Gene Mutations of the Three Ectodysplasin Pathway Key Players (EDA, EDAR, and EDARADD) Account for More than 60% of Egyptian Ectodermal Dysplasia: A Report of Seven Novel Mutations

Abstract

Ectodermal dysplasia (ED) is a diverse group of genetic disorders caused by congenital defects of two or more ectodermal-derived body structures, namely, hair, teeth, nails, and some glands, e.g., sweat glands. Molecular pathogenesis of ED involves mutations of genes encoding key proteins of major developmental pathways, including ectodysplasin (EDA) and wingless-type (WNT) pathways. The most common ED phenotype is hypohidrotic/anhidrotic ectodermal dysplasia (HED) featuring hypotrichosis, hypohidrosis/anhidrosis, and hypodontia. Molecular diagnosis is fundamental for disease management and emerging treatments. We used targeted next generation sequencing to study EDA, EDAR, EDARADD, and WNT10A genes in 45 Egyptian ED patients with or without hypohidrosis. We present genotype and phenotype data of 28 molecularly-characterized patients demonstrating genetic heterogeneity, variable expressivity, and intrafamilial phenotypic variability. Thirteen mutations were reported, including four novel EDA mutations, two novel EDARADD, and one novel EDAR mutations. Identified mutations congregated in exons encoding key functional domains. EDA is the most common gene contributing to 85% of the identified Egyptian ED genetic spectrum, followed by EDARADD (10%) and EDAR (5%). Our cohort represents the first and largest cohort from North Africa where more than 60% of ED patients were identified emphasizing the need for exome sequencing to explore unidentified cases.

Confirmation of a Phenotypic Entity for TSPEAR Variants in Egyptian Ectodermal Dysplasia Patients and Role of Ethnicity

“…Interestingly, the mother of P1, a heterozygous carrier of the (c.44delC; p.(Gly17Alafs*34)) variant, showed mild hypodontia in the form of a missing upper later incisor, see Figure 2 . Mild phenotypic features of heterozygous carriers of recessive alleles have previously been reported in carrier parents of ED patients harboring EDAR disease-causing variants [ 48 , 78 ], and similarly in a carrier father of a TA patient who carried a TSPEAR missense (c.1877T>C; p.(Phe626Ser)) variant [ 28 ]. Still, there is still the possibility that these parents carry a deep intronic TSPEAR variant, or alternatively, a variant of another TA-causing gene.…”

“…Having a relatively large number of phenotypically characterized ED patients from the same ethnic origin harboring the same disease-causing variant might propose a founder effect for c.1788-1790delAGA variant. We have previously shown that the HED mutation spectrum in Egyptians was different from that in other studied cohorts, whether this was due to the genes responsible for the phenotype or the incidence of founder mutations owing to high percentage of consanguineous marriages (~33–35%) among Egyptians [ 48 , 82 , 83 ]. Moreover, the recurrence of the c.1788-1790delAGA variant in eight ED patients shows the phenotypic heterogeneity of that variant.…”

“…We designed primers targeting TSPEAR exons which harbor the filtered variants of interest using Primer3 tool [ 47 ], Table 1 . PCR was carried out as previously described [ 48 ]. Reactions were sequenced according to manufacturer’s recommendation using the Big Dye Termination kit (Applied Biosystems, Waltham, MA, USA), and ABI Prism 3500 Genetic Analyzer (Applied Biosystems, Waltham, MA, USA).…”

Heterogeneity in biomarkers, mitogenome and genetic disorders of Arab population with special emphasis on large-scale whole-exome sequencing

“…familial Mediterranean fever (MEFV gene) [120], thiamine-responsive megaloblastic anemia (SLC19A2 gene) [121], cerebellar atrophy and developmental delay (PLA2G6, KIF1A and MOCS2A genes) [122], micro-/anophthalmia (VSX2, SOX2, and FOXE3 genes) [123], RAGdeficiency (RAG1 and RAG2 genes) [124], auriculocondylar syndrome (PLCB4, GNAI3, and EDN1 genes) [125], ectodermal dysplasia (EDA, EDAR, and EDARADD genes) [126], 3phosphoglycerate dehydrogenase deficiency (PHGDH gene) [127], carpenter syndrome (RAB23 gene) [128], disorders/differences of sex development (NR5A1, CYP19A1, AMH, AMHR2, WT1, HHAT, and FANCA and in the X-linked genes KDM6A and ARX genes) [129] and autosomal recessive polycystic kidney disease (PKHD1 gene) [130]. WES studies in Iraqi people revealed associated genes of epileptic encephalopathy (SLC13A5 gene) [131],…”

The EDA/EDAR/NF-κB pathway in non-syndromic tooth agenesis: A genetic perspective

“…In addition to TA, changes in the EDA/EDAR/NF-κB signaling pathway are also involved in other ectodermal structure development disorders, leading to ectodermal dysplasia (ED) ( Chassaing et al, 2006 ). Hypohidrotic ectodermal dysplasia (HED) is the most highly represented ED and is proven to be affected by mutations in EDA , EDAR , and EDARADD in most cases ( Cluzeau et al, 2011 ; Martínez-Romero et al, 2019 ; Ahmed et al, 2021 ). HED is often characterized by TA, sparse hair and eyelashes (hypotrichosis), abnormal swear glands (hypohidrosis), and dry thin skin ( Tariq et al, 2007 ; Mues et al, 2010 ; Bergendal et al, 2011 ) ( Figure 1 ).…”