Publications by authors named "Sairah Yousaf"

8 Publications

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PDE6C: Novel Mutations, Atypical Phenotype, and Differences Among Children and Adults.

Invest Ophthalmol Vis Sci 2020 Oct;61(12)

Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States.

Purpose: Genetic variation in PDE6C is associated with achromatopsia and cone dystrophy, with only a few reports of cone-rod dystrophy in the literature. We describe two pediatric and two adult patients with PDE6C related cone and cone-rod dystrophy and the first longitudinal data of a pediatric patient with PDE6C-related cone dystrophy.

Methods: This cohort of four patients underwent comprehensive ophthalmologic evaluation at the National Eye Institute's Ophthalmic Genetics clinic, including visual field testing, retinal imaging and electroretinogram (ERG). Next-generation sequencing-based genetic testing was performed and subsequent analysis of the variants was done through three-dimensional protein models generated by Phyre2 and Chimera.

Results: All cases shared decreased best-corrected visual acuity and poor color discrimination. Three of the four patients had a cone-rod dystrophy, presenting with an ERG showing decreased amplitude on both photopic and scotopic waveforms and a mild to moderately constricted visual field. One of the children was diagnosed with cone dystrophy, having a preserved peripheral field. The children had none to minor structural retinal changes, whereas the adults had clear macular dystrophy.

Conclusions: PDE6C-related cone-rod dystrophy consists of a severe phenotype characterized by early-onset nystagmus, decreased best-corrected visual acuity, poor color discrimination, progressive constriction of the visual field, and night blindness. Our work contributes with valuable information toward understanding the visual prognosis and allelic heterogeneity of PDE6C-related cone and cone-rod dystrophy.
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http://dx.doi.org/10.1167/iovs.61.12.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545085PMC
October 2020

Otitis media susceptibility and shifts in the head and neck microbiome due to variants.

J Med Genet 2020 Jul 24. Epub 2020 Jul 24.

Department of Otolaryngology-Head and Neck Surgery, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA

Background: Otitis media (OM) susceptibility has significant heritability; however, the role of rare variants in OM is mostly unknown. Our goal is to identify novel rare variants that confer OM susceptibility.

Methods: We performed exome and Sanger sequencing of >1000 DNA samples from 551 multiethnic families with OM and unrelated individuals, RNA-sequencing and microbiome sequencing and analyses of swabs from the outer ear, middle ear, nasopharynx and oral cavity. We also examined protein localisation and gene expression in infected and healthy middle ear tissues.

Results: A large, intermarried pedigree that includes 81 OM-affected and 53 unaffected individuals cosegregates two known rare variants, a common variant and a rare, novel pathogenic variant c.1682A>G (p.Glu561Gly) within (LOD=4.09). Carriage of the missense variant resulted in increased relative abundance of Microbacteriaceae in the middle ear, along with occurrence of Microbacteriaceae in the outer ear and oral cavity but not the nasopharynx. Eight additional novel variants were identified in 12 families and individuals with OM. A role for in OM susceptibility is further supported by lower RNA counts in variant carriers, strong SPINK5 localisation in outer ear skin, faint localisation to middle ear mucosa and eardrum and increased expression in human cholesteatoma.

Conclusion: variants confer susceptibility to non-syndromic OM. These variants potentially contribute to middle ear pathology through breakdown of mucosal and epithelial barriers, immunodeficiency such as poor vaccination response, alteration of head and neck microbiota and facilitation of entry of opportunistic pathogens into the middle ear.
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http://dx.doi.org/10.1136/jmedgenet-2020-106844DOI Listing
July 2020

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

Pigment Cell Melanoma Res 2020 07 27;33(4):556-565. Epub 2020 Apr 27.

Department of Otorhinolaryngology Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD, USA.

Skin pigmentation is a highly heterogeneous trait with diverse consequences worldwide. SLC24A5, encoding a potent K -dependent Na /Ca 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 (slc24a5 ) that harbors a nonsense (p.Tyr208*) allele of slc24a5. Similar to morphants, homozygous slc24a5 mutants had significantly reduced melanin content and pigmentation. Next, we used these slc24a5 zebrafish mutants to test the efficacy of nitisinone, a compound known to increase ocular and fur pigmentation in OCA1 (TYR) mutant mice. Treatment of slc24a5 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.
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http://dx.doi.org/10.1111/pcmr.12879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269830PMC
July 2020

Identities and frequencies of variants in causing primary congenital glaucoma in Pakistan.

Mol Vis 2019 22;25:144-154. Epub 2019 Feb 22.

Department of Otorhinolaryngology Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD.

Purpose: Primary congenital glaucoma (PCG) is a clinically and genetically heterogeneous disease. The present study was undertaken to find the genetic causes of PCG segregating in 36 large consanguineous Pakistani families.

Methods: Ophthalmic examination including fundoscopy, or slit-lamp microscopy was performed to clinically characterize the PCG phenotype. Genomic nucleotide sequences of the and genes were analyzed with either Sanger or whole exome sequencing. In silico prediction programs were used to assess the pathogenicity of identified alleles. ClustalW alignments were performed to determine evolutionary conservation, and three-dimensional (3D) modeling was performed using HOPE and Phyre2 software.

Results: Among the known loci, mutations in and are the common causes of PCG. Therefore, we analyzed the genomic nucleotide sequences of and , and detected probable pathogenic variants cosegregating with PCG in 14 families. These included the three novel (c.542T>A, c.1436A>G, and c.1325delC) and five known (c.868dupC, c.1168C>T, c.1169G>A, c.1209InsTCATGCCACC, and c.1310C>T) variants in . Two of the novel variants are missense substitutions [p.(Leu181Gln), p.(Gln479Arg)], which replaced evolutionary conserved amino acids, and are predicted to be pathogenic by various in silico programs, while the third variant (c.1325delC) is predicted to cause reading frameshift and premature truncation of the protein. A single mutation, p.(Arg390His), causes PCG in six (~43%) of the 14 mutations harboring families, and thus, is the most common variant in this cohort. Surprisingly, we did not find any pathogenic variants in the families, which further supports the genetic heterogeneity of PCG in the Pakistani population.

Conclusions: In conclusion, results of the present study enhance our understanding of the genetic basis of PCG, support the notion of a genetic modifier of , and contribute to the development of genetic testing protocols and genetic counseling for PCG in Pakistani families.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6386514PMC
June 2019

Delineation of Novel Compound Heterozygous Variants in LTBP2 Associated with Juvenile Open Angle Glaucoma.

Genes (Basel) 2018 Oct 30;9(11). Epub 2018 Oct 30.

Department of Ophthalmology and Visual Sciences, University of Maryland School of Medicine, Baltimore, MD 21201, USA.

Juvenile open angle glaucoma (JOAG), which is an uncommon form of primary open angle glaucoma, is a clinically and genetically heterogeneous disorder. We report on a family with a recessively inherited form of JOAG. The proband has a superior and an inferior never fiber layer thinning in both the eyes and the nasal visual field (VF) defects in the left eye, which are clinical findings consistent with glaucomatous optic neuropathy. Whole exome sequencing revealed two novel compound heterozygous variants [c.2966C>G, p.(Pro989Arg); c.5235T>G, p.(Asn1745Lys)] in latent transforming growth factor-beta-binding protein 2 () segregating with the phenotype. Both these variants are predicted to replace evolutionary conserved amino acids, have a pathogenic effect on the encode protein, and have very low frequencies in the control databases. Mutations in LTBP2 are known to cause the Weill-Marchesani syndrome and a Weill-Marchesani-like syndrome, which include glaucoma in their clinical presentation. However, to our knowledge, this is the first published case of a JOAG subject associated with recessively inherited variants of LTPB2 and, thus, expands the repertoire of the known genetic causes of JOAG and the phenotypic spectrum of LTBP2 alleles.
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http://dx.doi.org/10.3390/genes9110527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6266624PMC
October 2018

Molecular outcomes, clinical consequences, and genetic diagnosis of Oculocutaneous Albinism in Pakistani population.

Sci Rep 2017 03 7;7:44185. Epub 2017 Mar 7.

Department of Otorhinolaryngology Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD, USA.

Nonsyndromic oculocutaneous Albinism (nsOCA) is clinically characterized by the loss of pigmentation in the skin, hair, and iris. OCA is amongst the most common causes of vision impairment in children. To date, pathogenic variants in six genes have been identified in individuals with nsOCA. Here, we determined the identities, frequencies, and clinical consequences of OCA alleles in 94 previously unreported Pakistani families. Combination of Sanger and Exome sequencing revealed 38 alleles, including 22 novel variants, segregating with nsOCA phenotype in 80 families. Variants of TYR and OCA2 genes were the most common cause of nsOCA, occurring in 43 and 30 families, respectively. Twenty-two novel variants include nine missense, four splice site, two non-sense, one insertion and six gross deletions. In vitro studies revealed retention of OCA proteins harboring novel missense alleles in the endoplasmic reticulum (ER) of transfected cells. Exon-trapping assays with constructs containing splice site alleles revealed errors in splicing. As eight alleles account for approximately 56% (95% CI: 46.52-65.24%) of nsOCA cases, primarily enrolled from Punjab province of Pakistan, hierarchical strategies for variant detection would be feasible and cost-efficient genetic tests for OCA in families with similar origin. Thus, we developed Tetra-primer ARMS assays for rapid, reliable, reproducible and economical screening of most of these common alleles.
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http://dx.doi.org/10.1038/srep44185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5339803PMC
March 2017

Identification and clinical characterization of Hermansky-Pudlak syndrome alleles in the Pakistani population.

Pigment Cell Melanoma Res 2016 Mar 18;29(2):231-5. Epub 2015 Dec 18.

Department of Otorhinolaryngology Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD, USA.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5062593PMC
http://dx.doi.org/10.1111/pcmr.12438DOI Listing
March 2016

Identification and functional characterization of natural human melanocortin 1 receptor mutant alleles in Pakistani population.

Pigment Cell Melanoma Res 2015 Nov 22;28(6):730-5. Epub 2015 Sep 22.

Department of Otorhinolaryngology Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD, USA.

Melanocortin 1 receptor (MC1R), a Gs protein-coupled receptor of the melanocyte's plasma membrane, is a major determinant of skin pigmentation and phototype. Upon activation by α-melanocyte stimulating hormone, MC1R triggers the cAMP cascade to stimulate eumelanogenesis. We used whole-exome sequencing to identify causative alleles in Pakistani families with skin and hair hypopigmentation. Six MC1R mutations segregated with the phenotype in seven families, including a p.Val174del in-frame deletion and a p.Tyr298* nonsense mutation, that were analyzed for function in heterologous HEK293 cells. p.Tyr298* MC1R showed no agonist-induced signaling to the cAMP or ERK pathways, nor detectable agonist binding. Conversely, signaling was comparable for p.Val174del and wild-type in HEK cells overexpressing the proteins, but binding analysis suggested impaired cell surface expression. Flow cytometry and confocal imaging studies revealed reduced plasma membrane expression of p.Val174del and p.Tyr298*. Therefore, p.Tyr298* was a total loss-of-function (LOF) allele, while p.Val174del displayed a partial LOF attribute.
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http://dx.doi.org/10.1111/pcmr.12400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4609612PMC
November 2015