Amjad Khan, Bushra Al Shamsi, Maryam Al Shehhi, Amna A Kashgari, Aaisha Al Balushi, Fahad A Al Dihan, Mohannad A Alghamdi, Abothnain Manal, Ana C González-Álvarez, Stefan T Arold, Wafaa Eyaid
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引用次数: 0
摘要
维德曼-劳滕斯特劳赫综合征(Wiedemann-Rautenstrauch Syndrome,WRS;MIM 264090)是一种极其罕见的高度异质性综合征,为隐性遗传。患者具有产前和产后生长迟缓、身材矮小、早衰、肌张力低下、面部畸形、骨髓营养不良性白质营养不良和智力障碍等特征。RNA 聚合酶 III 亚基 A(POLR3A)中的双拷贝致病变体与 WRS 有关。在这里,我们报告了在三个近亲家庭(两个阿曼家庭和一个沙特家庭)中发现的首例具有新表型的 WRS 综合征病例,其特征是 POLR3A 的双链变体。通过全外显子组测序,我们在两个阿曼家族中发现了一个新的同源错义变体(NM_007055:c.2456C>T; p. Pro819Leu),在沙特家族中发现了一个新的同源变体(c.1895G>T; p Cys632Phe),该变体与 POLR3A 基因中的疾病分离。对野生型蛋白和突变型蛋白进行硅同源建模后发现,这两种蛋白的结构和稳定性都发生了很大变化,表明可能对功能产生了影响。通过确定 POLR3A 基因第 14 和 18 号外显子的同源变异,我们的研究结果将有助于更好地理解 WRS 综合征的表型-基因型关系和分子病因。
Further delineation of Wiedemann-Rautenstrauch syndrome linked with POLR3A.
Wiedemann-Rautenstrauch Syndrome (WRS; MIM 264090) is an extremely rare and highly heterogeneous syndrome that is inherited in a recessive fashion. The patients have hallmark features such as prenatal and postnatal growth retardation, short stature, a progeroid appearance, hypotonia, facial dysmorphology, hypomyelination leukodystrophy, and mental impairment. Biallelic disease-causing variants in the RNA polymerase III subunit A (POLR3A) have been associated with WRS. Here, we report the first identified cases of WRS syndrome with novel phenotypes in three consanguineous families (two Omani and one Saudi) characterized by biallelic variants in POLR3A. Using whole-exome sequencing, we identified one novel homozygous missense variant (NM_007055: c.2456C>T; p. Pro819Leu) in two Omani families and one novel homozygous variant (c.1895G>T; p Cys632Phe) in Saudi family that segregates with the disease in the POLR3A gene. In silico homology modeling of wild-type and mutated proteins revealed a substantial change in the structure and stability of both proteins, demonstrating a possible effect on function. By identifying the homozygous variants in the exon 14 and 18 of the POLR3A gene, our findings will contribute to a better understanding of the phenotype-genotype relationship and molecular etiology of WRS syndrome.
期刊介绍:
Molecular Genetics & Genomic Medicine is a peer-reviewed journal for rapid dissemination of quality research related to the dynamically developing areas of human, molecular and medical genetics. The journal publishes original research articles covering findings in phenotypic, molecular, biological, and genomic aspects of genomic variation, inherited disorders and birth defects. The broad publishing spectrum of Molecular Genetics & Genomic Medicine includes rare and common disorders from diagnosis to treatment. Examples of appropriate articles include reports of novel disease genes, functional studies of genetic variants, in-depth genotype-phenotype studies, genomic analysis of inherited disorders, molecular diagnostic methods, medical bioinformatics, ethical, legal, and social implications (ELSI), and approaches to clinical diagnosis. Molecular Genetics & Genomic Medicine provides a scientific home for next generation sequencing studies of rare and common disorders, which will make research in this fascinating area easily and rapidly accessible to the scientific community. This will serve as the basis for translating next generation sequencing studies into individualized diagnostics and therapeutics, for day-to-day medical care.
Molecular Genetics & Genomic Medicine publishes original research articles, reviews, and research methods papers, along with invited editorials and commentaries. Original research papers must report well-conducted research with conclusions supported by the data presented.