Skin and Connective Tissue Disorders Panel

Skin and connective tissue diseases are a group of disorders that can be inherited or acquired, and are characterized by abnormal function in one or more elements of connective tissue including collagen, elastin or mucopolysaccharides. Type VII collagen for example, is the main component of anchoring fibrils, and it plays a major role in stabilizing the skin. Variants in this gene disrupt the production of type VII collagen which then impairs its ability to anchor the dermis to the epidermis leading to skin separation (Pfendner and Lucky. 2018. PubMed ID: 20301481).

This panel includes genes associated with a variety of skin disorders (DeStefano and Christiano. 2014. PubMed ID: 25274756). This panel offers testing for the following conditions: congenital ichthyosis, xeroderma pigmentosum, dyskeratosis congenita, cutis laxa and epidermolysis bullosa. Skin and connective tissue disorders are genetically heterogeneous and can occur in an autosomal dominant (AD), autosomal recessive (AR) or X-linked form.

See individual gene test descriptions for more information on molecular biology of gene products and spectra of pathogenic variants.

Pathogenic variants in the COL7A1 gene can be found in ~95% of Dystrophic Epidermolysis Bullosa patients diagnosed via skin biopsy (Kern et al. 2006. PubMed ID: 16484981; Pfendner and Lucky. 2018. PubMed ID: 20301481). Only about 10 large genome rearrangements involving COL7A1 have been reported. In addition, one Dystrophic Epidermolysis Bullosa case with maternal COL7A1 Uniparental Disomy was reported (Fassihi et al. 2006. PubMed ID: 16710310; Human Gene Mutation Database).

In a retrospective study, all 76 studied patients diagnosed with severe Junctional Epidermolysis Bullosa based on skin biopsies, were found to have pathogenic variants in one of the LAMA3, COL17A, LAMB3, or LAMC2 genes (Hammersen et al. 2016. PubMed ID: 27375110). Pathogenic variants in ITGB4, PLEC, and ITGA6 account for ~60%, 15%, and 5%, respectively, of pathogenic variants reported in Epidermolysis Bullosa with Pyloric Atresia cases (Pfendner et al. 2017. PubMed ID: 20301336).

KRT5 and KRT14 pathogenic variants together account for ~75% of Epidermolysis Bullosa Simplex cases diagnosed with skin biopsy (Arin et al. 2010. PubMed ID: 20199538; Bolling et al. 2011. PubMed ID: 21375516). The percentage of cases due to each gene is approximately equal.

Ashton et al. found 17 different loss-of-function FERMT1 pathogenic variants in 41 clinically diagnosed Kindler syndrome families (Ashton et al. 2004. PubMed ID: 14987263). Several large del/dups have also been reported involving the FERMT1 gene (Chmel et al. 2015. PubMed ID: 26083552).

In one study, the pathogenic variant (c.2038_2039delTG) in the JUP gene was detected in all 19 Naxos patients of Greek origin (McKoy et al. 2000. PubMed ID: 10902626).

Pathogenic variants in the DSP gene were found in 16% of patients with clinical diagnosis of Arrhythmogenic right ventricular dysplasia (Bauce et al. 2005. PubMed ID: 15941723).

The proportion of Xeroderma Pigmentosum (in the US) that is attributed to pathogenic variants in DDB2, ERCC2, ERCC3, ERCC5, POLH, XPA and XPC are 3%, 28%, 1%, 3%, 7%, 9%, 43%, respectively. Causative variants in the XPA gene are more common in Japan and rare in the United States and Europe (Kraemer et al. 2016. PubMed ID: 20301571).

Pathogenic variants in ERCC1 and ERCC4 are rare, but have been reported in individuals affected with severe XP/Cockayne syndrome (Kashiyama et al. 2013. PubMed ID: 23623389) and cerebro-oculo-facio-skeletal syndrome (COFS) (Jaspers et al. 2007. PubMed ID: 17273966).

Only a few large del/dups involving the COL17A1, DSP, ITGB4, LAMB3, LAMC2, KRT14, PLEC, LAMA3, and KRT5 genes have been reported (Huber et al. 2002. PubMed ID: 11851893; Norgett et al. 2006. PubMed ID: 16628197; Schumann et al. 2013. PubMed ID: 23496044; Pulkkinen et al. 1995. PubMed ID: 7550237; Posteraro et al. 2004. PubMed ID: 15373767; Kopecková et al. 2016. PubMed ID: 26707537; Vahidnezhad et al. 2017. PubMed ID: 28830826; Has et al. 2017. PubMed ID: 28576738; Human Gene Mutation Database).

No large del/dups have been reported involving the DST, ITGA6, JUP, PKP1 genes.

For additional gene sensitivities, please refer to individual test descriptions.

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

This panel typically provides 94.6% 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).

Exon 3 of the FLG gene is not analyzed due to high paralogy in this region.

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).