Department of Human Genetics, Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, Byblos 1102-2801, Lebanon.
Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, Byblos 1102-2801, Lebanon.
Genes (Basel). 2023 Feb 27;14(3):598. doi: 10.3390/genes14030598.
Autism spectrum disorder (ASD) is a complex developmental disability that impairs the social communication and interaction of affected individuals and leads to restricted or repetitive behaviors or interests. ASD is genetically heterogeneous, with inheritable and de novo genetic variants in more than hundreds of genes contributing to the disease. However, these account for only around 20% of cases, while the molecular basis of the majority of cases remains unelucidated as of yet.
Two unrelated Lebanese patients, a 7-year-old boy (patient A) and a 4-year-old boy (patient B), presenting with ASD were included in this study. Whole-exome sequencing (WES) was carried out for these patients to identify the molecular cause of their diseases.
WES analysis revealed hemizygous variants in (NM_001184880.1) as being the candidate causative variants: p.Arg787Leu was detected in patient A and p.Asp1024Asn in patient B. PCDH19, located on chromosome X, encodes a membrane glycoprotein belonging to the protocadherin family. Heterozygous variants have been linked to epilepsy in females with mental retardation (EFMR), while mosaic mutations in males are responsible for treatment-resistant epilepsy presenting similarly to EFMR, with some reported cases of comorbid intellectual disability and autism. Interestingly, a hemizygous variant affecting the same amino acid that is altered in patient A was previously reported in a male patient with ASD.
Here, we report hemizygous variants in two males with autism without epilepsy. Reporting further variants in male patients with ASD is important to assess the possible involvement of this gene in autism.
自闭症谱系障碍（ASD）是一种复杂的发育障碍，会损害受影响个体的社交沟通和互动能力，导致受限或重复的行为或兴趣。ASD 在遗传上具有异质性，超过数百个基因中的遗传和新生基因变异都与该疾病有关。然而，这些只占大约 20%的病例，而大多数病例的分子基础尚未阐明。
本研究纳入了两名来自黎巴嫩的无亲缘关系的 ASD 患者，一名 7 岁男孩（患者 A）和一名 4 岁男孩（患者 B）。对这些患者进行全外显子组测序（WES），以确定其疾病的分子病因。
WES 分析显示， （NM_001184880.1）的半合子变异可能是致病变异：患者 A 中检测到 p.Arg787Leu，患者 B 中检测到 p.Asp1024Asn。PCDH19 位于 X 染色体上，编码属于原钙黏蛋白家族的膜糖蛋白。杂合性 变异与伴智力障碍的女性癫痫（EFMR）有关，而男性中的镶嵌性 突变则导致对抗癫痫药物治疗有抵抗的癫痫，表现与 EFMR 相似，有一些报道的病例合并智力残疾和自闭症。有趣的是，影响与患者 A 中改变的相同氨基酸的半合子 变异之前在一名患有 ASD 的男性患者中被报道过。
本研究报道了两名男性 ASD 患者中存在半合子 变异，而没有癫痫。进一步报道男性 ASD 患者中的 变异对于评估该基因是否可能与自闭症有关很重要。
