In two independent ongoing next-generation sequencing projects for individuals with holoprosencephaly and individuals with disorders of sex development, and through international research collaboration, we identified twelve individuals with de novo loss-of-function (LoF) variants in protein phosphatase 1, regulatory subunit 12a (PPP1R12A), an important developmental gene involved in cell migration, adhesion, and morphogenesis. This gene has not been previously reported in association with human disease, and it has intolerance to LoF as illustrated by a very low observed-to-expected ratio of LoF variants in gnomAD. Of the twelve individuals, midline brain malformations were found in five, urogenital anomalies in nine, and a combination of both phenotypes in two. Other congenital anomalies identified included omphalocele, jejunal, and ileal atresia with aberrant mesenteric blood supply, and syndactyly. Six individuals had stop gain variants, five had a deletion or duplication resulting in a frameshift, and one had a canonical splice acceptor site loss. Murine and human in situ hybridization and immunostaining revealed PPP1R12A expression in the prosencephalic neural folds and protein localization in the lower urinary tract at critical periods for forebrain division and urogenital development. Based on these clinical and molecular findings, we propose the association of PPP1R12A pathogenic variants with a congenital malformations syndrome affecting the embryogenesis of the brain and genitourinary systems and including disorders of sex development.

中文翻译：

---

PPP1R12A的功能丧失变异：从孤立的性逆转到全脑畸形谱和泌尿生殖器畸形。

在两个正在进行的独立的下一代测序项目中，针对全脑性前脑性个体和性发育障碍的个体，并通过国际研究合作，我们鉴定了十二个蛋白磷酸酶1（调节亚基）具有从新功能丧失（LoF）变异的个体12a（PPP1R12A），一个重要的发育基因，参与细胞迁移，粘附和形态发生。先前尚未报道该基因与人类疾病有关，并且它对LoF不耐受，如gnomAD中LoF变体的观察到/预期比率极低所说明。在十二个人中，中线大脑畸形在五个中发现，泌尿生殖系统异常在九个中发现，两种表型的组合在两个中被发现。识别出的其他先天性异常包括卵裂，空肠，回肠闭锁，肠系膜血供异常，并伴有回肠闭锁。六个人有终止增益变异，五个人缺失或重复导致移码，而一个人则有规范的剪接受体位点丢失。鼠和人的原位杂交和免疫染色显示在前脑分裂和泌尿生殖发育的关键时期，PPP1R12A在前脑神经折叠中表达，并且在下尿路中蛋白质定位。基于这些临床和分子发现，我们提出了PPP1R12A致病变异与先天性畸形综合症的关联，该综合症会影响大脑和泌尿生殖系统的胚胎发生，并包括性发育障碍。5个具有删除或重复现象，导致移码；另外5个具有规范的剪接受体位点丢失。鼠和人的原位杂交和免疫染色显示在前脑分裂和泌尿生殖发育的关键时期，PPP1R12A在前脑神经折叠中表达，并且在下尿路中蛋白质定位。基于这些临床和分子发现，我们提出了PPP1R12A致病变异与先天性畸形综合症的关联，该综合症会影响大脑和泌尿生殖系统的胚胎发生，并包括性发育障碍。5个具有删除或重复现象，导致移码；另外5个具有规范的剪接受体位点丢失。鼠和人的原位杂交和免疫染色显示在前脑分裂和泌尿生殖发育的关键时期，PPP1R12A在前脑神经折叠中表达，并且在下尿路中蛋白质定位。基于这些临床和分子发现，我们提出了PPP1R12A致病变异与先天性畸形综合症的关联，该综合症会影响大脑和泌尿生殖系统的胚胎发生，并包括性发育障碍。鼠和人的原位杂交和免疫染色显示在前脑分裂和泌尿生殖发育的关键时期，PPP1R12A在前脑神经折叠中表达，并且在下尿路中蛋白质定位。基于这些临床和分子发现，我们提出了PPP1R12A致病变异与先天性畸形综合症的关联，该综合症会影响大脑和泌尿生殖系统的胚胎发生，并包括性发育障碍。鼠和人的原位杂交和免疫染色显示在前脑分裂和泌尿生殖发育的关键时期，PPP1R12A在前脑神经折叠中表达，并且在下尿路中蛋白质定位。基于这些临床和分子发现，我们提出了PPP1R12A致病变异与先天性畸形综合症的关联，该综合症会影响大脑和泌尿生殖系统的胚胎发生，并包括性发育障碍。