Multiple genomic copy number variants associated with periventricular nodular heterotopia indicate extreme genetic heterogeneity
Multiple genomic copy number variants associated with periventricular nodular heterotopia indicate extreme genetic heterogeneity
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DOI：
10.1038/s41431-019-0335-3
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发表时间：
2019-06-01
影响因子：
5.2
通讯作者：
Guerrini, Renzo
中科院分区：
文献类型：
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作者：
Cellini, Elena;Vetro, Annalisa;Guerrini, Renzo
脑室周围结节性异位（PNH）是一种脑畸形，其神经元结节沿侧脑室异位保留。遗传原因包括FLNA异常（典型的x连锁PNH）， ARFGEF2、DCHS1、ERMARD、FAT4、INTS8、MAP1B、MCPH1和NEDD4L的罕见变异，以及几种染色体异常。我们对106名患有不同皮质发育畸形（MCD）的患者进行了阵列- cgh，寻找可能与PNH有关的共同途径。42例患者，包括两对父母/先证夫妇，表现出PNH与其他脑异常相关或不相关，44例患有多小回症，20例患有罕见的mcd。我们发现PNH（15/ 42,35.7%）与多小回症（4/ 44,9.1%）相比，大重排或隐拷贝数变异（CNV）富集（即PNH携带致病性CNV的风险增加5.6倍）。7个基因组区域（2p11.2q12.1、4p15、14q11.2q12、16p13.3、19q13.33、20q13.33、22q11）的CNVs与PNH存在新的、潜在的致病关系。通过对断点清晰的失衡中包含的基因进行计算机分析，我们发现在我们的系列研究中9/12名不相关的患者和15/24名先前发表的患者中，参与囊泡介导运输的基因显著（P < 0.05）过度代表。罕见的基因组失衡，无论是小的CNVs还是大的重排，都是PNH的常见原因。特定细胞机制的失调可能在PNH中起关键的致病作用，但这是通过单个基因还是通过更多基因的累积剂量效应发挥作用仍有待确定。阵列- cgh应被认为是PNH的一线诊断检查，特别是在散发和非经典的情况下。
Periventricular nodular heterotopia (PNH) is a brain malformation in which nodules of neurons are ectopically retained along the lateral ventricles. Genetic causes include FLNA abnormalities (classical X-linked PNH), rare variants in ARFGEF2, DCHS1, ERMARD, FAT4, INTS8, MAP1B, MCPH1, and NEDD4L, as well as several chromosomal abnormalities. We performed array-CGH in 106 patients with different malformations of cortical development (MCD) and looked for common pathways possibly involved in PNH. Forty-two patients, including two parent/proband couples, exhibited PNH associated or not with other brain abnormalities, 44 had polymicrogyria and 20 had rarer MCDs. We found an enrichment of either large rearrangements or cryptic copy number variants (CNVs) in PNH (15/42, 35.7%) vs polymicrogyria (4/44, 9.1%) (i.e., 5.6 times increased risk for PNH of carrying a pathogenic CNV). CNVs in seven genomic regions (2p11.2q12.1, 4p15, 14q11.2q12, 16p13.3, 19q13.33, 20q13.33, 22q11) represented novel, potentially causative, associations with PNH. Through in silico analysis of genes included in imbalances whose breakpoints were clearly detailed, we detected in 9/12 unrelated patients in our series and in 15/24 previously published patients, a significant (P < 0.05) overrepresentation of genes involved in vesicle-mediated transport. Rare genomic imbalances, either small CNVs or large rearrangements, are cumulatively a frequent cause of PNH. Dysregulation of specific cellular mechanisms might play a key pathogenic role in PNH but it remains to be determined whether this is exerted through single genes or the cumulative dosage effect of more genes. Array-CGH should be considered as a first-line diagnostic test in PNH, especially if sporadic and non-classical.