Distribution of pathogenic variants in the CFTR gene in a representative cohort of people with cystic fibrosis in the Kingdom of Bahrain.

IF 2.3 3区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Osama A Karim Majed, Fatema Osama Majed, Nabeel Jasim Almoamen, Husain Baqer Alsatrawi, Salma Dawood Shehabi, Jana Hrbková, Malgorzata Libik, Milan Macek
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引用次数: 0

Abstract

Background: Cystic fibrosis (CF) is a rare multi-systemic recessive disorder. The spectrum and the frequencies of CFTR mutations causing CF vary amongst different populations in Europe and the Middle East. In this study, we characterised the distribution of CF-causing mutations (i.e. pathogenic variants in the  CFTR gene) in a representative CF cohort from the Kingdom of Bahrain based on a three-decade-long analysis at a single tertiary centre. We aim to improve CF genetic diagnostics, introduce of CF neonatal screening and provide CFTR modulator therapy (CFTRm).

Methods: CFTR genotyping  and associated clinical information were drawn from a longitudinal cohort. We sequenced 56 people with CF (pwCF) that had one or both CFTR mutations unidentified and carried out comprehensive bioinformatic- and family-based segregation analyses of detected variants, including genotype-phenotype correlations and disease incidence estimates. The study methodology could serve as a basis for other non-European CF populations with a high degree of consanguinity.

Results: Altogether 18 CF-causing mutations  were identified, 15 of which were not previously detected in Bahrain, accounting for close to 100% of all population-specific alleles. The most common alleles comprise c.1911delG [2043delG; 22.8%], c.2988+1G > A [3120+1G>A; 16.3%], c.2989-1G>A [3121-1G>A; 14.1%], c.3909C>G [N1303K; 13.0%], and c.1521_1523delCTT [p.PheF508del; 7.6%]. Although the proportion of 1st cousin marriages has decreased to 50%, the frequency of homozygosity in our pwCF is 67.4%, thereby indicating that CF still occurs in large, often related, families. pwCF in Bahrain present with faltering growth, pancreatic insufficiency and classical sino-pulmonary manifestations. Interestingly, two pwCF also suffer from sickle cell disease. The estimated incidence of CF in Bahrain based on data from the last three decades is 1 in 9,880 live births.

Conclusion: The most commonCF-causing  mutations in Bahraini pwCF were identified, enabling more precise diagnosis, introduction of two-tier neonatal screening and fostering administration of CFTRm.

巴林王国具有代表性的囊性纤维化患者队列中 CFTR 基因致病变体的分布情况。
背景:囊性纤维化(CF)是一种罕见的多系统隐性疾病:囊性纤维化(CF)是一种罕见的多系统隐性疾病。在欧洲和中东地区的不同人群中,导致 CF 的 CFTR 突变的谱系和频率各不相同。在本研究中,我们根据一个三级中心长达三十年的分析,描述了巴林王国具有代表性的 CF 队列中 CF 致病突变(即 CFTR 基因中的致病变异)的分布特征。我们的目标是改进 CF 基因诊断,引入 CF 新生儿筛查,并提供 CFTR 调节器疗法(CFTRm):CFTR基因分型和相关临床信息来自一个纵向队列。我们对 56 名 CF 患者(pwCF)进行了测序,这些患者有一个或两个 CFTR 突变未被发现,我们对检测到的变异进行了全面的生物信息学分析和基于家族的分离分析,包括基因型与表型的相关性和疾病发病率估计。该研究方法可作为其他具有高度近亲关系的非欧洲 CF 群体的基础:结果:共发现了 18 种导致 CF 的突变,其中 15 种以前未在巴林发现过,占所有人群特异性等位基因的近 100%。最常见的等位基因包括 c.1911delG [2043delG; 22.8%]、c.2988+1G > A [3120+1G>A; 16.3%]、c.2989-1G>A [3121-1G>A; 14.1%]、c.3909C>G [N1303K; 13.0%]和 c.1521_1523delCTT [p.PheF508del; 7.6%]。虽然表兄妹结婚的比例已降至 50%,但我们的小儿先天性心脏病患者中的同源性频率为 67.4%,这表明 CF 仍发生在大家庭中,而且往往是有血缘关系的大家庭。巴林的小儿先天性心脏病患者表现为生长迟缓、胰腺功能不全和典型的协同肺部表现。有趣的是,有两名患儿还患有镰状细胞病。根据过去三十年的数据,巴林的 CF 发病率估计为每 9 880 名活产婴儿中有 1 例:结论:巴林儿童先天性心脏病最常见的致病基因突变已被确定,这有助于进行更精确的诊断、引入两级新生儿筛查和促进 CFTRm 的管理。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Molecular Genetics and Genomics
Molecular Genetics and Genomics 生物-生化与分子生物学
CiteScore
5.10
自引率
3.20%
发文量
134
审稿时长
1 months
期刊介绍: Molecular Genetics and Genomics (MGG) publishes peer-reviewed articles covering all areas of genetics and genomics. Any approach to the study of genes and genomes is considered, be it experimental, theoretical or synthetic. MGG publishes research on all organisms that is of broad interest to those working in the fields of genetics, genomics, biology, medicine and biotechnology. The journal investigates a broad range of topics, including these from recent issues: mechanisms for extending longevity in a variety of organisms; screening of yeast metal homeostasis genes involved in mitochondrial functions; molecular mapping of cultivar-specific avirulence genes in the rice blast fungus and more.
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