Two Novel Homozygous HPS6 Mutations (Double Mutant) Identified by Whole-Exome Sequencing in a Saudi Consanguineous Family Suspected for Oculocutaneous Albinism

Abstract

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 (HPS6), are distinguished by their genetic cause and pigmentation pattern. HPS6 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 HPS6 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 HPS6 (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 HPS6 mutations. Structural analysis revealed the transformation of abnormalities at protein level for both nonsense and frameshift mutations in HPS6. Conclusion: To the best of our knowledge, the double mutation in HPS6 (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 HPS6 and/or other disease-associated genetic variants in Saudi Arabia, particularly in consanguineous families.

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

“…However, the correlation between different HPS6 variants and their phenotypes has not been systematically studied. In this paper, we reported our findings of two novel different compound heterozygote variants of HPS6 in two Chinese families with suspected OA and integrated our findings with the worldwide reported HPS6 cases [1, 3‒5, 15‒17, 19‒23, 25‒36] to establish a systematic HPS6 variant profile. Moreover, a retrospective analysis of all collected HPS6 variants and the genotype-phenotype correlation are detailedly delineated here to aid the molecular diagnostics, genetic counseling, prognostics, and clinical intervention of HPS6 patients in future.…”

“…Articles were limited to full papers in the English or Chinese literature, and the search ended on March 27, 2023. According to these criteria, 24 relevant research articles published between 2003 and 2023 were selected [1, 3‒5, 15‒17, 19‒23, 25‒36].…”

“…Hermansky-Pudlak syndrome (HPS) is a rare autosomal-recessive disease characterized by ocular albinism (OA) or oculocutaneous albinism (OCA), platelet dysfunction, and in some cases, the change of skin and hair color, the occurrence of neutropenia, granulomatous colitis, or fatal pulmonary fibrosis could be observed [1,2]. Some typical ocular manifestations of HPS patients could include nystagmus, reduced iris pigment, retinal or fundus hypopigmentation, central fovea dysplasia, increased crossing of the optic nerve fibers, and significant decreased visual acuity [3][4][5]. Besides, the HPS-related bleeding diathesis can result in variable bruising, epistaxis, gingival bleeding, postpartum hemorrhage, colonic bleeding, and prolonged bleeding with menses or after tooth extraction, tonsillectomy, and other surgeries [6][7][8].…”

Phenotype of White Sika Deer Due to SCF Gene Structural Variation

“…However, we only selected the SV and five nonsynonymous mutations located in the exon sequence of the candidate gene, representing the coat color genes that may be related to the white phenotype of sika deer. The exon is an important gene coding sequence in animals, and changes in coat color and related diseases in mammals are mostly caused by mutation of the gene exon region [21]. In addition, synonymous mutation in the exon would not lead to transcription and translation changes, thus not affecting the functional activity of proteins.…”

“…By referring to the genetic variation analysis methods of albinism [21] and white tigers [22], a candidate genome of coat color was established, and the differential information between genes of the white sika deer and of the cluster located in exonic regions was screened. The candidate genome was established according to the gene information provided by the website of the IFPCs (International Federation of Pigment Cell Societies) (http://www.ifpcs.org/colorgenes/, accessed on 1 December 2021).…”