TY  - JOUR
TI  - TRIM71 mutations cause a neurodevelopmental syndrome featuring ventriculomegaly and hydrocephalus
KW  - Brain development
KW  -  de novo variants
KW  -  hydrocephalus
KW  -  neural stem cells
KW  -  structural brain disorders
KW  -  TRIM71
ID  - discovery10193398
N1  - This version is the author accepted manuscript. For information on re-use, please refer to the publisher?s terms and conditions.
AV  - restricted
N2  - 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.
PB  - Oxford University Press (OUP)
UR  - http://dx.doi.org/10.1093/brain/awae175
JF  - Brain
Y1  - 2024/06/04/
A1  - Duy, Phan Q
A1  - Jux, Bettina
A1  - Zhao, Shujuan
A1  - Mekbib, Kedous Y
A1  - Dennis, Evan
A1  - Dong, Weilai
A1  - Nelson-Williams, Carol
A1  - Mehta, Neel H
A1  - Shohfi, John P
A1  - Juusola, Jane
A1  - Allington, Garrett
A1  - Smith, Hannah
A1  - Marlin, Sandrine
A1  - Belhous, Kahina
A1  - Monteleone, Berrin
A1  - Schaefer, G Bradley
A1  - Pisarska, Margareta D
A1  - Vásquez, Jaime
A1  - Estrada-Veras, Juviannee I
A1  - Keren, Boris
A1  - Mignot, Cyril
A1  - Flore, Leigh A
A1  - Palafoll, Irene V
A1  - Alper, Seth L
A1  - Lifton, Richard P
A1  - Haider, Shozeb
A1  - Moreno-De-Luca, Andres
A1  - Jin, Sheng Chih
A1  - Kolanus, Waldemar
A1  - Kahle, Kristopher T
ER  -