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Article

Functional Characterization of Splice Variants in the Diagnosis of Albinism

by
Modibo Diallo
1,
Cécile Courdier
1,2,
Elina Mercier
1,
Angèle Sequeira
1,†,
Alicia Defay-Stinat
1,
Claudio Plaisant
2,
Shahram Mesdaghi
3,4,
Daniel Rigden
3,
Sophie Javerzat
1,
Eulalie Lasseaux
2,‡,
Laetitia Bourgeade
2,
Séverine Audebert-Bellanger
5,
Hélène Dollfus
6,
Smail Hadj-Rabia
7,
Fanny Morice-Picard
8,
Manon Philibert
9,
Mohamed Kole Sidibé
10,
Vasily Smirnov
11,
Ousmane Sylla
10,
Vincent Michaud
1,2 and
Benoit Arveiler
1,2,*add Show full author list remove Hide full author list
1
Laboratoire Maladies Rares, Génétique et Métabolisme, Bordeaux University, INSERM U1211, 33076 Bordeaux, France
2
Service de Génétique Médicale, Centre Hospitalier Universitaire de Bordeaux, 33076 Bordeaux, France
3
Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 7ZB, UK
4
Computational Biology Facility, MerseyBio, University of Liverpool, Crown Street, Liverpool L69 7ZB, UK
5
Service de Génétique Médicale, Centre Hospitalier Universitaire de Brest, 29200 Brest, France
6
Service de Génétique Médicale, Centre Hospitalier Universitaire de Strasbourg, 67091 Strasbourg, France
7
Service de Dermatologie, Hôpital Necker-Enfants Malades, 75015 Paris, France
8
Service de Dermatologie, Centre Hospitalier Universitaire de Bordeaux, 33076 Bordeaux, France
9
Hôpital Fondation Rothschild, 75019 Paris, France
10
Infirmerie Hôpital Militaire, Bamako BP 236, Mali
11
Service d’Exploration Fonctionnelle de la Vision et de Neuro-Ophtalmologie, Centre Hospitalier Universitaire de Lille, 59037 Lille, France
 
add Show full affiliation list
 
remove Hide full affiliation list
*
Author to whom correspondence should be addressed.
†
Current address: ImmunoConcEpT, Bordeaux University, CNRS UMR 5164, INSERM ERL 1303, 33076 Bordeaux, France.
‡
Current address: Institut Bergonié, 33000 Bordeaux, France.
Int. J. Mol. Sci. 2024, 25(16), 8657; https://doi.org/10.3390/ijms25168657
Submission received: 2 July 2024 / Revised: 26 July 2024 / Accepted: 3 August 2024 / Published: 8 August 2024
(This article belongs to the Section Molecular Genetics and Genomics)
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Abstract

Albinism is a genetically heterogeneous disease in which 21 genes are known so far. Its inheritance mode is autosomal recessive except for one X-linked form. The molecular analysis of exonic sequences of these genes allows for about a 70% diagnostic rate. About half (15%) of the unsolved cases are heterozygous for one pathogenic or probably pathogenic variant. Assuming that the missing variant may be located in non-coding regions, we performed sequencing for 122 such heterozygous patients of either the whole genome (27 patients) or our NGS panel (95 patients) that includes, in addition to all exons of the 21 genes, the introns and flanking sequences of five genes, TYR, OCA2, SLC45A2, GPR143 and HPS1. Rare variants (MAF < 0.01) in trans to the first variant were tested by RT-PCR and/or minigene assay. Of the 14 variants tested, nine caused either exon skipping or the inclusion of a pseudoexon, allowing for the diagnosis of 11 patients. This represents 9.8% (12/122) supplementary diagnosis for formerly unsolved patients and 75% (12/16) of those in whom the candidate variant was in trans to the first variant. Of note, one missense variant was demonstrated to cause skipping of the exon in which it is located, thus shedding new light on its pathogenic mechanism. Searching for non-coding variants and testing them for an effect on RNA splicing is warranted in order to increase the diagnostic rate.
Keywords: albinism; splice variants; exon skipping; pseudoexon; RT-PCR; minigene assay albinism; splice variants; exon skipping; pseudoexon; RT-PCR; minigene assay

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MDPI and ACS Style

Diallo, M.; Courdier, C.; Mercier, E.; Sequeira, A.; Defay-Stinat, A.; Plaisant, C.; Mesdaghi, S.; Rigden, D.; Javerzat, S.; Lasseaux, E.; et al. Functional Characterization of Splice Variants in the Diagnosis of Albinism. Int. J. Mol. Sci. 2024, 25, 8657. https://doi.org/10.3390/ijms25168657

AMA Style

Diallo M, Courdier C, Mercier E, Sequeira A, Defay-Stinat A, Plaisant C, Mesdaghi S, Rigden D, Javerzat S, Lasseaux E, et al. Functional Characterization of Splice Variants in the Diagnosis of Albinism. International Journal of Molecular Sciences. 2024; 25(16):8657. https://doi.org/10.3390/ijms25168657

Chicago/Turabian Style

Diallo, Modibo, Cécile Courdier, Elina Mercier, Angèle Sequeira, Alicia Defay-Stinat, Claudio Plaisant, Shahram Mesdaghi, Daniel Rigden, Sophie Javerzat, Eulalie Lasseaux, and et al. 2024. "Functional Characterization of Splice Variants in the Diagnosis of Albinism" International Journal of Molecular Sciences 25, no. 16: 8657. https://doi.org/10.3390/ijms25168657

APA Style

Diallo, M., Courdier, C., Mercier, E., Sequeira, A., Defay-Stinat, A., Plaisant, C., Mesdaghi, S., Rigden, D., Javerzat, S., Lasseaux, E., Bourgeade, L., Audebert-Bellanger, S., Dollfus, H., Hadj-Rabia, S., Morice-Picard, F., Philibert, M., Sidibé, M. K., Smirnov, V., Sylla, O., ... Arveiler, B. (2024). Functional Characterization of Splice Variants in the Diagnosis of Albinism. International Journal of Molecular Sciences, 25(16), 8657. https://doi.org/10.3390/ijms25168657

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