Congenital diaphragmatic hernia (CDH) is a relatively common and genetically heterogeneous structural birth defect associated with high mortality and morbidity. We describe eight unrelated families with an X-linked condition characterized by diaphragm defects, variable anterior body-wall anomalies, and/or facial dysmorphism. Using linkage analysis and exome or genome sequencing, we found that missense variants in plastin 3 (PLS3), a gene encoding an actin bundling protein, co-segregate with disease in all families. Loss-of-function variants in PLS3 have been previously associated with X-linked osteoporosis (MIM: 300910), so we used in silico protein modeling and a mouse model to address these seemingly disparate clinical phenotypes. The missense variants in individuals with CDH are located within the actin-binding domains of the protein but are not predicted to affect protein structure, whereas the variants in individuals with osteoporosis are predicted to result in loss of function. A mouse knockin model of a variant identified in one of the CDH-affected families, c.1497G>C (p.Trp499Cys), shows partial perinatal lethality and recapitulates the key findings of the human phenotype, including diaphragm and abdominal-wall defects. Both the mouse model and one adult human male with a CDH-associated PLS3 variant were observed to have increased rather than decreased bone mineral density. Together, these clinical and functional data in humans and mice reveal that specific missense variants affecting the actin-binding domains of PLS3 might have a gain-of-function effect and cause a Mendelian congenital disorder.

先天性膈疝（CDH）是一种相对常见且具有遗传异质性的结构性出生缺陷，与高死亡率和发病率相关。我们描述了 8 个不相关的 X 连锁家族，其特征是膈肌缺陷、可变的前体壁异常和/或面部畸形。通过连锁分析和外显子组或基因组测序，我们发现 plastin 3 ( PLS3 )（编码肌动蛋白捆绑蛋白的基因）中的错义变异与所有家族中的疾病共分离。PLS3中的功能丧失变异先前已被认为与 X 连锁骨质疏松症 (MIM: 300910 ) 相关，因此我们使用计算机蛋白质模型和小鼠模型来解决这些看似不同的临床表型。CDH 患者中的错义变异位于蛋白质的肌动蛋白结合域内，但预计不会影响蛋白质结构，而骨质疏松症患者中的变异预计会导致功能丧失。在受 CDH 影响的家族之一中鉴定出的变体 c.1497G>C (p.Trp499Cys) 的小鼠敲入模型显示出部分围产期致死性，并概括了人类表型的关键发现，包括膈肌和腹壁缺陷。小鼠模型和一名具有 CDH 相关PLS3变异的成年男性都被观察到骨矿物质密度增加而不是减少。总之，这些人类和小鼠的临床和功能数据表明，影响PLS3肌动蛋白结合域的特定错义变异可能具有功能获得效应并导致孟德尔先天性疾病。