De novo and inherited private variants in MAP1B in periventricular nodular heterotopia

Periventricular nodular heterotopia (PVNH) is a malformation of cortical development commonly associated with epilepsy. We exome sequenced 202 individuals with sporadic PVNH to identify novel genetic risk loci. We first performed a trio-based analysis and identified 219 de novo variants. Although no novel genes were implicated in this initial analysis, PVNH cases were found overall to have a significant excess of nonsynonymous de novo variants in intolerant genes (p = 3.27x10-7), suggesting a role for rare new alleles in genes yet to be associated with the condition. Using a gene-level collapsing analysis comparing cases and controls, we identified a genome-wide significant signal driven by four ultra-rare loss-of-function heterozygous variants in MAP1B, including one de novo variant. In at least one instance, the MAP1B variant was inherited from a parent with previously undiagnosed PVNH. The PVNH was frontally predominant and associated with perisylvian polymicrogyria. These results implicate MAP1B in PVNH. More broadly, our findings suggest that detrimental mutations likely arising in immediately preceding generations with incomplete penetrance may also be responsible for some apparently sporadic diseases.

脑室周围结节性异位（Periventricular nodular heterotopia, PVNH）是一种常与癫痫相关的皮层发育畸形。本研究对202例散发性PVNH患者开展外显子组测序，以鉴定新型遗传风险位点。研究首先开展核心家系分析，共检出219个新发变异。尽管初始分析未发现新的关联基因，但整体来看，PVNH患者在不耐受基因中存在显著过量的非同义新发变异（p = 3.27×10^-7），提示尚未与该病建立关联的基因中，稀有新发等位基因可能参与致病。通过比较病例组与对照组的基因水平聚合分析，我们鉴定到全基因组显著信号，该信号由MAP1B基因上4个超罕见功能丧失型杂合变异驱动，其中1个为新发变异。至少有1例患者的MAP1B变异来自既往未确诊PVNH的亲本。该类PVNH以额叶受累为主，且合并外侧裂周围多微小脑回畸形（perisylvian polymicrogyria）。上述结果证实MAP1B与PVNH的发病相关。从更广泛的视角来看，本研究结果提示，外显率不完全的前代有害突变，也可能是部分表观散发性疾病的致病原因。