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

Kévin Uguen (1) , Kilannin Krysiak (2) , Séverine Audebert-Bellanger (1) , Sylvia Redon (1) , Caroline Benech (3) , Eléonore Viora-Dupont (4) , Frederic Tran Mau-Them (5) , Sophie Rondeau (6) , Ibrahim Elsharkawi (2) , Jorge L Granadillo (2) , Julie Neidich (2) , Celia Azevedo Soares (7, 8) , Natáliya Tkachenko (8) , Shivarajan M Amudhavalli (9) , Kendra Engleman (9) , Anne Boland (10, 11) , Jean-François Deleuze (10, 11) , Stéphane Bezieau (12) , Sylvie Odent (13, 14, 15) , Annick Toutain (16) , Dominique Bonneau (17) , Brigitte Gilbert-Dussardier (18) , Laurence Faivre (19) , Marlène Rio (6) , Cedric Le Marechal (1) , Claude Ferec (1) , Elena Repnikova (9) , Yang Cao (2)

1 CHRU Brest - Centre Hospitalier Régional Universitaire de Brest
2 Washington University School of Medicine in St. Louis
3 GGB - Génétique, génomique fonctionnelle et biotechnologies (UMR 1078)
4 Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon)
5 CHU Dijon - Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand
6 Hôpital Necker - Enfants Malades [AP-HP]
7 Universidade do Porto = University of Porto
8 Centro Hospitalar do Porto
9 Children's Mercy Hospital [Kansas City]
10 Université Paris-Saclay
11 CNRGH - Centre National de Recherche en Génomique Humaine
12 CHU Nantes - Centre Hospitalier Universitaire de Nantes
13 IGDR - Institut de Génétique et Développement de Rennes
14 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Ponchaillou]
15 Centre de référence Maladies Rares CLAD-Ouest [Rennes]
16 CHRU Tours - Centre Hospitalier Régional Universitaire de Tours
17 MITOVASC - MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale
18 CHU de Poitiers - Centre hospitalier universitaire de Poitiers = Poitiers University Hospital
19 LNC - Lipides - Nutrition - Cancer [Dijon - U1231]

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.

Mots clés: HMGB1; developmental disabilities; dysmorphic features; loss of function mutation

Domaines: Sciences du Vivant [q-bio]

Kévin Uguen, Kilannin Krysiak, Séverine Audebert-Bellanger, Sylvia Redon, Caroline Benech, et al.. Heterozygous HMGB1 loss-of-function variants are associated with developmental delay and microcephaly. Clinical Genetics, 2021, 100 (4), pp.386-395. ⟨10.1111/cge.14015⟩. ⟨hal-03282329⟩