Search for missing mutations in patients with albinism

Albinism is a clinically and genetically heterogeneous condition characterized by variable degrees of hypopigmentation (extending from a complete absence of pigmentation to a normal pigmentation) and by ophthalmological anomalies including reduced visual acuity, chiasmatic misrouting of the optic nerves, nystagmus, foveal hypoplasia, iris transillumination, and retinal hypopigmentation, all leading to reduced visual acuity. Twenty genes are involved in the oculocutaneous, ocular and syndromic (Hermansky-Pudlak Syndrome and Chediak-Higashi Syndrome) forms of the disease.

Our laboratory at University Hospital of Bordeaux has been performing the molecular diagnosis of albinism since 2003. It is a reference laboratory at the national and international levels, being the only one in Europe to perform an extensive analysis of all 20 genes in order to identify both point mutation (next generation sequencing, NGS) and intragenic rearrangements (high resolution array-CGH). Our series of more than 1600 patients constitutes probably the largest cohort of patients with albinism worldwide.

Despite our extensive analyses, about 30% of the patients remain without a molecular diagnosis, because either only one or no mutation at all has been identified in the 20 known genes.

Our research program at INSERM U 1211 comprises:

1) Intensifying the analysis of the 20 genes by looking for variants in the flanking genomic regions and in the introns. More specifically our aim is to search for pathogenic variants in the regulatory elements of the genes. These elements are largely unknown as yet. We shall identify them by a double approach combining bioinformatics analyses and promoter capture Hi-C. The candidate regulatory elements will be sequenced in the patients remaining without a molecular diagnosis. Functional tests will be undertaken in order to evaluate the variants’ pathogenicity.

2) Searching for new albinism genes. 129 functional candidates involved in melanogenesis have been selected and were sequenced in about 250 patients. We identified two new genes: DCT/TYRP2 as novel gene for oculocutaneous albinism (OCA8), and BLOC1S5 as novel gene for Hermanski-Pudlak Syndrome (HPS-11). This work will be continued in order to identify more genes by WES and/or WGS.

3) Developing a new panel of genes (80-100 genes) for the differential diagnosis in patients presenting with an incomplete form of “ocular albinism “.

4) Functional validation of variants of unknown significance found during diagnostic process. These are essentially splicing, missense and synonymous variants.

This project is typically at the interface between healthcare and research and exemplifies the advantage of collecting large national and international cohorts of patients with rare diseases.

Contributing Members

Benoit Arveiler [University Professor – Hospital Practitioner, Principal Investigator]

Sophie Javerzat [University Professor]

Angèle Tingaud-Sequeira [Engineer]

Vincent Michaud [Hospital and University Assistant, PhD student]

Modibo Diallo [PhD Student]

Aurélien Trimouille [Hospital and University Assistant]

Christophe Hubert [Engineer]

Elina Mercier [PhD Student] 

National and International Collaborations

Pr. Alain Taieb. [INSERM U1035 (Biothérapie des Maladies Génétiques Inflammatoires et Cancers, Bordeaux]
Dr. Isabelle Drumare-Bouvet | Dr Vasily Smirnov | Dr. Sabine Defoort-Dhellemmes. [Service d’Exploration de la vision et de neuro-ophtalmologie, CHRU de Lille]
Dr Valentine Coste. [Service d’Ophtalmologie, CHU de Bordeaux]
Dr. Cédric Delevoye. [Institut Curie, Paris]
Pr. Mickael Marks. [University of Pennsylvania, Philadelphia, USA]

Project publications

Rooryck C, Roudaut C, Robine E, Müsebeck J, Arveiler B. Oculocutaneous Albinism Type 3 in a Caucasian Patient. Pigm Cell Res. 19, 239-242 (2006).

Rooryck C, Morice F, Mortemousque B, Lacombe L, Taïeb T, Arveiler B. Albinisme oculo-cutané. Revue générale. Ann Dermatol Vénérol. 134, 55-64 (2007).

Rooryck C., Morice-Picard F, Elçioglu NH., Lacombe D, Taieb A, Arveiler B. Molecular diagnosis of oculocutaneous albinism: new mutations in the OCA1 4 genes and practical aspects. Pigm Cell Melan Res (2008), 21:583-587.

Rooryck C, Morice-Picard F, Lacombe D, Taieb A, Arveiler B. Genetic basis of oculocutaneous albinism. Expert Rev. Dermatol., (2009) 4, 611-622.

Rooryck C, Morice-Picard F, Lasseaux E, Cailley D, Dollfus H, Defoort-Dhellemme S, Duban-Bedu B, de Ravel TJ, Taieb A, Lacombe D, Arveiler B. High resolution mapping of OCA2 intragenic rearrangements and identification of a founder effect associated with a deletion in Polish albino patients. Hum Genet (2011) 129:199–208.

Bocquet B, A Lacroux, M-O Surget, C Baudoin, V Marquette, G. Manes, M. Hebrard, A Sénéchal, A-F Roux, C.-M. Dhaenens, D. Allorge, J-M Rozet, I Perrault, J-P Bonnefont, J. Kaplan, H. Dollfus, P. Bonneau, I Audo, C Zeitz, V Paquis, P. Calvas, B. Arveiler, S. Kohl, B. Wissinger, C. Blanchet, I. Meunier, C. Hamel. Prevalence of inherited retinal dystrophies and optic neuropathies in Southern France: assessment from a 21-year data management. Ophthalmic Epidemiology, 2013;20:13-25.

Morice-Picard F, Lasseaux E, François S, Simon D, Rooryck C, Bieth E, Colin E, Bonneau D, Journel H, Walraedt S, Leroy B, Meire F, Lacombe D, Arveiler B. SLC24A5 mutations are associated with non-syndromic oculocutaneous albinism. J. Invest. Dermatol, 2014, 134:568-571.

Morice-Picard F, Lasseaux E, Cailley D, Gros A, Toutain J, Plaisant C, Simon D, François S, Gilbert-Dussardier B, Kaplan J, Rooryck C, Lacombe D, Arveiler B. High resolution array-CGH in patients with oculocutaneous albinism identifies new deletions of the TYR, OCA2 and SLC45A2 genes, and a complex rearrangement of the OCA2 gene. Pigm. Cell Melan. Res., 2014, 27:59-71

Montoliu L, Grønskov K, Wei AH, Martínez-García M, Fernández A, Arveiler B, Morice-Picard F, Riazuddin S, Suzuki T, Ahmed ZM, Rosenberg T, Li W. Increasing the complexity: new genes and new types of albinism. Pigment Cell Melan. Res. 2014, 27:11-18.

Bertolotti A, Lasseaux E, Plaisant C, Trimouille A, Morice-Picard F, Rooryck C, Lacombe D, Couppie P, Arveiler B. Identification of a homozygous mutation of SLC24A5 (OCA6) in two patients with oculocutaneous albinism from French Guiana. Pigment Cell Melanoma Res. 2016, 29:104-106.

Morice-Picard F, Lasseaux E, Plaisant C, Cailley D, Bouron J, Rooryck C, Lacombe D, Pelletier V, Lipsker D, Perdomo-Trujillo Y, Dollfus H, Arveiler B. Albinism in a patient with mutations at both the OA1 and OCA3 loci. Pigment Cell Melanoma Res. 2016, 29:107-109.

Goldman-Levy G, de la Fouchardiere A, Hamel CP, Lasseaux E, Yordanova Y, Guillot B, Bessis D, Pernet C, Frouin E, Boulle N, Haddad V, Pissaloux D, Costes V, Arveiler B, Rigau V. Primary leptomeningeal melanocytic tumour with a plaque-like blue nevus in a patient with ocular albinism. Eur J Dermatol. 2016, 26:496-498.

Morice-Picard F, Benard G, Rezvani HR, Lasseaux E, Simon D, Moutton S, Rooryck C, Lacombe D, Baumann C, Arveiler B. Complete loss of function of the ubiquitin ligase HERC2 causes a severe neurodevelopmental phenotype. Eur J Hum Genet. 2016, 25:52-58.

Arveiler B, Lasseaux E, Morice-Picard F. Clinical and genetic aspects of albinism. Presse Med. 2017, 46:648-654.

Michaud V, Lasseaux E, Plaisant C, Verloes A, Perdomo-Trujillo Y, Hamel C, Elcioglu NH, Leroy B, Kaplan J, Jouk PS, Lacombe D, Fergelot P, Morice-Picard F, Arveiler B. Clinico-molecular analysis of eleven patients with Hermansky-Pudlak type 5 syndrome, a mild form of HPS. Pigment Cell Melanoma Res. 2017, 30:563-570.

Marti A, Lasseaux E, Ezzedine K, Léauté-Labrèze C, Boralevi F, Paya C, Coste V, Deroissart V, Arveiler B, Taieb A, Morice-Picard F. Lessons of a day hospital: Comprehensive assessment of patients with albinism in a European setting. Pigment Cell Melanoma Res. 2018 Mar 31(2):318-329. https://doi.org/10.1111/pcmr.12651

Lasseaux E, Plaisant C, Michaud V, Pennamen P, Trimouille A, Gaston L, Monfermé S, Lacombe D, Rooryck C, Morice-Picard F, Arveiler B. Molecular characterization of a series of 990 index patients with albinism. Pigment Cell Melanoma Res., 2018, 31:466-474.
https://doi.org/10.1111/pcmr.12688

Monfermé S, et al., 2018 Mild form of oculocutaneous albinism type 1: phenotypic analysis of compound heterozygous patients with the R402Q variant of the TYR gene. Br J Ophthalmol. 2018 Nov 24. pii: bjophthalmol-2018-312729. https://doi.org/10.1136/bjophthalmol-2018-312729

Michaud V, Defoort-Dhellemmes S, Drumare I, Pennamen P, Plaisant C, Lasseaux E, Arveiler B. Clinical and molecular findings of FRMD7 related congenital nystagmus as adifferential diagnosis of ocular albinism. Ophthalmic Genet. 2019 Apr;40(2):161-164. doi: 10.1080/13816810.2019.1592201.

Ndiaye R, Dia Y, Lasseaux E, Mbaye S, Plaisant C, Diop JPD, Ba SA, Mbengue B, Ly F, Arveiler B, Dieye A.  A Novel Non-Sense Mutation in a Senegalese Patient with Hermansky-Pudlak Type 1 Syndrome. J Mol Genet Med 2019, 13: 415.

Arveiler B, Michaud V, Lasseaux E. Albinism: An Underdiagnosed Condition. J Invest Dermatol. 2020, 140:1449-1451.

Michaud V, Fiore M, Coste V, Huguenin Y, Bordet JC, Plaisant C, Lasseaux E, Morice-Picard F, Arveiler B. A New Case With Hermansky-Pudlak Syndrome Type 9, a Rare Cause of Syndromic Albinism With Severe Defect of Platelets Dense Bodies. Platelets. 2020 Apr 3:1-4. doi: 10.1080/09537104.2020.1742315. Online ahead of print.

Pennamen P, Le L, Tingaud-Sequeira A, Fiore M, Bauters A, Van Duong Béatrice N, Coste V, Bordet JC, Plaisant C, Diallo M, Michaud V, Trimouille A, Lacombe D, Lasseaux E, Delevoye C, Morice-Picard F, Delobel B, Marks MS, Arveiler B. BLOC1S5 Pathogenic Variants Cause a New Type of Hermansky-Pudlak Syndrome. Genet Med. 2020 Oct;22(10):1613-1622. doi: 10.1038/s41436-020-0867-5.

Pennamen P, Tingaud-Sequeira A, Gazova I, Keighren M, McKie L, Marlin S, Gherbi Halem S, Kaplan J, Delevoye C, Lacombe D, Plaisant C, Michaud V, Lasseaux E, Javerzat S, Jackson I, Arveiler B. Dopachrome tautomerase variants in patients with oculocutaneous albinism. Genet Med. 2020 Oct 26. doi: 10.1038/s41436-020-00997-8. Online ahead of print.

Pennamen P, Tingaud-Sequeira A, Michaud V, Morice-Picard F, Plaisant C, Vincent-Delorme C, Giuliano F, Azarnoush S, Capri Y, Marçon C, Lacombe D, Lasseaux E, Arveiler B. Novel variants in the BLOC1S3 gene in patients presenting a mild form of Hermansky-Pudlak syndrome. Pigment Cell Melanoma Res. 2021 Jan;34(1):132-135. doi: 10.1111/pcmr.12915.

Tingaud-Sequeira A, Mercier E, Michaud V, Pinson B, Gazova I, Gontier E, Decoeur F, McKie L, Jackson IJ, Arveiler B, Javerzat S. The Dct-/- Mouse Model to Unravel Retinogenesis Misregulation in Patients with Albinism. Genes (Basel). 2022 Jun 27;13(7):1164. doi: 10.3390/genes13071164