Department of Pediatrics, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Systems Biology, Columbia University Irving Medical Center, New York, NY 10032, USA.
Department of Pediatrics, University of California, San Diego Medical School, San Diego, CA 92093, USA.
Am J Hum Genet. 2021 Oct 7;108(10):1964-1980. doi: 10.1016/j.ajhg.2021.08.011. Epub 2021 Sep 20.
Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly that is often accompanied by other anomalies. Although the role of genetics in the pathogenesis of CDH has been established, only a small number of disease-associated genes have been identified. To further investigate the genetics of CDH, we analyzed de novo coding variants in 827 proband-parent trios and confirmed an overall significant enrichment of damaging de novo variants, especially in constrained genes. We identified LONP1 (lon peptidase 1, mitochondrial) and ALYREF (Aly/REF export factor) as candidate CDH-associated genes on the basis of de novo variants at a false discovery rate below 0.05. We also performed ultra-rare variant association analyses in 748 affected individuals and 11,220 ancestry-matched population control individuals and identified LONP1 as a risk gene contributing to CDH through both de novo and ultra-rare inherited largely heterozygous variants clustered in the core of the domains and segregating with CDH in affected familial individuals. Approximately 3% of our CDH cohort who are heterozygous with ultra-rare predicted damaging variants in LONP1 have a range of clinical phenotypes, including other anomalies in some individuals and higher mortality and requirement for extracorporeal membrane oxygenation. Mice with lung epithelium-specific deletion of Lonp1 die immediately after birth, most likely because of the observed severe reduction of lung growth, a known contributor to the high mortality in humans. Our findings of both de novo and inherited rare variants in the same gene may have implications in the design and analysis for other genetic studies of congenital anomalies.
先天性膈疝 (CDH) 是一种严重的先天性异常，常伴有其他异常。虽然遗传学在 CDH 的发病机制中的作用已得到确立，但仅鉴定出少数与疾病相关的基因。为了进一步研究 CDH 的遗传学，我们分析了 827 个先证者-父母三体型中的从头编码变异，并证实了破坏性从头变异的总体显著富集，尤其是在受约束的基因中。我们基于假发现率低于 0.05 的从头变异，确定 LONP1（Lon 肽酶 1，线粒体）和 ALYREF（Aly/REF 出口因子）为候选 CDH 相关基因。我们还在 748 名受累个体和 11220 名匹配种族的对照个体中进行了超罕见变异关联分析，并确定 LONP1 是通过从头和超罕见遗传的主要杂合变体聚集在结构域核心并在受累家族个体中与 CDH 共分离的风险基因，这些变体在核心中聚类，并与 CDH 共分离。我们的 CDH 队列中约 3%的个体携带 LONP1 中的超罕见预测破坏性变体的杂合性，具有一系列临床表型，包括一些个体的其他异常和较高的死亡率以及需要体外膜氧合。肺上皮细胞特异性缺失 Lonp1 的小鼠在出生后立即死亡，很可能是因为观察到的肺生长严重减少，这是导致人类高死亡率的已知因素。我们在同一基因中发现的从头和遗传罕见变异可能对其他先天性异常的遗传研究的设计和分析具有影响。
