Report of Hermansky–Pudlak Syndrome in Two Families with Novel Variants in HPS3 and HPS4 Genes

Zaman, Qaiser; Sadeeda,; Anas, Muhammad; Rehman, Gauhar; Khan, Qadeem; Iftikhar, Aiman; Ahmad, Mashal; Owais, Muhammad; Ahmad, Ilyas; Muthaffar, Osama; Abdulkareem, Angham Abdulrhman; Bibi, Fehmida; Jelani, Musharraf; Naseer, Muhammad Imran

doi:10.3390/genes14010145

Cited by 7 publications

(12 citation statements)

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“…In societies such as Pakistan, where consanguineous marriages are common, the incidence of mutant alleles is higher. 22,38 To mitigate this, premarital testing, newborn genetic disorder screening and parental genetic screening can be undertaken to reduce the disease allele burden. Carrier genetic screening, parental counseling and neonatal work-up are also recommended for future progeny.…”

Section: Discussionmentioning

confidence: 99%

“…Carrier genetic screening, parental counseling and neonatal work-up are also recommended for future progeny. 22,[38][39][40] Whole exome sequencing can be used as the primary molecular diagnostic tool in cutis laxa patients. 41,42 This approach is highly efficient and more precise in large consanguineous families.…”

Section: Discussionmentioning

confidence: 99%

“…41,42 This approach is highly efficient and more precise in large consanguineous families. 22,38 Therefore, reporting further cases associated with this gene could aid…”

Section: Discussionmentioning

confidence: 99%

“…The alignment covered approximately 99.3% of the RefSeq protein coding region. Variant calling and filtration were performed using standard data analysis pipelines of 3Billion Inc., South Korea, as described elsewhere 20–22 . Variants with a co‐allele frequency of > 5% were filtered out according to the American College of Medical Genetics (ACMG) guidelines 23 .…”

Section: Methodsmentioning

confidence: 99%

“…Variant calling and filtration were performed using standard data analysis pipelines of 3Billion Inc., South Korea, as described elsewhere. [20][21][22] Variants with a co-allele frequency of > 5% were filtered out according to the American College of Medical Genetics (ACMG) guidelines. 23 The frequency of the variant in the general population was checked using ensembl.org/index.html) and the 1000 Genomes browser (https:// www.internationalgenome.org/1000-genomes-browsers/index.html).…”

Section: Genomic Dna Extraction and Whole Exome Analysismentioning

confidence: 99%

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Two novel homozygous variants of ATP6V0A2 and ALDH18A1 lead to autosomal recessive cutis laxa type 2 and 3 in two Pakistani families

Zaman

Iftikhar²,

Rehman

et al. 2023

The Journal of Gene Medicine

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BackgroundAutosomal recessive cutis laxa type 2A (ARCL2A; OMIM: 219200) is characterized by neurovegetative, developmental and progeroid elastic skin anomalies. It is caused by biallelic variation in ATPase, H+ transporting V0 subunit A2 (ATP6V0A2; OMIM: 611716) located on chromosome 12q24.31. Autosomal recessive cutis laxa type 3A (ARCL3A; OMIM: 219150) is another subclinical type characterized by short stature, ophthalmological abnormalities and a progeria‐like appearance. The ARCL3A is caused by loss of function alterations in the aldehyde dehydrogenase 18 family member A1 (ALDH18A1; OMIM: 138250) gene located at chromosome 10q24.1.MethodsWhole‐exome sequencing (WES), and Sanger sequencing were performed for molecular diagnosis. 3D protein modeling was performed to investigate the deleterious effect of the variant on protein structure.ResultsIn this study, clinical and molecular diagnosis were performed for two families, ED‐01 and DWF‐41, which displayed hallmark features of ARCL2A and ARCL3A, respectively. Three affected individuals in the ED‐01 family (IV‐4, IV‐5 and V‐3) displayed sagging loose skin, down‐slanting palpebral fissures, excessive wrinkles on the abdomen, hands and feet, and prominent veins on the trunk. Meanwhile the affected individuals in the DWF‐41 family (V‐2 and V‐3) had progeroid skin, short stature, dysmorphology, low muscle tone, epilepsy, lordosis, scoliosis, delayed puberty and internal genitalia. WES in the index patient (ED‐01: IV‐4) identified a novel homozygous deletion (NM_012463.3: c.1977_1980del; p.[Val660LeufsTer23]) in exon 16 of the ATP6V0A2 while in DWF‐41 a novel homozygous missense variant (NM_001323413.1:c.1867G>A; p.[Asp623Asn]) in exon 15 of the ALDH18A1 was identified. Sanger validation in all available family members confirmed the autosomal recessive modes of inheritances in each family. Three dimensional in‐silico protein modeling suggested deleterious impact of the identified variants. Furthermore, these variants were assigned class 1 or “pathogenic” as per guidelines of American College of Medical Genetics 2015. Screening of ethnically matched healthy controls (n = 200 chromosomes), excluded the presence of these variations in general population.ConclusionsTo the best of our knowledge, this is the first report of ATP6V0A2 and ALDH18A1 variations in the Pakhtun ethnicity of Pakistani population. The study confirms that WES can be used as a first‐line diagnostic test in patients with cutis laxa, and provides basis for population screening and premarital testing to reduce the diseases burden in future generations.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…41,42 This approach is highly efficient and more precise in large consanguineous families. 22,38 Therefore, reporting further cases associated with this gene could aid…”

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Genomic Dna Extraction and Whole Exome Analysismentioning

confidence: 99%

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Two novel homozygous variants of ATP6V0A2 and ALDH18A1 lead to autosomal recessive cutis laxa type 2 and 3 in two Pakistani families

Zaman

Iftikhar²,

Rehman

et al. 2023

The Journal of Gene Medicine

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

Zhou,

Yang,

Bai

et al. 2023

Ophthalmic Res

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Introduction: 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 HPS6 variants and their genotype-phenotype correlations. Methods: 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 HPS6 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 HPS6 reported in the literatures were reviewed. Results: We identified two different compound heterozygous truncating variants of HPS6 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>T and a frameshift variant of c.1556del. Among them, c.1674dup and c.1556del variants in HPS6 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 HPS6 variants and revealed a significant overlap between CpG islands and variants of HPS6, suggesting a potential link between DNA methylation and HPS6 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. Conclusion: Our research expands the spectrum of HPS6 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.

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Mutational spectrum associated with oculocutaneous albinism and Hermansky-Pudlak syndrome in nine Pakistani families

Khan,

Asif,

Ghani

et al. 2024

BMC Ophthalmol

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Background Oculocutaneous albinism (OCA) is a genetically heterogeneous condition that is associated with reduced or absent melanin pigment in the skin, hair, and eyes, resulting in reduced vision, high sensitivity to light, and rapid and uncontrolled eye movements. To date, seventeen genes have been associated with OCA including syndromic and non-syndromic forms of the condition. Methods Whole exome sequencing (WES) was performed to identify pathogenic variants in nine Pakistani families with OCA, with validation and segregation of candidate variants performed using Sanger sequencing. Furthermore, the pathogenicity of the identified variants was assessed using various in-silico tools and 3D protein structural analysis software. Results WES identified biallelic variants in three genes explaining the OCA in these families, including four variants in TYR, three in OCA2, and two in HPS1 , including two novel variants c.667C > T: p.(Gln223*) in TYR, and c.2009 T > C: p.(Leu670Pro) in HPS1 . Conclusions Overall, this study adds further knowledge of the genetic basis of OCA in Pakistani communities and facilitates improved management and counselling services for families suffering from severe genetic diseases in Pakistan. Supplementary Information The online version contains supplementary material available at 10.1186/s12886-024-03611-6.

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Report of Hermansky–Pudlak Syndrome in Two Families with Novel Variants in HPS3 and HPS4 Genes

Cited by 7 publications

References 30 publications

Two novel homozygous variants of ATP6V0A2 and ALDH18A1 lead to autosomal recessive cutis laxa type 2 and 3 in two Pakistani families

Two novel homozygous variants of ATP6V0A2 and ALDH18A1 lead to autosomal recessive cutis laxa type 2 and 3 in two Pakistani families

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

Mutational spectrum associated with oculocutaneous albinism and Hermansky-Pudlak syndrome in nine Pakistani families

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