Family-based genetic analysis in schizophrenia by whole-exome sequence to identify rare pathogenic variants

IF 1.6 3区 医学 Q3 GENETICS & HEREDITY
Binli Shang, Runxu Yang, Kun Lian, Lei Dong, Hongbing Liu, Tianlan Wang, Guangya Yang, Kang Xi, Xiufeng Xu, Yuqi Cheng
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Abstract

Schizophrenia (SCZ) is influenced by a combination of genetic and environmental factors. Although several studies have been conducted to identify the causative loci and genes, few of these loci or genes can be repeated due to the high phenotypic and genetic heterogeneity of disease, and their mechanisms are not fully understood. There may be some “missing heritability” that has not yet been found. In order to investigate the deleterious heritable mutations, whole-exome sequencing (WES) in pedigrees with SCZ was used in the current work. Two unrelated pedigrees with SCZ were recruited to perform WES. Genetic analysis was next performed to find potential variants in accordance with the prioritized strategy. Followed by genetic analysis to detect candidate variants according to the prioritized strategy. Next, a series of algorithms was used to predict the pathogenicity of variants. Sanger sequencing was finally conducted to verify the co-segregation. Recessive mutations in six genes (TFEB, SNAI2, TFAP2B, PRKDC, ST18 in Pedigree 1 and PKHD1L1 in Pedigree 2) that co-segregated with SCZ in two families were discovered through genetic analysis by WES. Sanger sequencing verified that all of the mutations in the affected siblings were homozygous. These results corroborated the hypothesis that SCZ exhibits strong heterogeneity and complex inheritance patterns. The newly discovered homozygous variations deepen our understanding of the mutation spectrum and offer more proof for the involvement of TFEB, SNAI2, TFAP2B, PRKDC, ST18, and PKHD1L1 in the development of SCZ.

通过全外显子组序列对精神分裂症进行家族遗传分析,以确定罕见的致病变异。
精神分裂症(SCZ)受遗传和环境因素的共同影响。虽然已经开展了多项研究来确定致病位点和基因,但由于疾病的表型和遗传异质性很高,这些位点或基因很少能够重复出现,其机制也尚未完全明了。可能还有一些 "缺失的遗传性 "尚未被发现。为了研究有害的遗传突变,本研究采用了全外显子组测序(WES)技术。我们招募了两个无血缘关系的 SCZ pedigrees 进行 WES 测序。接下来进行遗传分析,按照优先策略寻找潜在变异。然后进行遗传分析,根据优先策略检测候选变异。接着,使用一系列算法预测变异体的致病性。最后进行桑格测序以验证共分离。通过WES遗传分析,发现了两个家族中与SCZ共分离的六个基因(TFEB、SNAI2、TFAP2B、PRKDC、ST18(Pedigree 1)和PKHD1L1(Pedigree 2))的隐性突变。桑格测序验证了受影响兄弟姐妹中的所有突变均为同基因突变。这些结果证实了 SCZ 具有很强的异质性和复杂的遗传模式这一假设。新发现的同源变异加深了我们对突变谱的理解,并进一步证明了TFEB、SNAI2、TFAP2B、PRKDC、ST18和PKHD1L1参与了SCZ的发病。
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
CiteScore
5.90
自引率
7.10%
发文量
40
审稿时长
4-8 weeks
期刊介绍: Neuropsychiatric Genetics, Part B of the American Journal of Medical Genetics (AJMG) , provides a forum for experimental and clinical investigations of the genetic mechanisms underlying neurologic and psychiatric disorders. It is a resource for novel genetics studies of the heritable nature of psychiatric and other nervous system disorders, characterized at the molecular, cellular or behavior levels. Neuropsychiatric Genetics publishes eight times per year.
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