Ectodermal Dysplasia Panel

Ectodermal dysplasia (ED) is a clinically and genetically heterogeneous disorder characterized by abnormal development of hair, teeth, nail or sweat glands (Visinoni et al. 2009). ED can be clinically divided into more than 150 subtypes. Hypohidrotic ectodermal dysplasia (HED) is characterized by hypodontia, hypohidrosis and hypotrichosis. The major clinical signs are thin and dry scalp hair, eyelashes and eyebrows, reduced ability to sweat, and congenital missing or abnormal formed teeth. Some patients may have abnormal craniofacial features such as prominent forehead, saddle-back nose, and protruding lips (Visinoni et al. 2009; Wright et al. 2014). HED is currently known to be caused by pathogenic variants in the EDA, EDAR, EDARADD, WNT10A, KRT85 and NECTIN1 genes (Cluzeau et al. 2011; Shimomura et al. 2010; Sözen et al. 2001).

Pathogenic variants in EDA cause X-linked HED, while pathogenic variants in EDAR, WNT10A, and EDARADD cause autosomal dominant and recessive forms of ectodermal dysplasia and tooth agenesis. In general, female carriers of EDA pathogenic variants and males and females with autosomal dominant HED have mild clinical features. A variety of pathogenic variants in EDA, EDAR, WNT10A, and EDARADD account for 55-60%, 16%, 15-20% and 1-2% of pathogenic variants identified in HED patients, respectively (Cluzeau et al. 2011). Truncating EDAR pathogenic variants exhibit loss of function, while heterozygous missense pathogenic variants in the functional domain of the EDAR gene may have dominant negative effect (van Der Hout et al. 2008).

The EDA, EDAR, and EDARADD proteins are the key proteins in the EDA-EDAR-EDARADD and the NF-kappa-B pathways, which play a prominent role in the development of ectodermal structures such as hair follicles, sweat glands, and teeth (Cluzeau et al. 2011; Wright et al. 2014). The WNT10A protein is a secreted signaling protein and serves as a ligand for members of the frizzled family of seven transmembrane receptors which are involved in regulation of cell fate and patterning during embryogenesis.

Pathogenic variants in the KRT85 gene cause autosomal recessive ectodermal dysplasia 4, hair/nail type, which is characterized by congenital abnormal development of the hair and nails (Naeem et al. 2006; Shimomura et al. 2010). KRT85 protein coded by KRT85 belongs to the type II keratin gene family, a basic protein which heterodimerizes with type I keratins to form hair and nails. To date, only one small homozygous truncating pathogenic variant (c.1448_1449delCT, p.Pro483Argfs*18) was identified in two affected consanguineous Pakistani families (Shimomura et al. 2010 and Human Gene Mutation Database).

Pathogenic variants in the NECTIN1 gene (also known as PVRL1) cause autosomal recessive cleft lip/palate-ectodermal dysplasia (CLPED1, also known as Zlotogora-Ogur syndrome and Margarita Island ectodermal dysplasia), autosomal recessive Orofacial cleft 7, as well as non-syndromic cleft of the lip/palate. NECTIN1 protein coded by NECTIN1 is a member of the immunoglobin (Ig) superfamily and plays a role in cell–cell adhesion. To date, more than 10 unique pathogenic variants have been reported. They include: missense (7), nonsense (2), small del/dup (3) and splicing (1). No large deletions/duplications have been reported (Sözen et al. 2001; Sözen et al. 2009; Avila et al. 2006, Huma Gene Mutation Database). The 554G>A, p.Trp185* variant is commonly found in non-syndromic sporadic clefting cases in Northern Venezuela, with a carrier frequency of 1 in 26 of the native population in that particular region (Sözen et al. 2001). In addition, heterozygous carriers of the 554G>A, p.Trp185* variant often have a broad and flat upper lip (Avila et al. 2006).

Mutations in EDA, EDAR, WNT10A and EDARADD together are responsible for ~90% of clinically diagnosed HED patients (Cluzeau et al. 2011). Due to limited publications, clinical sensitivity for the KRT85 and NECTIN1 genes is currently unknown. Analytical sensitivity may be high as the only reported pathogenic variants are detectable by sequencing.

Gross deletions account for ~7% of pathogenic variants found in the EDA gene (Cluzeau et al. 2011; Orstavik et al. 2007; Human Gene Mutation Database). Only one large deletion was reported in each of the EDAR and WNT10A genes (Griggs et al. 2009; Iglesias et al. 2014), and no large deletions or duplications involving KRT85, NECTIN1. and EDARADD have been reported to date (Human Gene Mutation Database).

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).