The role of CNVs in the etiology of rare autosomal recessive disorders: the example of TRAPPC9-associated intellectual disability

Jeremie Mortreux (1, 2) , Tiffany Busa (1, 2) , Dominique P. Germain (3) , Gwenaël Nadeau (4) , Jacques Puechberty (5) , Christine Coubes (6) , Vincent Gatinois (7, 8) , Pierre Cacciagli (1) , Yannis Duffourd (9, 10, 11) , Jean-Marc Pinard (12) , Hélène Tevissen (13) , Laurent Villard (1) , Damien Sanlaville (14) , Nicole Philip (1, 2) , Chantal Missirian (2, 1)

1 MMG - Marseille medical genetics - Centre de génétique médicale de Marseille
2 Département de génétique médicale [Hôpital de la Timone - APHM]
3 Hôpital Raymond Poincaré [AP-HP]
4 Service de Cytogénétique
5 IGH - Institut de génétique humaine
6 Service de Génétique Clinique
7 Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB)
8 CHU Montpellier
9 FHU TRANSLAD (CHU de Dijon)
10 UBFC - Université Bourgogne Franche-Comté [COMUE]
11 Equipe GAD (LNC - U1231)
12 Service de neurologie pédiatrique
13 CH DE VALENCE - Centre Hospitalier de Valence
14 HFME - Service de Cytogénétique

Introduction A large number of genes involved in autosomal recessive forms of intellectual disability (ID) were identified over the past few years through whole-exome sequencing (WES) or whole-genome sequencing in consanguineous families. Disease-associated variants in TRAPPC9 were reported in eight multiplex consanguineous sibships from different ethnic backgrounds, and led to the delineation of the phenotype. Affected patients have microcephaly, obesity, normal motor development, severe ID, and language impairment and brain anomalies. Patients We report six new patients recruited through a national collaborative network. Results In the two patients heterozygous for a copy-number variation (CNV), the phenotype was clinically relevant with regard to the literature, which prompted to sequence the second allele, leading to identification of disease-associated variants in both. The third patient was homozygote for an intragenic TRAPPC9 CNV. The phenotype of the patients reported was concordant with the literature. Recent reports emphasized the role of CNVs in the etiology of rare recessive disorders. Conclusion This study demonstrates that CNVs significantly contribute to the mutational spectrum of TRAPPC9 gene, and also confirms the interest of combining WES with CNV analysis to provide a molecular diagnosis to patients with rare Mendelian disorders.

Mots clés: Cytogenetics; Medical genetics; Neurodevelopmental disorders

Domaines: Sciences du Vivant [q-bio]; Génétique; Médecine humaine et pathologie; Neurosciences [q-bio.NC]

Jeremie Mortreux, Tiffany Busa, Dominique P. Germain, Gwenaël Nadeau, Jacques Puechberty, et al.. The role of CNVs in the etiology of rare autosomal recessive disorders: the example of TRAPPC9-associated intellectual disability. European Journal of Human Genetics, 2018, 26 (1), pp.143-148. ⟨10.1038/s41431-017-0018-x⟩. ⟨hal-01668647⟩