Novel Variants of <i>HPS6</i> Cause Suspected Ocular Albinism: A Report of 2 Cases and the Profile of <i>HPS6</i> Variants

Abstract

<b><i>Introduction:</i></b> Hermansky-Pudlak syndrome (HPS) is a rare autosomal-recessive disease characterized by ocular albinism (OA) or oculocutaneous albinism (OCA), platelet dysfunction, and other symptoms. This study aimed to analyze the molecular defect in two Chinese families with suspected OA, as well as to investigate the profile of <i>HPS6</i> variants and their genotype-phenotype correlations. <b><i>Methods:</i></b> Seven members from two families were recruited and underwent clinical ophthalmologic examinations. The genomic DNA was extracted from peripheral blood leukocytes. Whole-exome sequencing was performed on the proband of family JX. The single coding exon of <i>HPS6</i> was directly Sanger sequenced based on PCR amplification in all available family members. An additional 46 probands from families or sporadic cases with the pathogenic variants of <i>HPS6</i> reported in the literature were reviewed. <b><i>Results:</i></b> We identified two different compound heterozygous truncating variants of <i>HPS6</i> in probands with suspected OA from two independent families. The proband of family JX had c.1674dup and c.503-504del variants, and the other proband from family CZ had a nonsense variant of c.1114C&gt;T and a frameshift variant of c.1556del. Among them, c.1674dup and c.1556del variants in <i>HPS6</i> have not been reported previously. Therefore, our patients were diagnosed as HPS6 disease by molecular diagnostics. In the retrospective cohort of HPS6 patients, we delineated the profile of <i>HPS6</i> variants and revealed a significant overlap between CpG islands and the variants of <i>HPS6</i>, suggesting a potential link between DNA methylation and <i>HPS6</i> variants. We also observed a spatial aggregation of the variants in 3D structure of HPS6 protein, implying the possible functional significance of these structural regions. In addition, we did not find any significant genotype-phenotype correlation of HPS6, and neither did we observe a correlation between the truncation length of the HPS6 protein and the phenotype of HPS6 disease. <b><i>Conclusion:</i></b> Our research expands the spectrum of <i>HPS6</i> variants, providing a comprehensive delineation of their profile and systematically investigating genotype-phenotype correlations in HPS6. These findings could offer potentially valuable clues for investigating the molecular mechanism underlying HPS6 pathogenesis, as well as aiding the clinical diagnosis of HPS6 patients and improving disease prognosis.