Intellectual disability (ID) is a common neurodevelopmental disorder characterized by significantly impaired adaptive behavior and cognitive capacity. High throughput sequencing approaches have revealed the genetic etiologies for 25–50% of ID patients, while inherited genetic mutations were detected in <5% cases. Here, we investigated the genetic cause for non-syndromic ID in a Han Chinese family. Whole genome sequencing was performed on identical twin sisters diagnosed with ID, their respective children, and their asymptomatic parents. Data was filtered for rare variants, and in silico prediction tools were used to establish pathogenic alleles. Candidate mutations were validated by Sanger sequencing. In silico modeling was used to evaluate the mutation’s effects on the protein encoded by a candidate coding gene. A novel heterozygous variant in the ZBTB18 gene c.1323C>G (p.His441Gln) was identified. This variant co-segregated with affected individuals in an autosomal dominant pattern and was not detected in asymptomatic family members. Molecular studies reveal that a p.His441Gln substitution disrupts zinc binding within the second zinc finger and disrupts the capacity for ZBTB18 to bind DNA. This is the first report of an inherited ZBTB18 mutation for ID. This study further validates WGS for the accurate molecular diagnosis of ID.

智力障碍（ID）是一种常见的神经发育障碍，其特征是适应行为和认知能力显着受损。高通量测序方法揭示了 25-50% ID 患者的遗传病因，而在< 5% 的病例中检测到遗传性基因突变。在这里，我们调查了一个汉族家庭中非综合征性智力障碍的遗传原因。对被诊断患有 ID 的同卵双胞胎姐妹、她们各自的孩子以及她们无症状的父母进行了全基因组测序。数据被过滤以寻找罕见变异，并使用计算机预测工具来建立致病等位基因。通过桑格测序验证候选突变。计算机模拟用于评估突变对候选编码基因编码的蛋白质的影响。鉴定出ZBTB18基因 c.1323C>G (p.His441Gln)中的新杂合变体。这种变异以常染色体显性模式与受影响的个体共分离，并且在无症状的家庭成员中未检测到。分子研究表明，p.His441Gln 取代会破坏第二锌指内的锌结合，并破坏 ZBTB18 结合 DNA 的能力。这是关于 ID遗传性ZBTB18突变的第一份报告。这项研究进一步验证了全基因组测序（WGS）对 ID 的准确分子诊断。