Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland.
Eur J Hum Genet. 2018 Aug;26(8):1121-1131. doi: 10.1038/s41431-018-0137-z. Epub 2018 Apr 30.
Malformations of cortical development (MCDs) manifest with structural brain anomalies that lead to neurologic sequelae, including epilepsy, cerebral palsy, developmental delay, and intellectual disability. To investigate the underlying genetic architecture of patients with disorders of cerebral cortical development, a cohort of 54 patients demonstrating neuroradiologic signs of MCDs was investigated. Individual genomes were interrogated for single-nucleotide variants (SNV) and copy number variants (CNV) with whole-exome sequencing and chromosomal microarray studies. Variation affecting known MCDs-associated genes was found in 16/54 cases, including 11 patients with SNV, 2 patients with CNV, and 3 patients with both CNV and SNV, at distinct loci. Diagnostic pathogenic SNV and potentially damaging variants of unknown significance (VUS) were identified in two groups of seven individuals each. We demonstrated that de novo variants are important among patients with MCDs as they were identified in 10/16 individuals with a molecular diagnosis. Three patients showed changes in known MCDs genes and a clinical phenotype beyond the usual characteristics observed, i.e., phenotypic expansion, for a particular known disease gene clinical entity. We also discovered 2 likely candidate genes, CDH4, and ASTN1, with human and animal studies supporting their roles in brain development, and 5 potential candidate genes. Our findings emphasize genetic heterogeneity of MCDs disorders and postulate potential novel candidate genes involved in cerebral cortical development.
皮质发育障碍（MCDs）表现为结构脑异常，导致神经后遗症，包括癫痫、脑瘫、发育迟缓以及智力残疾。为了研究脑皮质发育障碍患者的潜在遗传结构，对 54 名表现出 MCD 神经影像学征象的患者进行了研究。对个体基因组进行了单核苷酸变异（SNV）和拷贝数变异（CNV）的全外显子测序和染色体微阵列研究。在 16/54 例中发现了影响已知 MCDs 相关基因的变异，包括 11 例 SNV、2 例 CNV 和 3 例 CNV 和 SNV，位于不同的位置。在两组各 7 名个体中，鉴定出了诊断致病性 SNV 和具有未知意义的潜在破坏性变异（VUS）。我们证明，MCDs 患者中的新生变异很重要，因为在 10/16 名具有分子诊断的个体中发现了新生变异。3 名患者显示出已知 MCDs 基因的变化以及超出常见特征的临床表现，即特定已知疾病基因临床实体的表型扩展。我们还发现了 2 个可能的候选基因，CDH4 和 ASTN1，人类和动物研究支持它们在大脑发育中的作用，以及 5 个潜在的候选基因。我们的研究结果强调了 MCDs 疾病的遗传异质性，并推测了可能涉及大脑皮质发育的新候选基因。
