ED Sciences de la Vie et de la Santé
Contribution to the molecular diagnosis of albinism: analysis of splicing variants, search for regulatory variants and study of the genotypic spectrum in Mali.
by Modibo DIALLO (Maladies Rares : Génétique et Métabolisme)
The defense will take place at 14h00 - Amphi Service de Génétique Médicale (CHU de Bordeaux) Ecole de Sages Femmes Hopital Pellegrin 1 Place Amélie Raba-Léon 33076 Bordeaux Cedex
in front of the jury composed of
- Véronique PINGAULT - Maîtresse de conférences - praticienne hospitalière - SERVICE DE MEDECINE GENOMIQUE DES MALADIES RARES Université Paris Cité - Rapporteur
- Anne-Françoise ROUX - Praticienne hospitalière - LBMR Pathologies neurosensorielles rares Laboratoire de Génétique Moléculaire CHU Montpellier INM - Inserm U1298 - Rapporteur
- Smail HADJ-RABIA - Professeur des universités - praticien hospitalier - Service de dermatologie (Bâtiment Robert Debré 1er étage) - Examinateur
- Christophe CULLIN - Professeur des universités - Institute of Chemistry & Biology of Membranes & Nanoobjects (UMR5248 CBMN) - Examinateur
- Martin TEICHMANN - Professeur des universités - Unité BRIC, Bordeaux Institute in Oncology INSERM U1312 - Examinateur
Albinism is a phenotypically and genetically heterogeneous genetic condition characterized by a variable degree of hypopigmentation and ocular damage. Molecular diagnosis of albinism is based on systematic analysis of the 20 known genes for SNV and CNV. The diagnostic yield is around 70%. The aim of this thesis is to improve the diagnostic rate. On the one hand, we have expanded our NGS panel to include all introns of the genes of the 5 most frequent forms of albinism, TYR, OCA2, SLC45A2, GPR143 and HPS1, and on the other hand, whole genome sequencing was performed. In part 1, we analyzed 23 patients with albinism from Mali. Diagnosis was obtained in all patients. Four were diagnosed with OCA 1 (oculocutaneous albinism type 1), 17 with OCA 2 and 2 with OCA 4. The NM_000275.3:c.819_822delinsGGTC variant of OCA2 was the most frequently encountered. Four new variants were identified (2 in TYR, 2 in OCA2). A deep intronic variant alters OCA2 RNA splicing by inclusion of a pseudo-exon. Of note, deletion of exon 7 of OCA2, commonly observed in East, Central and Southern Africa, was absent from this series. African patients with OCA 1 and OCA 4 had only been reported twice and once respectively in previous publications. This study is the first report on the genotypic spectrum of albinism in a western sub-Saharan country. Part 2 involved the analysis of splice variants in patients with a pathogenic heterozygous variant. We identified 3 new deep intronic variants that generate a pseudoexon with a frameshift leading to a premature stop. This allowed us to establish the diagnosis in these and other patients in the cohort. In part 3, we identified 10 new rare variants in candidate regulatory elements of albinism genes. These variants require functional testing to validate their pathogenic effect.