Connective Tissue Disorders Panel

Connective tissue disorders mainly involve three systems: musculoskeletal, ocular and cardiovascular. Connective tissue disorders include many conditions such as Ehlers-Danlos syndrome (EDS) and Marfan syndrome. Due to clinical overlap with other syndromes and disorders, diagnosis can be challenging (Armon and Bale. 2012. PubMed ID: 22916581; Vanakker et al. 2015. PubMed ID: 26002060).

This panel includes genes associated with variety of genetic conditions such as Ehlers-Danlos syndrome (EDS), cutis laxa, Marfan syndrome, Loeys-Dietz syndrome, Stickler syndrome, frontometaphyseal dysplasia, Larsen syndrome, and newly identified genes involving joint problems. Connective disorders are genetically heterogenous and can be inherited in an autosomal dominant (AD), autosomal recessive (AR), and X-linked (XL) manner.

See also individual gene test descriptions for information on clinical features, molecular biology of gene products, and spectra of pathogenic variants.

This test is predicted to detect a disease-causing variant in approximately 30% of individuals with familial thoracic aortic aneurysm and dissection (TAAD) (Milewicz and Regalado. 2017. PubMed ID: 20301299). This test is predicted to detect pathogenic variants in 22%-35% of Supravalvar aortic stenosis patients that do not have gross deletions in the ELN gene (Metcalfe et al. 2000. PubMed ID: 11175284; Micale et al. 2010. PubMed ID: 19844261). Deletions of 7q11.23 which encompasses the ELN gene are commonly found in individuals with Williams syndrome. This NGS test will detect copy number changes in the ELN gene.

COL3A1 pathogenic variants have been identified in approximately 95% of individuals with Ehlers-Danlos Syndrome (EDS) IV (Byers. 2019. PubMed ID: 20301667). COL5A1 or COL5A2 pathogenic variants have been identified in at least 50% of affected individuals with classic EDS (Malfait et al. 2018. PubMed ID: 20301422).

Causative variants in COL2A1 and COL11A1 account for 80-90% and 10-20% of variants identified in autosomal dominant Stickler Syndrome (STL), respectively; causative variants in COL11A2 account for rare dominant cases. Causative variants in COL9A1, COL9A2, COL9A3, LOXL3, and LRP2 have been found only in a few families affected with autosomal recessive inheritance of STL syndrome (Robin et al. 2017. PubMed ID: 20301479; Schrauwen et al. 2014. PubMed ID: 23992033; Alzahrani et al. 2015. PubMed ID: 25663169).

The sensitivity for large deletions and duplications in the COL2A1, COL11A2, COL9A1, COL9A2, and COL9A3 genes is probably low, because only a few cases with large deletions and insertions involving these five genes have been reported (Van Der Hout et al. 2002. PubMed ID: 12204008; Human Mutation Database). However, large deletions in the COL11A1 gene were detected in six unrelated Stickler syndrome patients by MLPA (Vijzelaar et al. 2013. PubMed ID: 23621912).

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

This panel typically provides 97.7% 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. TNXB exons 32-44 are not analyzed due to multiple close copies of these sequences in the genome. If full coverage of TNXB is needed, we can offer that enhancement for an additional cost.

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).