| Summary: | Background: Oculocutaneous albinism (OCA) is an autosomal recessive disorder of low or missing pigmentation in the eyes, hair, and skin. Multiple types of OCA, including Hermansky-Pudlak syndrome 6 (<i>HPS6</i>), are distinguished by their genetic cause and pigmentation pattern. <i>HPS6</i> is characterized by OCA, nose bleeding due to platelet dysfunction, and lysosome storage defect. To date, 25 disease-associated mutations have been reported in the <i>HPS6</i> gene. Methods: DNA was extracted from proband, and whole-exome sequencing (WES) was performed using the Illumina NovaSeq platform. Bioinformatic analysis was done with a custom-designed filter pipeline to detect the causative variant. We did Sanger sequencing to confirm the candidate variant and segregation analysis, and protein-based structural analysis to evaluate the functional impact of variants. Result: Proband-based WES identified two novel homozygous mutations in <i>HPS6</i> (double mutation, c.1136C>A and c.1789delG) in an OCA suspect. Sanger sequencing confirmed the WES results. Although no platelet and/or lysosome storage defect was detected in the patient or family, an oculocutaneous albinism diagnosis was established based on the <i>HPS6</i> mutations. Structural analysis revealed the transformation of abnormalities at protein level for both nonsense and frameshift mutations in <i>HPS6</i>. Conclusion: To the best of our knowledge, the double mutation in <i>HPS6</i> (p.Ser379Ter and p.Ala597GlnfsTer16) represents novel pathogenic variants, not described previously, which we report for the first time in the Saudi family. In silico analyses showed a significant impact on protein structure. WES should be used to identify <i>HPS6</i> and/or other disease-associated genetic variants in Saudi Arabia, particularly in consanguineous families.
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