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.

Background: Jalili syndrome (JS) is a rare cone‐rod dystrophy (CRD) associated with amelogenesis imperfecta (AI). The first clinical presentation of JS patients was published in 1988 by Jalili and Smith. Pathogenic mutations in the Cyclin and CBS Domain Divalent Metal Cation Transport Mediator 4 (CNNM4) magnesium transporter protein have been reported as the leading cause of this anomaly.Methods: In the present study, a clinical and genetic investigation was performed in a consanguineous family of Pakistani origin, showing characteristic features of JS. Sanger sequencing was successfully used to identify the causative variant in CNNM4. Molecular dynamics (MD) simulations were performed to study the effect of amino acid change over CNNM4 protein.Results: Sequence analysis of CNNM4 revealed a novel missense variant (c.1220G>T, p.Arg407Leu) in exon‐1 encoding cystathionine‐β‐synthase (CBS) domain. To comprehend the mutational consequences in the structure, the mutant p.Arg407Leu was modeled together with a previously reported variant (c.1484C>T, p.Thr495Ile) in the same domain. Additionally, docking analysis deciphered the binding mode of the adenosine triphosphate (ATP) cofactor. Furthermore, 60ns MD simulations were carried out on wild type (p.Arg407/p.Thr495) and mutants (p.Arg407Leu/p.Thr495Ile) to understand the structural and energetic changes in protein structure and its dynamic behavior. An evident conformational shift of ATP in the binding site was observed in simulated mutants disrupting the native ATP‐binding mode.Conclusion: The novel identified variant in CNNM4 is the first report from the Pakistani population. Overall, the study is valuable and may give a novel insight into metal transport in visual function and biomineralization.

Background/ Aim: Pregnancy induced hypertension (PIH) has been a leading cause of maternal mortality worldwide. It could be responsible for several complications like hemodilution, altered lipid metabolism and deficiencies of different minerals in body. Although the causes of Pregnancy induced hypertension (PIH) remains indistinct. The aim of our present study was to evaluate the changes in magnesium serum levels and lipid profile in hypertensive and normotensive pregnant women. Materials and Methods: An analytical case control study comprising 60 individuals was designed. From which 30 normotensive pregnant women served as control group (A) and 30 pregnancy induced hypertensive women served as case group (B). Patients with pre-existing hypertension were excluded. Results: The independent t-test was used for comparison of various parameters between group A and B. Triacylglycerol (TAG) and low density lipoprotein cholesterol (LDL-C) levels were significantly high in PIH (B) as compare to normotensive group (A). Mean serum values of TG were measured as (195.73 ± 70.28 vs 156.27 ± 55.60 mg dL^-1) and LDL-C vs control (87.33 ± 37.74 vs 69.45 ± 28.58 mg dL^-1) in PIH and normotensive groups respectively. HDL-C in PIH vs Control (47.40±1.12 vs 54.43 ±1.27 mg dL^-1) and Mg⁺² PIH vs control (1.36±0.07 vs 1.94±0.35 mg dL^-1) were measured respectively. High density lipoprotein cholesterol (HDL-C) and magnesium Mg⁺² levels were significantly reduced in PIH. Conclusion: The lower serum magnesium levels and abnormal lipids profile may indicate their possible role as risk factors in the development of PIH in pregnant women. Hence initial diagnosis of hypomagnesemia in PIH cases may help in minimizing the complications and development of new cure strategies.