Oculocutaneous albinism variants in 28 consanguineous families and functional classification of a pathogenic deep...

Oculocutaneous albinism (OCA) are genetically and clinically heterogeneous recessive disorders with at least 23 associated genes. Isolated OCA is characterized by hypopigmentation in the skin, hair, and eyes combined with ocular abnormalities. Hermansky Pudlak syndrome (HPS) and Chediak-Higaski syndrome are syndromic forms of OCA, distinguished by immunological and hematological symptoms in addition to hypopigmentation and ocular anomalies. Targeted clinical care is crucial for the patients and molecular genetic diagnosis is important for classification of patients. Current diagnostic yield is approximately 70%, and a high proportion of patients are heterozygous for pathogenic variants in OCA genes, suggesting the presence of disease-causing non-coding variants. We describe here next generation sequencing (NGS) analysis, including copy number variant (CNV) analysis, of 28 consanguineous families, comprising a total of 136 individuals presenting with OCA. We provide a molecular genetic diagnosis in all 28 families. Noteworthy, five families (18%) had pathogenic variants in a gene associated with HPS, showing the importance of an in-depth molecular genetic investigation, which should be offered to persons with albinism. Furthermore, we report the first deep intron variant in TYR causing OCA and show by minigene analysis that the variant causes inclusion of a pseudoexon.