (3 missense and 1 frameshift) were identified (Sparrow et al. 2013. PubMed ID: 23897666; Human Gene Mutation Database). The c.400_409dupAAACCGCCCC (p.Arg137Glnfs*42) variant was identified in 3 Arab families from the same geographical location with spondylocostal dysostosis and dextrocardia with situs inversus (Sparrow et al. 2013. PubMed ID: 23897666).

Only two RIPPLY2 truncating variants and one splicing variant were reported in three patients from two families with autosomal recessive vertebral segmentation defects or Klippel–Feil syndrome (Karaca et al. 2015. PubMed ID: 26238661; McInerney-Leo et al. 2015. PubMed ID: 25343988).

No large pathogenic deletions/duplications have been reported in the MESP2, HES7, DLL3 and RIPPLY2 genes (Human Gene Mutation Database).

To date, ~30 TBX6 variants have been listed in HGMD database; they are missense (10), nonsense (3), frameshift (8), splicing and regulatory (2) and large deletions/duplications (19). Large duplications involving TBX6 were found in one patient with tetralogy of fallot, one with scoliosis, and one with autism, respectively (Silversides et al. 2012. PubMed ID: 22912587; O'Roak et al. 2012. PubMed ID: 22495309; Al-Kateb et al. 2014. PubMed ID: 24458548). Two large deletions involving TBX6 were reported in one patient with Mullerian aplasia and another with scoliosis , however, their pathogenicity related to scoliosis need to be further investigated (Sandbacka et al. 2013. PubMed ID: 23954021; Al-Kateb et al. 2014. PubMed ID: 24458548). The deletions/duplications were reported to be de novo in some of these cases (O'Roak et al. 2012. PubMed ID: 22495309; Verbitsky et al. 2019. PubMed ID: 30578417).

See individual gene summaries for more information about molecular biology of gene products and spectra of pathogenic variants.

Pathogenic MESP2 variants were found in all studied 14 Puerto Rican SCD families (Cornier et al. 2008. PubMed ID: 18485326). DLL3 pathogenic variants were found in 10 out of 12 studied families (Turnpenny et al. 2003. PubMed ID: 12746394). In one study, TBX6 pathogenic variants were reported to account for ~11% of congenital scoliosis cases (Wu et al. 2015. PubMed ID: 25564734). In a retrospective study of 73 patients with segmentation defect of the vertebrae, pathogenic variants were detected in 80% of patients meeting the criteria of spondylocostal dysostosis (Lefebvre et al. 2018. PubMed ID: 29459493).

Due to limited publication of case studies, clinical sensitivity for LFNG, RIPPLY2, and HES7 cannot be estimated.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes 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 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).