Genetic Variability in Slovenian Cohort of Patients with Oculocutaneous Albinism

Tinka Hovnik,Manca Tekavčič Pompe,Tadej Battelino,Sara Bertok,Branka Stirn Kranjc,Maruša Debeljak,Katarina Trebušak Podkrajšek

doi:10.17344/acsi.2021.6690

Abstract

Oculocutaneous albinism (OCA) is an inherited disorder affecting the visual system and skin pigmentation. Our aim was to evaluate genetic and clinical heterogeneity in a cohort of Slovenian paediatric patients with clinically suspected OCA using advanced molecular-genetics approach. In as much as 20 out of 25 patients, genetic variants explaining their clinical phenotype were identified. The great majority of patients (15/25) had genetic variants in TYR gene associated with OCA type 1, followed by variants in TYRP1, SLC45A2 and HPS1 genes causative for OCA3, OCA4 and Hermansky-Pudlak syndrome type 1, respectively. We concluded that OCA phenotype could not predict genotype and vice versa. Nevertheless, the diagnostic yield after targeted next generation sequencing (NGS) was 80% and proved to be affective in our paediatric cohort of patients with various degree of OCA. Even in 16 patients with normal complexion the diagnostic yield was 62,5%. Interestingly, we have identified a patient of white European ancestry with OCA3, which is an extremely rare report, and one patient with OCA due to the Hermansky-Pudlak syndrome type 1.

Highlights

Albinism is a rare inherited disorder affecting visual system and skin pigmentation, and has a global incidence of approximately 1 in 17.000.1,2 The most handicapping manifestations are ocular abnormalities, namely reduced visual acuity with nystagmus, strabismus, photophobia, foveal hypoplasia and misrouting of optic nerve fibres at the chiasm.[3,4] Albinism is clinically classified in three groups
In as much as 20 out of 25 patients (80%) in the entire cohort, genetic variants explaining their clinical phenotype were identified (Table 2). This is in accordance with other recent reports, where molecular diagnosis was achieved in 92% of patients with mild partial albinism[10] and 72,3% of patients with albinism.[12]
High frequency of TYR disease causing variants can partly be explained with the fact that ocular albinism due to GPR143 variants was previously excluded from our group of patients.[26]

Summary

Introduction

Albinism is a rare inherited disorder affecting visual system and skin pigmentation, and has a global incidence of approximately 1 in 17.000.1,2 The most handicapping manifestations are ocular abnormalities, namely reduced visual acuity with nystagmus, strabismus, photophobia, foveal hypoplasia and misrouting of optic nerve fibres at the chiasm.[3,4] Albinism is clinically classified in three groups. In ocular albinism (OA, OMIM # 300500) pigmentation is impaired only in the eyes, while in oculocutaneous albinism (OCA) pigmentation of the skin and/. OCA1 is caused by disease causing variants in TYR gene (OMIM* 606933)[7] encoding enzyme tyrosinase catalysing the first two steps in melanin biosynthesis.[8] In OCA1A subtype, enzyme activity is completely abolished and patients have no pigment and severe ocular symptoms. In OCA1B subtype, residual tyrosinase activity is present and patients may develop some pigment after infancy.[9] Among patients with mild OCA1B, two relatively common TYR variants, namely NM_000372.4:c.575C>A (p.Ser192Tyr) and NM_000372.4: c.1205G>A (p.Arg402Gln) located in cis and were reported as a prevalent cause when inherited in trans with pathogenic TYR variant.[10,11,12,13,14]

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Conclusion