Unsuspected consequences of synonymous and missense variants in OCA2 can be detected in blood cell RNA samples of patients with albinism

Vincent Michaud; Angèle Sequeira; Elina Mercier; Eulalie Lasseaux; Claudio Plaisant; Smail Hadj-Rabia; Sandra Whalen; Dominique Bonneau; Anne Dieux-Coeslier; Fanny Morice-Picard; Juliette Coursimault; Benoît Arveiler; Sophie Javerzat

doi:10.1111/pcmr.13123

Unsuspected consequences of synonymous and missense variants in OCA2 can be detected in blood cell RNA samples of patients with albinism

Pigment Cell Melanoma Res. 2023 Aug 31. doi: 10.1111/pcmr.13123. Online ahead of print.

Authors

Affiliations

¹ Rare Diseases Genetics and Metabolism, INSERM U1211, SBM Department, University of Bordeaux, Bordeaux, France.
² Department of Medical Genetics, University Hospital of Bordeaux, Bordeaux, France.
³ Department of Dermatology, Reference Center for Genodermatoses and Rare Skin Diseases (MAGEC), INSERM U1163, University of Paris, Imagine Institute, AP-HP5, Necker-Enfants Malades Hospital, Paris, France.
⁴ Clinical Genetics, Centre de Référence Maladies Rares Anomalies du développement et syndromes malformatifs, APHP, Sorbonne University, Hospital Armand Trousseau, Paris, France.
⁵ Department of Genetics, University Hospital Angers, Angers, France.
⁶ Clinical Genetics Department, Reference Center for Developmental Anomalies, CHU Lille, Lille, France.
⁷ Pediatric Dermatology Unit, National Center for Rare Skin Disorders, University Hospital of Bordeaux, Bordeaux, France.
⁸ Department of Genetics and Reference Center for Developmental Disorders, Normandie Univ, UNIROUEN, CHU Rouen, Inserm U1245, Rouen, France.

PMID: 37650133
DOI: 10.1111/pcmr.13123

Abstract

Oculocutaneous albinism type 2 (OCA2) is the second most frequent form of albinism and represents about 30% of OCA worldwide. As with all types of OCA, patients present with hypopigmentation of hair and skin, as well as severe visual abnormalities. We focused on a subgroup of 29 patients for whom genetic diagnosis was pending because at least one of their identified variants in or around exon 10 of OCA2 is of uncertain significance (VUS). By minigene assay, we investigated the effect of these VUS on exon 10 skipping and showed that not only intronic but also some synonymous variants can result in enhanced exon skipping. We further found that excessive skipping of exon 10 could be detected directly on blood samples of patients and of their one parent with the causal variant, avoiding invasive skin biopsies. Moreover, we show that variants, which result in lack of detectable OCA2 mRNA can be identified from blood samples as well, as shown for the most common OCA2 pathogenic missense variant c.1327G>A/p.(Val443Ile). In conclusion, blood cell RNA analysis allows testing the potential effect of any OCA2 VUS on transcription products. This should help to elucidate yet unsolved OCA2 patients and improve genetic counseling.

Keywords: OCA2; albinism; diagnosis; exon skipping; mRNA; noninvasive; variant of unknown significance.

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