Brachyolmia, dental anomalies and short stature (DASS): Phenotype and genotype analyses of Egyptian and Pakistani patients

Brachyolmia is a heterogeneous group of developmental disorders characterized by a short trunk, short stature, scoliosis, and generalized platyspondyly without significant deformities in the long bones. DASS (Dental Abnormalities and Short Stature), caused by alterations in the LTBP3 gene, was previously considered as a subtype of brachyolmia.The present study investigated three unrelated consanguineous families (A, B, C) with Brachyolmia and DASS from Egypt and Pakistan. In our Egyptian patients, we also observed hearing impairment. Exome sequencing was performed to determine the genetic causes of the diverse clinical conditions in the patients. Exome sequencing identified a novel homozygous splice acceptor site variant (LTBP3:c.3629-1G > T; p. ?) responsible for DASS phenotypes and a known homozygous missense variant (CABP2: c.590T > C; p.Ile197Thr) causing hearing impairment in the Egyptian patients. In addition, two previously reported homozygous frameshift variants (LTBP3:c.132delG; p.Pro45Argfs*25) and (LTBP3:c.2216delG; p.Gly739Alafs*7) were identified in Pakistani patients.This study emphasizes the vital role of LTBP3 in the axial skeleton and tooth morphogenesis and expands the mutational spectrum of LTBP3. We are reporting LTBP3 variants in seven patients of three families, majorly causing brachyolmia with dental and cardiac anomalies. Skeletal assessment documented short webbed neck, broad chest, evidences of mild long bones involvement, short distal phalanges, pes planus and osteopenic bone texture as additional associated findings expanding the clinical phenotype of DASS. The current study reveals that the hearing impairment phenotype in Egyptian patients of family A has a separate transmission mechanism independent of LTBP3

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

Ectodermal dysplasia (ED) are hereditary disorders characterized by the disturbance of the ectodermal development of at least two of four ectodermal tissues: teeth, hair, nails and sweat glands. Clinical classification of ED is challenged by overlapping features, variable expressivity, and low number of patients, hindering full phenotypic spectrum identification. Disease-causing variants in elements of major developmental pathways, e.g., Ectodysplasin/NFκB, Wnt, and Tp63 pathways, have been identified in fewer than half of ED phenotypes. Whole-exome sequencing (WES) was performed for ten Egyptian ED patients presenting with tooth agenesis, normal sweating, scalp hypotrichosis, and sharing characteristic facial features. WES was followed by in silico analysis of the effects of novel detected genetic variants on mRNA and protein structure. The study identified four novel rare pathogenic and likely pathogenic TSPEAR variants, a gene which was recently found to be involved in ectodermal organogenesis. A novel in-frame deletion recurred in eight patients from six unrelated families. Comparing our cohort to previously reported TSPEAR cohorts highlighted the influence of ethnicity on TSPEAR phenotypic affection. Our study expands the clinical and mutational spectrum of the growing TSPEAR associated phenotypes, and pinpoints the influence of WES and in silico tools on identification of rare disease-causing variants

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

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

Deleterious Variants in WNT10A, EDAR, and EDA Causing Isolated and Syndromic Tooth Agenesis: A Structural Perspective from Molecular Dynamics Simulations

The dental abnormalities are the typical features of many ectodermal dysplasias along with congenital malformations of nails, skin, hair, and sweat glands. However, several reports of non-syndromic/isolated tooth agenesis have also been found in the literature. The characteristic features of hypohidrotic ectodermal dysplasia (HED) comprise of hypodontia/oligodontia, along with hypohidrosis/anhidrosis, and hypotrichosis. Pathogenic variants in EDA, EDAR, EDARADD, and TRAF6, cause the phenotypic expression of HED. Genetic alterations in EDA and WNT10A cause particularly non-syndromic/isolated oligodontia. In the current project, we recruited 57 patients of 17 genetic pedigrees (A-Q) from different geographic regions of the world, including Pakistan, Egypt, Saudi Arabia, and Syria. The molecular investigation of different syndromic and non-syndromic dental conditions, including hypodontia, oligodontia, generalized odontodysplasia, and dental crowding was carried out by using exome and Sanger sequencing. We have identified a novel missense variant (c.311G>A; p.Arg104His) in WNT10A in three oligodontia patients of family A, two novel sequence variants (c.207delinsTT, p.Gly70Trpfs*25 and c.1300T>G; p.Try434Gly) in EDAR in three patients of family B and four patients of family C, respectively. To better understand the structural and functional consequences of missense variants in WNT10A and EDAR on the stability of the proteins, we have performed extensive molecular dynamic (MD) simulations. We have also identified three previously reported pathogenic variants (c.1076T>C; p.Met359Thr), (c.1133C>T; p.Thr378Met) and (c.594_595insC; Gly201Argfs*39) in EDA in family D (four patients), E (two patients) and F (one patient), correspondingly. Presently, our data explain the genetic cause of 18 syndromic and non-syndromic tooth agenesis patients in six autosomal recessive and X-linked pedigrees (A-F), which expand the mutational spectrum of these unique clinical manifestations.status: publishe