Ehlers-Danlos syndrome Musculocontractural Type 1 via the CHST14 Gene

Pathogenic variants in CHST14 have been reported in patients with adducted thumb-clubfoot syndrome (ATCS) as well as musculocontratural Ehlers-Danlos syndrome (MCEDS). These two disorders are considered a single clinical entity with variable expression and different presentations based on the patients' ages. Ehlers-Danlos syndrome (EDS) pertains to a clinically and genetically heterogeneous group of heritable connective tissue disorders that mainly affect the skin, joints, ligaments, blood vessels, and internal organs (Byers and Murray. 2012. PubMed ID: 23154631). The clinical hallmarks of EDS include skin hyperelasticity, joint hypermobility, and pronounced tissue fragility. Clinical features of CHST14-related disorders include joint dislocations and deformities; skin hyperextensibility, bruisability, and fragility; craniofacial features; multiple congenital contractures; and congenital defects in cardiovascular, gastrointestinal, renal, ocular, and central nervous systems (Miyake et al. 2010. PubMed ID: 20533528; Shimizu et al. 2011. PubMed ID: 21744491).

CHST14-related disorders are inherited in an autosomal recessive manner. Causative variants reported in this gene to date are missense, nonsense, small frameshift deletions/duplications and indels resulting in premature protein termination, and a larger 25 bp deletion (Human Gene Mutation Database).

The CHST14 gene encodes dermatan 4-O-sulfotransferase 1 (D4ST1) which transfers active sulfate to N-acetyl-D-galatosamine (GalNAc) residues of dermatan sulfate.

Due to the low incidence of this disorder clinical sensitivity cannot be precisely estimated. However, all coding and non-coding regions of the CHST14 gene that harbor causative variants reported in the Human Gene Mutation Database (http://www.hgmd.cf.ac.uk/) as of 06/28/2019 are covered in this test.

Copy number variants (CNVs) are also detected from NGS data. We utilize a CNV-calling algorithm that compares mean read depth and distribution for each target in the test sample against multiple matched controls. Neighboring target read depth and distribution and zygosity of any variants within each target region are used to reinforce CNV calls. All CNVs are confirmed using another technology such as aCGH, MLPA, or PCR before they are reported.

This test provides full coverage of all coding exons of the CHST14 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).