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.

中文翻译：

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通过全外显子组序列对精神分裂症进行基于家族的遗传分析，以识别罕见的致病变异

精神分裂症（SCZ）受到遗传和环境因素的共同影响。尽管已经进行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较高，这些位点或基因很少可以重复，并且其机制尚不完全清楚。可能存在一些尚未被发现的“遗传性缺失”。为了研究有害的遗传突变，目前的工作中使用了 SCZ 家系的全外显子组测序 (WES)。招募了两个与 SCZ 无关的血统来进行 WES。接下来进行遗传分析，以根据优先策略找到潜在的变异。随后进行遗传分析，根据优先策略检测候选变异。接下来，使用一系列算法来预测变异的致病性。最后进行桑格测序来验证共分离。通过WES基因分析，发现两个家系中与SCZ共分离的6个基因（家系1中的TFEB、 SNAI2、TFAP2B、PRKDC、ST18和家系2中的PKHD1L1 ）的隐性突变。桑格测序证实受影响兄弟姐妹的所有突变都是纯合的。这些结果证实了 SCZ 表现出强烈的异质性和复杂的遗传模式的假设。新发现的纯合变异加深了我们对突变谱的理解，并为TFEB、SNAI2、TFAP2B、PRKDC、ST18和PKHD1L1参与SCZ 的发展提供了更多证据。