Multiple genome sequencing studies have identified genetic abnormalities as major causes of severe intellectual disability (ID). However, many children affected by mild ID and borderline intellectual functioning (BIF) lack a genetic diagnosis because known causative ID genetic mutations have not been identified or the role of genetic variants in mild cases is less understood. Genetic variant testing in mild cases is necessary to provide information on prognosis and risk of occurrence. In this study, we report two sibling patients who were 5 years 9 months old and 3 years 3 months old and presented to the hospital due to developmental delay. Clinical assessment and chromosomal microarray analysis were performed. The patients were diagnosed with mild intellectual disability (ID) and borderline intellectual functioning (BIF). Genetic analysis identified a loss of 12p11.22, including the OVCH1-AS1, OVCH1, and TMTC1 genes, which was the only variant that occurred in both sisters. Identical variants were found in their father with probable BIF. Neither patient presented any brain structural abnormalities or dysmorphism, and no exogenous factors or parenting problems were reported. Thus, loss of 12p11.22 may be associated with our patients’ cognitive impairment. The OVCH1, OVCH1-AS1 and TMTC1 variants identified in this study are the most likely disease-causing genes in the sisters. Our findings may expand as yet limited knowledge on mild ID and BIF causative variants, which would further support the diagnosis even if the severity is mild.

中文翻译：

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病例报告：两姐妹因 12p11.22 缺失而出现智力障碍和边缘智力功能

多项基因组测序研究已确定遗传异常是严重智力障碍 (ID) 的主要原因。然而，许多受轻度智力障碍和边缘智力功能 (BIF) 影响的儿童缺乏基因诊断，因为尚未确定已知的致病性智力障碍基因突变，或者遗传变异在轻度病例中的作用知之甚少。轻度病例的基因变异检测对于提供预后和发生风险的信息是必要的。在这项研究中，我们报告了两名兄弟姐妹患者，他们分别为 5 岁 9 个月和 3 岁 3 个月，因发育迟缓而到医院就诊。进行了临床评估和染色体微阵列分析。患者被诊断为轻度智力障碍（ID）和边缘智力功能（BIF）。遗传分析发现 12p11.22 缺失，包括OVCH1-AS1,OVCH1， 和TMTC1基因，这是两姐妹身上出现的唯一变异。他们的父亲也发现了相同的变异，可能患有 BIF。两名患者均未出现任何大脑结构异常或畸形，也没有外源因素或养育问题的报道。因此，12p11.22 的缺失可能与患者的认知障碍有关。这OVCH1,OVCH1-AS1和TMTC1这项研究中发现的变异是姐妹中最有可能致病的基因。我们的研究结果可能会扩展对轻度 ID 和 BIF 致病变异的有限了解，即使严重程度较轻，这也将进一步支持诊断。