Exome sequencing utility in defining the genetic landscape of hearing loss and novel-gene discovery in Iran

Hearing loss (HL) is one of the most common sensory defects affecting more than 466 million individuals worldwide. It is clinically and genetically heterogeneous with over 120 genes causing non-syndromic HL identified to date. Here, we performed exome sequencing (ES) on a cohort of Iranian families with no disease-causing variants in known deafness-associated genes after screening with a targeted gene panel. We identified likely causal variants in 20 out of 71 families screened. Fifteen families segregated variants in known deafness-associated genes. Eight families segregated variants in novel candidate genes for HL: DBH, TOP3A, COX18, USP31, TCF19, SCP2, TENM1, and CARMIL1. In the three of these families, intrafamilial locus heterogeneity was observed with variants in both known and novel candidate genes. In aggregate, we were able to identify the underlying genetic cause of HL in nearly 30 of our study cohort using ES. This study corroborates the observation that high-throughput DNA sequencing in populations with high rates of consanguineous marriages represents a more appropriate strategy to elucidate the genetic etiology of heterogeneous conditions such as HL. © 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Lt

Zinc Supplementation and the Effects on Pregnancy Outcomes in Gestational Diabetes: A Randomized, Double-blind, Placebo-controlled Trial

Objective: The current study was designed to determine the beneficial effects of zinc intake on biomarkers of inflammation, oxidative stress, and pregnancy outcomes among pregnant women with gestational diabetes (GDM). Methods: This randomized, double-blind, placebo-controlled clinical trial was conducted among 50 women with GDM. Patients were randomly allocated to intake either 233 mg zinc gluconate (containing 30 mg zinc) (n=25) or a placebo (n=25) for 6 weeks. Fasting blood samples were taken at the fist of the study and after 6 weeks of intervention to quantify related variables. Newborn's weight, height, head circumference, Apgar score, and hyperbilirubinemia were determined. Results: The change in serum zinc levels after 6 weeks of supplementation was greater in women consuming zinc than in the placebo group (+8.5±13.5 vs. -3.6±16.2 mg/dL, P=0.006). Changes in serum high sensitivity C-reactive protein (hs-CRP) (-110.1±1 475.5 vs. +1 137.8±2 429.2 ng/mL, P=0.03) and plasma total antioxidant capacity (TAC) concentrations (+60.0±129.0 vs. -28.4±81.4 mmol/L, P=0.006) were significantly different between the supplemented women and placebo group. We did not find any significant effect of zinc administration on pregnancy outcomes. Conclusion: Taken together, zinc administration among patients with GDM was associated with decreased hs-CRP and increased TAC concentrations; however, it did not influence maternal plasma nitric oxide (NO), glutathione (GSH), malondialdehyde (MDA) levels, or pregnancy outcomes. © J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York

Zinc supplementation and the effects on metabolic status in gestational diabetes: A randomized, double-blind, placebo-controlled trial

Objective To the best of our knowledge, no reports are available indicating the effects of zinc supplementation on metabolic status in women with gestational diabetes (GDM). This study was designed to determine the effects of zinc supplementation on glucose homeostasis parameters and lipid concentrations in GDM women. Methods This randomized, double-blind, placebo-controlled trial was performed among 58 women diagnosed with GDM, primigravida and aged 18-40 years old. Patients were randomly divided into two groups to receive 233 mg zinc gluconate (containing 30 mg zinc) supplements (n = 29) or placebo (n = 29) per day for 6 weeks. Fasting blood samples were taken at the beginning and end of the trial to quantify glucose, insulin and lipid concentrations. Results Patients who received zinc supplements had significantly higher serum zinc concentrations (+ 6.9 ± 13.2 vs. - 1.5 ± 16.5 mg/dL, P = 0.03) than those received the placebo. In addition, zinc-supplemented patients had reduced fasting plasma glucose (FPG) (- 6.6 ± 11.2 vs. + 0.6 ± 6.7 mg/dL, P = 0.005), serum insulin levels (- 1.3 ± 6.6 vs. + 6.6 ± 12.2 μIU/mL, P = 0.003), homeostasis model of assessment-insulin resistance (HOMA-IR) (- 0.5 ± 1.6 vs. + 1.5 ± 2.7, P = 0.001), homeostatic model assessment-Beta cell function (HOMA-B) (- 0.7 ± 25.0 vs. + 26.5 ± 49.5, P = 0.01) and increased quantitative insulin sensitivity check index (QUICKI) (+ 0.01 ± 0.01 vs. - 0.01 ± 0.02, P = 0.004) compared with the placebo. Additionally, significant differences in serum triglycerides (+ 13.6 ± 61.4 vs. + 45.9 ± 36.5 mg/dL, P = 0.01) and VLDL-cholesterol concentrations (+ 2.7 ± 12.3 vs. + 9.2 ± 7.3 mg/dL, P = 0.01) were observed following the administration of zinc supplements compared with the placebo.We did not observe any significant effects of taking zinc supplements on other lipid profiles. Conclusions Taken together, 30 mg zinc supplementation per day for 6 weeks among GDM women had beneficial effects on metabolic profiles. © 2015 Elsevier Inc. All rights reserved

Homozygosity mapping in consanguineous families reveals extreme heterogeneity of non-syndromic autosomal recessive mental retardation and identifies 8 novel gene loci

Autosomal recessive gene defects are arguably the most important, but least studied genetic causes of severe cognitive dysfunction. Homozygosity mapping in 78 consanguineous Iranian families with nonsyndromic autosomal recessive mental retardation (NS-ARMR) has enabled us to determine the chromosomal localization of at least 8 novel gene loci for this condition. Our data suggest that in the Iranian population NS-ARMR is very heterogeneous, and they argue against the existence of frequent gene defects that account for more than a few percent of the cases

Characterising the spectrum of autosomal recessive hereditary hearing loss in Iran

Background Countries with culturally accepted consanguinity provide a unique resource for the study of rare recessively inherited genetic diseases. Although hereditary hearing loss (HHL) is not uncommon, it is genetically heterogeneous, with over 85 genes causally implicated in non-syndromic hearing loss (NSHL). This heterogeneity makes many gene-specific types of NSHL exceedingly rare. We sought to define the spectrum of autosomal recessive HHL in Iran by investigating both common and rarely diagnosed deafness-causing genes. Design Using a custom targeted genomic enrichment (TGE) panel, we simultaneously interrogated all known genetic causes of NSHL in a cohort of 302 GJB2- negative Iranian families. Results We established a genetic diagnosis for 67 of probands and their families, with over half of all diagnoses attributable to variants in five genes: SLC26A4, MYO15A, MYO7A, CDH23 and PCDH15. As a reflection of the power of consanguinity mapping, 26 genes were identified as causative for NSHL in the Iranian population for the first time. In total, 179 deafness-causing variants were identified in 40 genes in 201 probands, including 110 novel single nucleotide or small insertion-deletion variants and three novel CNV. Several variants represent founder mutations. Conclusion This study attests to the power of TGE and massively parallel sequencing as a diagnostic tool for the evaluation of hearing loss in Iran, and expands on our understanding of the genetics of HHL in this country. Families negative for variants in the genes represented on this panel represent an excellent cohort for novel gene discovery