TRIM71 mutations cause a neurodevelopmental syndrome featuring ventriculomegaly and hydrocephalus

心室肥大 错义突变 外显子组测序 生物 外显子组 遗传学 多小脑回 先证者 医学 表型 突变 神经科学 基因 胎儿 癫痫 怀孕
作者
Phan Q. Duy,Bettina Jux,Shujuan Zhao,Kedous Y. Mekbib,Evan Dennis,Weilai Dong,Carol Nelson‐Williams,Neel H. Mehta,John Shohfi,Jan M. Friedman,Garrett Allington,Hannah Smith,Sandrine Marlin,Kahina Belhous,Berrin Monteleone,G. Bradley Schaefer,Margareta D. Pisarska,Jaime Martínez Vásquez,Juviannee I Estrada-Veras,Boris Keren,Cyril Mignot,Leigh Anne Flore,Irene Valenzuela,Seth L. Alper,Richard P. Lifton,Shozeb Haider,Andres Moreno‐De‐Luca,Sheng Chih Jin,Waldemar Kolanus,Kristopher T. Kahle
出处
期刊:Brain [Oxford University Press]
标识
DOI:10.1093/brain/awae175
摘要

Abstract Congenital hydrocephalus (CH), characterized by cerebral ventriculomegaly, is one of the most common reasons for pediatric brain surgery. Recent studies have implicated lin-41 (lineage variant 41)/TRIM71 (tripartite motif 71) as a candidate CH risk gene, however, TRIM71 variants have not been systematically examined in a large patient cohort or conclusively linked with an OMIM syndrome. Through cross-sectional analysis of the largest assembled cohort of patients with cerebral ventriculomegaly, including neurosurgically-treated CH (totaling 2,697 parent-proband trios and 8,091 total exomes), we identified 13 protein-altering de novo variants (DNVs) in TRIM71 in unrelated children exhibiting variable ventriculomegaly, CH, developmental delay, dysmorphic features, and other structural brain defects including corpus callosum dysgenesis and white matter hypoplasia. Eight unrelated patients were found to harbor arginine variants, including two recurrent missense DNVs, at homologous positions in RPXGV motifs of different NHL domains. Seven additional patients with rare, damaging, unphased or transmitted variants of uncertain significance were also identified. NHL-domain variants of TRIM71 exhibited impaired binding to the canonical TRIM71 target CDKN1A; other variants failed to direct the subcellular localization of TRIM71 to processing bodies. Single-cell transcriptomic analysis of human embryos revealed expression of TRIM71 in early first-trimester neural stem cells of the brain. These data show TRIM71 is essential for human brain morphogenesis and that TRIM71 mutations cause a novel neurodevelopmental syndrome featuring ventriculomegaly and CH.
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