Genetics and Prenatal Diagnosis Center, The First Affiliated Hospital of Zhengzhou University, Henan Engineering Research Center for Gene Editing of Human Genetic Disease, Erqi District, Zhengzhou, People's Republic of China.
Henan provincial key laboratory of children's genetics and metabolic diseases, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou Children's Hospital, Zhengzhou, Zhengzhou, China.
Mol Genet Genomic Med. 2020 Jun;8(6):e1234. doi: 10.1002/mgg3.1234. Epub 2020 Apr 21.
Epilepsy limited to females with mental retardation (EFMR) is a rare type of epilepsy with an X-linked mode of inheritance, which affect heterozygous females while the males are not affected. Mutations within the protocadherin 19 (PCDH19) gene have been identified as the direct cause of EFMR. The phenotype of EFMR is characterized by seizure onset in infancy with or without cognitive impairment, intellectual disturbances, and autistic features.
Whole-exome sequencing (WES) was performed in the proband to identify the underlying genetic mutations. The candidate genes were confirmed by Sanger sequencing following PCR amplification. In silico analyses were conducted to predict the effect of the novel missense mutation on the function of PCDH19 protein.
We identified three female patients in a family with a novel missense mutation in PCDH19, c.812G>A (p. (Gly271Asp)). The patients III-1 and III-2 presented with more severe clinical phenotypes and an earlier age of onset (6 and 11 months, respectively), intellectual disability, and movement disorders. By contrast, patient II-4 has a later age of onset (23 months), and there was no relapse of seizures without antiepileptic treatment after the age of six. In silico analyses showed that p. (Gly271Asp) in the PCDH19 affects a highly conserved residue.
Our results indicated that patients with the same PCDH19 mutation in a family may show intrafamilial phenotypic variability. Givening the mother of the proband was 18 weeks pregnant and intends to have a prenatal diagnosis, the more reasonable and less harmful strategies for prenatal diagnosis could be chosen based on the results of noninvasive prenatal testing and genetic testing.
局限于女性智力障碍的癫痫（EFMR）是一种罕见的癫痫类型，具有 X 连锁遗传模式，影响杂合女性，而男性不受影响。原钙黏蛋白 19（PCDH19）基因突变已被确定为 EFMR 的直接原因。EFMR 的表型特征是婴儿期发作癫痫，伴有或不伴有认知障碍、智力障碍和自闭症特征。
对先证者进行全外显子组测序（WES）以确定潜在的遗传突变。通过 PCR 扩增后的 Sanger 测序验证候选基因。进行计算机分析以预测新错义突变对 PCDH19 蛋白功能的影响。
我们在一个家族中发现了 3 名女性患者，她们在 PCDH19 中存在新的错义突变，c.812G>A（p.（Gly271Asp））。患者 III-1 和 III-2 表现出更严重的临床表型和更早的发病年龄（分别为 6 个月和 11 个月）、智力障碍和运动障碍。相比之下，患者 II-4 的发病年龄较晚（23 个月），6 岁后无需抗癫痫治疗即可停止发作。计算机分析表明，PCDH19 中的 p.（Gly271Asp）影响高度保守的残基。
我们的结果表明，一个家族中具有相同 PCDH19 突变的患者可能表现出家族内表型的可变性。鉴于先证者的母亲已怀孕 18 周并打算进行产前诊断，根据非侵入性产前检测和基因检测的结果，可以选择更合理、危害更小的产前诊断策略。
