TY - JOUR
T1 - TRIM71 mutations cause a neurodevelopmental syndrome featuring ventriculomegaly and hydrocephalus
AU - Duy, Phan Q.
AU - Jux, Bettina
AU - Zhao, Shujuan
AU - Mekbib, Kedous Y.
AU - Dennis, Evan
AU - Dong, Weilai
AU - Nelson-Williams, Carol
AU - Mehta, Neel H.
AU - Shohfi, John P.
AU - Juusola, Jane
AU - Allington, Garrett
AU - Smith, Hannah
AU - Marlin, Sandrine
AU - Belhous, Kahina
AU - Monteleone, Berrin
AU - Schaefer, G. Bradley
AU - Pisarska, Margareta D.
AU - Vásquez, Jaime
AU - Estrada-Veras, Juvianee I.
AU - Keren, Boris
AU - Mignot, Cyril
AU - Flore, Leigh A.
AU - Palafoll, Irene V.
AU - Alper, Seth L.
AU - Lifton, Richard P.
AU - Haider, Shozeb
AU - Moreno-De-Luca, Andres
AU - Jin, Sheng Chih
AU - Kolanus, Waldemar
AU - Kahle, Kristopher T.
N1 - Publisher Copyright:
© 2024 The Author(s).
PY - 2024/12/1
Y1 - 2024/12/1
N2 - Congenital hydrocephalus, characterized by cerebral ventriculomegaly, is one of the most common reasons for paediatric brain surgery. Recent studies have implicated lin-41 (lineage variant 41)/TRIM71 (tripartite motif 71) as a candidate congenital hydrocephalus 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 congenital hydrocephalus (totalling 2697 parent-proband trios and 8091 total exomes), we identified 13 protein-altering de novo variants (DNVs) in TRIM71 in unrelated children exhibiting variable ventriculomegaly, congenital hydrocephalus, developmental delay, dysmorphic features and other structural brain defects, including corpus callosum dysgenesis and white matter hypoplasia. Eight unrelated patients were found to harbour arginine variants, including two recurrent missense DNVs, at homologous positions in RPXGV motifs of different NHL domains. Seven 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 that we term 'TRIM71-associated developmental disorders (TADD)', featuring variable ventriculomegaly, congenital hydrocephalus and other structural brain defects.
AB - Congenital hydrocephalus, characterized by cerebral ventriculomegaly, is one of the most common reasons for paediatric brain surgery. Recent studies have implicated lin-41 (lineage variant 41)/TRIM71 (tripartite motif 71) as a candidate congenital hydrocephalus 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 congenital hydrocephalus (totalling 2697 parent-proband trios and 8091 total exomes), we identified 13 protein-altering de novo variants (DNVs) in TRIM71 in unrelated children exhibiting variable ventriculomegaly, congenital hydrocephalus, developmental delay, dysmorphic features and other structural brain defects, including corpus callosum dysgenesis and white matter hypoplasia. Eight unrelated patients were found to harbour arginine variants, including two recurrent missense DNVs, at homologous positions in RPXGV motifs of different NHL domains. Seven 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 that we term 'TRIM71-associated developmental disorders (TADD)', featuring variable ventriculomegaly, congenital hydrocephalus and other structural brain defects.
KW - brain development
KW - de novo variants
KW - hydrocephalus
KW - neural stem cells
KW - structural brain disorders
KW - TRIM71
UR - http://www.scopus.com/inward/record.url?scp=85208936077&partnerID=8YFLogxK
U2 - 10.1093/brain/awae175
DO - 10.1093/brain/awae175
M3 - Article
C2 - 38833623
AN - SCOPUS:85208936077
SN - 0006-8950
VL - 147
SP - 4292
EP - 4305
JO - Brain
JF - Brain
IS - 12
ER -