Molecular characterization of 1q44 microdeletion in 11 patients reveals three candidate genes for intellectual disability and seizures.

Gaelle Thierry (1) , Claire Bénéteau (1) , Olivier Pichon (1) , Elisabeth Flori (2) , Bertrand Isidor (1) , Françoise Popelard (3) , Marie-Ange Delrue (4) , Laetitia Duboscq-Bidot (5) , Ann-Charlotte Thuresson (6) , Bregje van Bon (7) , Dorothée Cailley (4) , Caroline Rooryck (4) , Agathe Paubel (8) , Corinne Metay (9) , Anne Dusser (10) , Laurent Pasquier (11) , Mylène Béri (12) , Céline Bonnet (12) , Sylvie Jaillard (13) , Christèle Dubourg (14) , Bassim Tou (15) , Marie-Pierre Quéré (16) , Cecilia Soussi-Zander (6) , Annick Toutain (8) , Didier Lacombe (4) , Benoit Arveiler (4) , Bert B. A. de Vries (7) , Philippe Jonveaux (12) , Albert David (1) , Cédric Le Caignec (1, 5)

1 Service de génétique médicale - Unité de génétique clinique [Nantes]
2 Service de cytogénétique
3 Service de Pédiatrie
4 MRGM - Maladies Rares - Génétique et Métabolisme
5 Institut du thorax
6 IGP - Department of Immunology, Genetics and Pathology [Uppsala, Sueden]
7 Department of Human Genetics
8 Service de génétique [Tours]
9 Plateforme Génétique Constitutionnelle CGH Array
10 Service de neurologie pédiatrique
11 Service de génétique clinique [Rennes]
12 Service de Génétique [CHRU Nancy]
13 Service de Cytogénétique et de Biologie Cellulaire
14 IGDR - Institut de Génétique et Développement de Rennes
15 Service de génétique moléculaire, pharmacogénétique et hormonologie
16 Service de Radiologie Pédiatrique

Patients with a submicroscopic deletion at 1q43q44 present with intellectual disability (ID), microcephaly, craniofacial anomalies, seizures, limb anomalies, and corpus callosum abnormalities. However, the precise relationship between most of deleted genes and the clinical features in these patients still remains unclear. We studied 11 unrelated patients with 1q44 microdeletion. We showed that the deletions occurred de novo in all patients for whom both parents' DNA was available (10/11). All patients presented with moderate to severe ID, seizures and non-specific craniofacial anomalies. By oligoarray-based comparative genomic hybridization (aCGH) covering the 1q44 region at a high resolution, we obtained a critical deleted region containing two coding genes-HNRNPU and FAM36A-and one non-coding gene-NCRNA00201. All three genes were expressed in different normal human tissues, including in human brain, with highest expression levels in the cerebellum. Mutational screening of the HNRNPU and FAM36A genes in 191 patients with unexplained isolated ID did not reveal any deleterious mutations while the NCRNA00201 non-coding gene was not analyzed. Nine of the 11 patients did not present with microcephaly or corpus callosum abnormalities and carried a small deletion containing HNRNPU, FAM36A, and NCRNA00201 but not AKT3 and ZNF238, two centromeric genes. These results suggest that HNRNPU, FAM36A, and NCRNA00201 are not major genes for microcephaly and corpus callosum abnormalities but are good candidates for ID and seizures. © 2012 Wiley Periodicals, Inc.

Mots clés: 1q44; deletion; chromosome; HNRNPU; FAM36A; ncRNA; intellectual disability; corpus callosum; seizure

Domaines: Biologie du développement; Génétique; Neurosciences [q-bio.NC]

Gaelle Thierry, Claire Bénéteau, Olivier Pichon, Elisabeth Flori, Bertrand Isidor, et al.. Molecular characterization of 1q44 microdeletion in 11 patients reveals three candidate genes for intellectual disability and seizures.. American Journal of Medical Genetics Part A, 2012, 158A (7), pp.1633-40. ⟨10.1002/ajmg.a.35423⟩. ⟨inserm-00706725⟩