Felker Stephanie A, Lawlor James Mj, Hiatt Susan M, Thompson Michelle L, Latner Donald R, Finnila Candice R, Bowling Kevin M, Bonnstetter Zachary T, Bonini Katherine E, Kelly Nicole R, Kelley Whitley V, Hurst Anna Ce, Kelly Melissa A, Nakouzi Ghunwa, Hendon Laura G, Bebin E Martina, Kenny Eimear E, Cooper Gregory M
HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA 35806.
Washington University School of Medicine, Saint Louis, MO, USA 63110.
bioRxiv. 2023 Jan 13:2023.01.12.523654. doi: 10.1101/2023.01.12.523654.
Neurodevelopmental disorders (NDDs) often result from rare genetic variation, but genomic testing yield for NDDs remains around 50%, suggesting some clinically relevant rare variants may be missed by standard analyses. Here we analyze "poison exons" (PEs) which, while often absent from standard gene annotations, are alternative exons whose inclusion results in a premature termination codon. Variants that alter PE inclusion can lead to loss-of-function and may be highly penetrant contributors to disease.
We curated published RNA-seq data from developing mouse cortex to define 1,937 PE regions conserved between humans and mice and potentially relevant to NDDs. We then analyzed variants found by genome sequencing in multiple NDD cohorts.
Across 2,999 probands, we found six clinically relevant variants in PE regions that were previously overlooked. Five of these variants are in genes that are part of the sodium voltage-gated channel alpha subunit family ( , and ), associated with epilepsies. One variant is in , associated with Cerebrocostomandibular Syndrome. These variants have moderate to high computational impact assessments, are absent from population variant databases, and were observed in probands with features consistent with those reported for the associated gene.
With only a minimal increase in variant analysis burden (most probands had zero or one candidate PE variants in a known NDD gene, with an average of 0.77 per proband), annotation of PEs can improve diagnostic yield for NDDs and likely other congenital conditions.
神经发育障碍（NDDs）通常由罕见的基因变异引起，但NDDs的基因组检测阳性率仍在50%左右，这表明一些具有临床相关性的罕见变异可能会被标准分析遗漏。在这里，我们分析了“毒性外显子”（PEs），这些外显子虽然在标准基因注释中常常缺失，但它们是选择性外显子，其包含会导致提前终止密码子。改变PEs包含的变异可能导致功能丧失，并且可能是疾病的高外显率致病因素。
我们整理了已发表的来自发育中小鼠皮层的RNA测序数据，以定义1937个在人类和小鼠之间保守且可能与NDDs相关的PE区域。然后，我们分析了在多个NDD队列中通过基因组测序发现的变异。
在2999名先证者中，我们在PE区域发现了6个先前被忽视的具有临床相关性的变异。其中5个变异位于钠电压门控通道α亚基家族（ 、 和 ）的基因中，这些基因与癫痫相关。1个变异位于 ，与脑肋骨下颌综合征相关。这些变异具有中度到高度的计算影响评估，在人群变异数据库中不存在，并且在先证者中被观察到，其特征与相关基因报道的特征一致。
仅略微增加变异分析负担（大多数先证者在已知的NDD基因中有零个或一个候选PE变异，平均每个先证者0.77个），PEs注释就可以提高NDDs以及可能其他先天性疾病的诊断阳性率。
