PDF(Pubmed)
Abstract：
We report the genetic analysis of two consanguineous pedigrees of Pakistani ancestry in which two siblings in each family exhibited developmental delay, epilepsy, intellectual disability and aggressive behavior. Whole-genome sequencing was performed in Family 1, and we identified ~80,000 variants located in regions of homozygosity. Of these, 615 variants had a minor allele frequency ≤ 0.001, and 21 variants had CADD scores ≥ 15. Four homozygous exonic variants were identified in both affected siblings: PDZD7 (c.1348_1350delGAG, p.Glu450del), ALG6 (c.1033G>C, p.Glu345Gln), RBM20 (c.1587C>G, p.Ser529Arg), and CNTNAP2 (c.785G>A, p.Gly228Arg). Sanger sequencing revealed co-segregation of the PDZD7, RBM20, and CNTNAP2 variants with disease in Family 1. Pathogenic variants in PDZD7 and RBM20 are associated with autosomal recessive non-syndromic hearing loss and autosomal dominant dilated cardiomyopathy, respectively, suggesting that these variants are unlikely likely to contribute to the clinical presentation. Gene panel analysis was performed on the two affected siblings in Family 2, and they were found to also be homozygous for the p.Gly228Arg CNTNAP2 variant. Together these families provide a LOD score 2.9 toward p.Gly228Arg CNTNAP2 being a completely penetrant recessive cause of this disease. The clinical presentation of the affected siblings in both families is also consistent with previous reports from individuals with homozygous CNTNAP2 variants where at least one allele was a nonsense variant, frameshift or small deletion. Our data suggests that homozygous CNTNAP2 missense variants can also contribute to disease, thereby expanding the genetic landscape of CNTNAP2 dysfunction.
摘要：
我们报告了巴基斯坦血统的两个近亲谱系的遗传分析，其中每个家庭中的两个兄弟姐妹表现出发育迟缓，癫痫,智力障碍和攻击性行为。在家族1中进行全基因组测序，我们鉴定了约80,000个位于纯合性区域的变体。其中,615个变体的次要等位基因频率≤0.001，21个变体的CADD评分≥15。在两个受影响的兄弟姐妹中都鉴定了四个纯合外显子变体：PDZD7（c.1348_1350delGAG，p.Glu450del)，ALG6（c.1033G>C，p.Glu345Gln)，RBM20（c.1587C>G，p.Ser529Arg)，和CNTNAP2（c.785G>A，p.Gly228Arg)。Sanger测序显示PDZD7、RBM20和CNTNAP2变体与家族1中的疾病共分离。PDZD7和RBM20的致病变异与常染色体隐性非综合征性听力损失和常染色体显性扩张型心肌病相关,分别,这表明这些变异不太可能有助于临床表现。对家族2中的两个受影响的兄弟姐妹进行基因组分析,发现它们对于p.Gly228ArgCNTNAP2变体也是纯合的。这些家族一起提供了对p.Gly228ArgCNTNAP2的LOD评分2.9,p.Gly228ArgCNTNAP2是该疾病的完全渗透隐性原因。两个家庭中受影响的兄弟姐妹的临床表现也与以前的纯合CNTNAP2变体个体的报道一致，其中至少一个等位基因是无义变体。移码或小的缺失。我们的数据表明，纯合CNTNAP2错义变体也可能导致疾病，从而扩大了CNTNAP2功能障碍的遗传景观。
