Genetic studies of multiple consanguineous Pakistani families segregating oculocutaneous albinism identified novel and reported mutations

Gul, Hadia; Shah, Abdul Haleem; Harripaul, Ricardo; Mikhailov, Anna; Prajapati, Kamalben; Khan, Ejazullah; Ullah, Farman; Zubair, Muhammad; Ali, Muhammad; Shah, Ayesha Haleem; Salman, Said; Khan, Saadullah; Vincent, John B.; Khan, Muzammil Ahmad

doi:10.1111/ahg.12307

Cited by 7 publications

(12 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Junctions 1 and 3 of our CxSV alleles indicated two breakpoints in OCA2 intron 19. Interestingly, sequences within intron 19 of OCA2 appear prone to structural rearrangement, as multiple other albinism‐associated OCA2 deletions involving breakpoints in intron 19 have been previously reported (Chuan et al, 2021; Gul et al, 2019; Lasseaux et al, 2018; Morice‐Picard et al, 2014; Rooryck et al, 2011; Shahzad et al, 2017; Yi et al, 2003). In some cases, precise sequence breakpoint coordinates were not reported for intron 19‐documented rearrangements (Chuan et al, 2021; Shahzad et al, 2017), thus not allowing for a direct comparison of the intron 19 junctions.…”

Section: Discussionmentioning

confidence: 65%

“…In some cases, precise sequence breakpoint coordinates were not reported for intron 19‐documented rearrangements (Chuan et al, 2021; Shahzad et al, 2017), thus not allowing for a direct comparison of the intron 19 junctions. In the remaining five studies reporting sequence breakpoint information on intron 19 rearrangement (Gul et al, 2019; Lasseaux et al, 2018; Morice‐Picard et al, 2014; Rooryck et al, 2011; Yi et al, 2003), we found similarities between our complex rearrangement and OCA2 intron 19 rearrangements in three patients first identified with altered copy number alleles by array comparative genomic hybridization (CGH; Rooryck et al, 2011), and in a follow‐up study, two additional patients exhibiting evidence of a complex rearrangement at OCA2 (Morice‐Picard et al, 2014). This analysis identified an identical Junction 3 fragment, indicating a 184 kb deletion from intron 2—intron 19 (chr15:28119923‐28303782), and also found evidence of the Junction 1/RR breakpoint, but the corresponding Junction 2/LL breakpoint was not identified (Morice‐Picard et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

A custom capture sequence approach for oculocutaneous albinism identifies structural variant alleles at the OCA2 locus

et al. 2021

View full text Add to dashboard Cite

Oculocutaneous albinism (OCA) is a heritable disorder of pigment production that manifests as hypopigmentation and altered eye development. Exon sequencing of known OCA genes is unsuccessful in producing a complete molecular diagnosis for a significant number of affected individuals. We sequenced the DNA of individuals with OCA using short‐read custom capture sequencing that targeted coding, intronic, and noncoding regulatory regions of known OCA genes, and genome‐wide association study‐associated pigmentation loci. We identified an OCA2 complex structural variant (CxSV), defined by a 143 kb inverted segment reintroduced in intron 1, upstream of the native location. The corresponding CxSV junctions were observed in 11/390 probands screened. The 143 kb CxSV presents in one family as a copy number variant duplication for the 143 kb region. In the remaining 10/11 families, the 143 kb CxSV acquired an additional 184 kb deletion across the same region, restoring exons 3–19 of OCA2 to a copy‐number neutral state. Allele‐associated haplotype analysis found rare SNVs rs374519281 and rs139696407 are linked with the 143 kb CxSV in both OCA2 alleles. For individuals in which customary molecular evaluation does not reveal a biallelic OCA diagnosis, we recommend preliminary screening for these haplotype‐associated rare variants, followed by junction‐specific validation for the OCA2 143 kb CxSV.

show abstract

Section: Discussionmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 99%

A custom capture sequence approach for oculocutaneous albinism identifies structural variant alleles at the OCA2 locus

et al. 2021

View full text Add to dashboard Cite

show abstract

“…The most common pathogenic variant of the TYR gene reported in Pakistani OCA families, with a frequency of about 23%, is c.1255G>A; p.Gly419Arg and is predominantly found in the Punjabi-speaking language group. On the other hand, OCA families of other language groups, including Saraiki, Sindhi, Balochi, and Kashmiri, are reported for this common pathogenic variant [ 1 , 2 , 8 , 24 , 25 , 26 , 27 ]. The c.832C>T; p.Arg278Ter pathogenic variant is the second most frequent pathogenic variant, representing about 21% of total reported pathogenic variants, and it is also documented in the current study [ 23 , 25 ].…”

Section: Discussionmentioning

confidence: 99%

Delineating Novel and Known Pathogenic Variants in TYR, OCA2 and HPS-1 Genes in Eight Oculocutaneous Albinism (OCA) Pakistani Families

Shakil

Akbar

Aisha

et al. 2022

Genes

View full text Add to dashboard Cite

Oculocutaneous albinism (OCA) is associated with a wide range of clinical presentations and has been categorized with syndromic and non-syndromic features. The most common causative genes in non-syndromic OCA are TYR and OCA2 and HSP1 is in the syndromic albinism. The objective of this study was to identify pathogenic variants in congenital OCA families from Pakistan. Eight consanguineous families were recruited, and clinical and ophthalmological examination was carried out to diagnose the disease. Whole blood was collected from the participating individuals, and genomic DNA was extracted for sequencing analysis. TruSight one-panel sequencing was carried out on one affected individual of each family, and termination Sanger sequencing was carried out to establish the co-segregation of the causative gene or genes. In silico analysis was conducted to predict the causative pathogenic variants. Two families were found to have novel genetic pathogenic variants, and six families harbored previously reported variants. One novel compound heterozygous pathogenic variant in the TYR gene, c.1002delA; p.Ala335LeufsTer20, a novel frameshift deletion pathogenic variant and c.832C>T; and p.Arg278Ter (a known pathogenic variant) were found in one family, whereas HPS1; c.437G>A; and p.Trp146Ter were detected in another family. The identification of new and previous pathogenic variants in TYR, OCA2, and HPS1 genes are causative of congenital OCA, and these findings are expanding the heterogeneity of OCA.

show abstract

“…Genetically, albinism can manifest via many inheritance patterns, although autosomal recessive albinism is the most common mode (Tomita & Suzuki, 2004). To date, pathogenic variants of six genes, TYR , OCA2 , TYRP1 , SLC45A2 , SLC24A5 , and C10ORF11 , have been identified in humans suffering from non‐syndromic OCA (Gronskov et al., 2013; Gul et al., 2019; Ye et al., 2019).…”

Section: Introductionmentioning

confidence: 99%

Molecular characterization of SLC24A5 variants and evaluation of Nitisinone treatment efficacy in a zebrafish model of OCA6

Yousaf

Sethna

Chaudhary

et al. 2020

Pigment Cell Melanoma Res

View full text Add to dashboard Cite

Skin pigmentation is a highly heterogeneous trait with diverse consequences worldwide. SLC24A5, encoding a potent K+‐dependent Na+/Ca2+ exchanger, is among the known color‐coding genes that participate in melanogenesis by maintaining pH in melanosomes. Deficient SLC24A5 activity results in oculocutaneous albinism (OCA) type 6 in humans. In this study, by utilizing a exome sequencing (ES) approach, we identified two new variants [p. (Gly110Arg) and p. (IIe189Ilefs*1)] of SLC24A5 cosegregating with the OCA phenotype, including nystagmus, strabismus, foveal hypoplasia, albinotic fundus, and vision impairment, in three large consanguineous Pakistani families. Both of these variants failed to rescue the pigmentation in zebrafish slc24a5 morphants, confirming the pathogenic effects of the variants. We also phenotypically characterized a commercially available zebrafish mutant line (slc24a5ko) that harbors a nonsense (p.Tyr208*) allele of slc24a5. Similar to morphants, homozygous slc24a5ko mutants had significantly reduced melanin content and pigmentation. Next, we used these slc24a5ko zebrafish mutants to test the efficacy of nitisinone, a compound known to increase ocular and fur pigmentation in OCA1 (TYR) mutant mice. Treatment of slc24a5ko mutant zebrafish embryos with varying doses of nitisinone did not improve melanin production and pigmentation, suggesting that treatment with nitisinone is unlikely to be therapeutic in OCA6 patients.

show abstract

Genetic studies of multiple consanguineous Pakistani families segregating oculocutaneous albinism identified novel and reported mutations

Cited by 7 publications

References 14 publications

A custom capture sequence approach for oculocutaneous albinism identifies structural variant alleles at the OCA2 locus

A custom capture sequence approach for oculocutaneous albinism identifies structural variant alleles at the OCA2 locus

Delineating Novel and Known Pathogenic Variants in TYR, OCA2 and HPS-1 Genes in Eight Oculocutaneous Albinism (OCA) Pakistani Families

Molecular characterization of SLC24A5 variants and evaluation of Nitisinone treatment efficacy in a zebrafish model of OCA6

Contact Info

Product

Resources

About