A Novel Homozygous Frameshift Variant in DYM Causing Dyggve-Melchior-Clausen Syndrome in Pakistani Patients.

Background: Dyggve-Melchior-Clausen syndrome (DMC) is a skeletal dysplasia with associated defects of brain development and intelligence. The truncating pathogenic variants in DYM are the most frequent cause of DMC. Smith-McCort (SMC), another skeletal dysplasia, is also caused by non-synonymous DYM variants. Methods and Results: In the current study, we examined a Pakistani consanguineous family with three affected members. Clinical features like spondyloepimetaphyseal dysplasia, indicative of characteristic skeletal abnormalities, and intellectual disability were observed. Our male patients had microcephaly and coarse facial features while the female patient did not represent microcephaly or abnormal facies, which are significant features of DMC patients. Sanger sequencing identified a novel homozygous frameshift insertion (c.95_96insT, p.W33Lfs*14) in DYM, which likely leads to nonsense-mediated decay (NMD). Conclusion: The novel frameshift change verifies the fact that pathogenic variants in DYM are the most frequent cause of DMC.

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.

A Novel Homozygous Frameshift Mutation in CCN6 Causing Progressive Pseudorheumatoid Dysplasia (PPRD) in a Consanguineous Yemeni Family.

Background: Progressive pseudorheumatoid dysplasia (PPRD) inherited in an autosomal recessive fashion, is a disabling disease, characterized by platyspondyly, irregularities of the vertebral bodies, narrowing of the intervertebral discs and intraarticular spaces, widening of the epiphysis-metaphysis, polyarthralgia, multiple joint contractures, and disproportionate short stature. A number of studies have been performed on this deformity in various populations around the globe, including the Arab population. Mutations in CCN6, located on 6q22, are reported to cause this anomaly. Case Presentation: The present study describes the investigation of a consanguineous family of Yemeni origin. Clinical examination of the patient revealed short stature with progressive skeletal abnormalities, stiffness and enlargement of small joints of the hands along with restriction of movements of proximal interphalangeal (PIP) and distal interphalangeal (DIP) joints with weakness and gait disturbance. Sanger sequencing revealed a novel homozygous frameshift deletion mutation (c.746delT; p.Val249Glyfs*10) in CCN6 which may lead to NMD (Nonsense mediated decay). This mutation expands the spectrum of pathogenic variants in CCN6 causing PPRD.