Heterozygous HMGB1 loss-of-function variants are associated with developmental delay and microcephaly

6533b7d5fe1ef96bd1263da3

RESEARCH PRODUCT

Heterozygous HMGB1 loss-of-function variants are associated with developmental delay and microcephaly

Laurence Faivre Natáliya Tkachenko Celia Azevedo Soares Annick Toutain Marlène Rio Anne Boland Kendra Engleman Eléonore Viora-dupont Kévin Uguen Cédric Le Maréchal Yang Cao Sophie Rondeau Kilannin Krysiak Jean-françois Deleuze Caroline Benech Frédéric Tran Mau-them Sylvie Odent Jorge L. Granadillo Dominique Bonneau Claude Férec Ibrahim Elsharkawi Séverine Audebert-bellanger Julie Neidich Stéphane Bézieau Brigitte Gilbert-dussardier Elena Repnikova Sylvia Redon Shivarajan Manickavasagam Amudhavalli

subject

Male 0301 basic medicine Heterozygote Microcephaly Adolescent DNA Copy Number Variations Language delay [SDV]Life Sciences [q-bio]Karyotype Inheritance Patterns chemical and pharmacologic phenomena 030105 genetics & heredity Biology dysmorphic features loss of function mutation 03 medical and health sciences Exome Sequencing Intellectual disability Genetics medicine Humans Genetic Predisposition to Disease HMGB1 Protein Child Gene Genetic Association Studies In Situ Hybridization Fluorescence Genetics (clinical)Loss function Genetics HMGB1 Facies Exons developmental disabilities Microdeletion syndrome medicine.disease Phenotype Phenotype 030104 developmental biology Child Preschool Microcephaly Female Haploinsufficiency

description

International audience; 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.

year	journal	country	edition	language
2021-06-24

10.1111/cge.14015 https://hal.science/hal-03282329