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Heterozygous HMGB1 loss‐of‐function variants are associated with developmental delay and microcephaly
Author(s) -
Uguen Kévin,
Krysiak Kilannin,
AudebertBellanger Séverine,
Redon Sylvia,
Benech Caroline,
VioraDupont Eléonore,
Tran MauThem Frederic,
Rondeau Sophie,
Elsharkawi Ibrahim,
Granadillo Jorge L.,
Neidich Julie,
Soares Celia Azevedo,
Tkachenko Natáliya,
M. Amudhavalli Shivarajan,
Engleman Kendra,
Boland Anne,
Deleuze JeanFrançois,
Bezieau Stéphane,
Odent Sylvie,
Toutain Annick,
Bonneau Dominique,
GilbertDussardier Brigitte,
Faivre Laurence,
Rio Marlène,
Le Marechal Cedric,
Ferec Claude,
Repnikova Elena,
Cao Yang
Publication year - 2021
Publication title -
clinical genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.543
H-Index - 102
eISSN - 1399-0004
pISSN - 0009-9163
DOI - 10.1111/cge.14015
Subject(s) - haploinsufficiency , microcephaly , loss function , genetics , biology , gene , phenotype , global developmental delay , in silico , compound heterozygosity , intellectual disability , microdeletion syndrome , hearing loss , medicine , audiology
13q12.3 microdeletion syndrome is a rare cause of syndromic intellectual disability. Identification and genetic characterization of patients with 13q12.3 microdeletion syndrome continues to expand the phenotypic spectrum associated with it. Previous studies identified four genes within the approximately 300 Kb minimal critical region including two candidate protein coding genes: KATNAL1 and HMGB1 . To date, no patients carrying a sequence‐level variant or a single gene deletion in HMGB1 or KATNAL1 have been described. Here we report six patients with loss‐of‐function variants involving HMGB1 and who had phenotypic features similar to the previously described 13q12.3 microdeletion syndrome cases. Common features included developmental delay, language delay, microcephaly, obesity and dysmorphic features. In silico analyses suggest that HMGB1 is likely to be intolerant to loss‐of‐function, and previous in vitro data are in line with the role of HMGB1 in neurodevelopment. These results strongly suggest that haploinsufficiency of the HMGB1 gene may play a critical role in the pathogenesis of the 13q12.3 microdeletion syndrome.