This paper reports the clinical and metabolic findings in two sibling sisters born with fetal hydrops and eventually found to have deficient S‐adenosylhomocysteine hydrolase (AHCY) activity due to compound heterozygosity for two novel mutations, c.145C>T; p.Arg49Cys and c.257A>G; p.Asp86Gly. Clinically, the major abnormalities in addition to fetal hydrops (very likely due to impaired synthetic liver function) were severe hypotonia/myopathy, feeding problems, and respiratory failure. Metabolic abnormalities included elevated plasma S‐adenosylhomocysteine, S‐adenosylmethionine, and methionine, with hypoalbuminemia, coagulopathies, and serum transaminase elevation. The older sister died at age 25 days, but the definitive diagnosis was made only retrospectively. The underlying genetic abnormality was diagnosed in the second sister, but treatment by means of dietary methionine restriction and supplementation with phosphatidylcholine and creatine did not prevent her death at age 122 days. These cases extend the experience with AHCY deficiency in humans, based until now on only the four patients previously identified, and suggest that the deficiency in question may be a cause of fetal hydrops and developmental abnormalities of the brain.
Aim. To search for causal mutations in candidate genes responsible for the development of sudden cardiac death (SCD) in men who died under the age of 45.Material and methods. The SCD group (n=37) was formed using the criteria the World Health Organization and the European Society of Cardiology. Autopsy material was collected from men who died suddenly outside medical institutions and underwent forensic medical examination according to the standard protocol. Autopsy revealed no morphological changes that could explain sudden death. The mean age was 32,4±6,4 years. Genomic DNA was isolated from myocardial tissue using phenol-chloroform extraction. Clinical exome sequencing was performed. At first, we analyzed the results of sequencing of 24 genes, mutations in which lead to cardiovascular diseases associated with an increased risk of SCD: KCNQ1, KCNH2, SCN5A, AKAP9, ANK2, CACNA1C, CALM1, CALM2, CAV3, KCNE1, KNCJNE2, KCNE2, SCN4B, SNTA1, MYH2, APOB, KCNA5, TGFB3, NEB, PDX1, FLNC, PLEC, KCND3.Results. Of 37 samples, we revealed 13 probable pathogenic missense mutations in 9 samples (24,3%). Of 13 probable pathogenic variants, 5 were new.Conclusion. This pilot study provides following conclusions: it is necessary to continue molecular autopsy research in Russia; to increase the effectiveness of detecting causal mutations, it is necessary to reduce the age of patients with SCD included in the study; studying the families of deceased; cooperation of experienced specialists — forensic pathologist, laboratory geneticist, cardiologist.
Цель. Исследование ассоциации метилирования промотора гена ABCA1 с внезапной сердечной смертью (ВСС).Материалы и методы. Дизайн исследования построен по принципу «случай -контроль». Группа ВСС включала 150 мужчин (средний возраст (46,7 ± 9,2) года), умерших внезапной сердечной смертью согласно данным судебно-медицинской экспертизы (основные патологоанатомические диагнозы -острая недостаточность кровообращения, острая коронарная недостаточность). Контрольная группа включает 150 мужчин (средний возраст (42,6 ± 1,2) года), умерших внезапно, но не вследствие сердечно-сосудистой патологии. ДНК выделена методом фенол-хлороформной экстракции из ткани миокарда. Оценка статуса метилирования промотора гена ABCA1 проведена методом метил-специфической полимеразной цепной реакции. Полученные результаты статистически обработаны в SPSS 16.0 с применением критерия Пирсона, критерия Фишера с поправкой Йетса на непрерывность. В качестве уровня значимости использован р < 0,05.Результаты. При сравнении групп выявлены статистически значимые различия по статусу метилирования промотора гена ABCA1 между группами (р = 0,015). В группе ВСС доля лиц, у которых промотор гена ABCA1 метилирован, статистически значимо больше по сравнению с контрольной группой (p = 0,020; ОШ = 5,86; 95%-й доверительный интервал (1,89)). Заключение. Метилирование промотора гена ABCA1 ассоциировано с внезапной сердечной смертью. Ключевые слова: внезапная сердечная смерть, метилирование, ABCA1, промотор. Конфликт интересов. Авторы декларируют отсутствие явных и потенциальных конфликтов интересов, связанных с публикацией настоящей статьи. Источник финансирования. Исследование выполнено при финансовой поддержке РФФИ и Правительства Новосибирской области (проект № 19-415-543001). Соответствие принципам этики. Исследование одобрено локальным этическим комитетом НИИТПМфилиалом ФИЦ ИЦИГ СО РАН (протокол № 77 от 04.06.2019).
Highlights. Probably causal mutations of QT interval prolongation in genes associated with LQTS were found in men of the Siberian population.Aim. To detect and study mutations in individuals with borderline prolongation of the QT interval in Siberian males.Methods. The study was conducted on the material of the international project HAPIEE in the period from 2003 to 2005 and screening of young people aged 25–44, performed in Novosibirsk. The total sample of men was 1353 people aged 25 to 69 years. From each age subgroup (25–29, 30–34, ..., 65–69 years old) 2–3 samples with the highest QT values were selected . The study group consisted of 30 men who subsequently underwent sequencing of a panel of genes. The search for mutations was carried out in genes associated with long QT syndrome (LQTS): KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, KCNJ2, CACNA1, SCN4B, KCNJ5, ANK2, CAV3, SNTA1, AKAP9, CALM1 and CALM2. All identified single nucleotide variants were verified by direct Sanger sequencing.Results. Three rare variants in the LQTS genes have been identified: p.P197L of the KCNQ1 gene, p.R176W, and p.D1003GfsX116 of the KCNH2 gene.Conclusion. In Caucasian men from the Novosibirsk population with borderline prolongation of the QT interval, probably causal substitutions in the LQTS genes – KCNH2 and KCNQ1, contributing to the prolongation of the QT interval, were found. To clarify the spectrum and frequency of occurrence of various mutations in genes, life-threatening arrhythmias in the population, additional studies are needed on extended samples.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.