مؤسسة عبد الحميد شومان > البحث العلمي > صندوق دعم البحث العلمي

الرجوع

Using Next-generation sequencing to study the genetic prevalence and discovery for Retinitis Pigmentosa and Leber Congenital Amaurosis in the Jordanian Population.

مجال مشروع البحث–الرئيسي: العلوم الطبية والصحية
مجال مشروع البحث–الثانوي: الامراض المزمنة
المؤسسة العلمية: الجامعة الأردنية
المحافظة: عمان
قيمة الدعم: JD15000
سنة الدعم: 2017
حالة المشروع: منتهي مع النشر
البحث منشور: (1) Azab, B., Barham, R., Ali, D., Dardas, Z., Rashdan, L., Bijawi, M., ... & Awidi, A. (2019). Novel CERKL variant in consanguineous Jordanian pedigrees with inherited retinal dystrophies. Canadian Journal of Ophthalmology, 54(1), 51-59. (2) Al-Bdour, M., Pauleck, S., Dardas, Z., Barham, R., Ali, D., Amr, S., ... & Awidi, A. (2020). Clinical heterogeneity in retinitis pigmentosa caused by variants in RP1 and RLBP1 in five extended consanguineous pedigrees. Molecular Vision, 26, 445. (3) Abu‐Ameerh, M., Mohammad, H., Dardas, Z., Barham, R., Ali, D., Bijawi, M., ... & Azab, B. (2020). Extending the spectrum of CLRN1‐and ABCA4‐associated inherited retinal dystrophies caused by novel and recurrent variants using exome sequencing. Molecular genetics & genomic medicine, 8(3), e1123.
ملخص عن مشروع البحث: 1. Objective: To identify the disease-causing variants in 2 families with autosomal recessive inherited retinal dystrophies (IRDs) and to characterize phenotypic variability across the affected family members.Design:Exome sequencing and ophthalmic clinical examination study.Participants:Six members from 2 consanguineous Jordanian families with IRD. Methods: Ophthalmic examinations and whole-exome sequencing (WES) were performed to identify IRD-causing variants in affected individuals from each family, followed by segregation analysis of candidate variants in affected and unaffected family members by Sanger sequencing. Results:We identified 2 different homozygous deletion variants in CERKL in each family: a novel pathogenic variant, c.450_451delAT, and a known variant, c.1187_1188delTG. Both variants co-segregated with the disease in all affected family members. The resulting phenotypes further supported that CERKL is associated with cone–rod dystrophy (CRD) rather than retinitis pigmentosa (RP), as originally established. Conclusion:Our study expands the genotypic spectra of CERKL variants, providing insights into the relevant pathogenesis of RP/CRD. We also confirm that the WES approach is a valuable tool for the molecular diagnosis of retinopathies. https://pubmed.ncbi.nlm.nih.gov/30851774/ 2. Purpose: The aim of this study is to identify disease-causing variants in five consanguineous Jordanian families with a history of autosomal recessive retinitis pigmentosa (RP), and to investigate the clinical variability across the affected individuals. Methods: Exome sequencing (ES) and ophthalmic examinations were performed to classify the underlying RP-causative variants and their pathogenic consequences. The candidate variants in the affected and unaffected family members underwent segregation analyses with Sanger sequencing. Results: We described four variants in the RP1 and RLBP1 genes as disease-causing across the five families, including novel (c.398delC; p.Pro133GlnfsTer126) and recurrent (c.79delA; p.Thr27ProfsTer26) variants in RLBP1 and two previously reported variants in RP1 ((c.1126C>T; p.Arg376Ter) and (c.607G>A; p.Gly203Arg)). The consequent clinical manifestations were thoroughly investigated using a battery of ophthalmic tests, including electroretinography (ERG), optical coherence tomography (OCT), visual acuity (VA), and fundus examination. The phenotypes indicated clinical heterogeneity, typical RP for variants in RP1, and retinitis punctata albescens (RPA) for variants in RLBP1. Conclusions: This study extends the pathogenic variant spectrum for the RP1 and RLBP1 genes. The study also revealed the consequent clinical progression, severity, and presentation of RP. Furthermore, we confirm that ES is an efficient molecular diagnostic approach for RP. https://pubmed.ncbi.nlm.nih.gov/32587456/ 3. Background: Inherited retinal dystrophies (IRDs) are characterized by extreme genetic and clinical heterogeneity. There are many genes that are known to cause IRD which makes the identification of the underlying genetic causes quite challenging. And in view of the emergence of therapeutic options, it is essential to combine molecular and clinical data to correctly diagnose IRD patients. In this study, we aimed to identify the disease-causing variants (DCVs) in four consanguineous Jordanian families with IRDs and describe genotype-phenotype correlations. Methods: Exome sequencing (ES) was employed on the proband patients of each family, followed by segregation analysis of candidate variants in affected and unaffected family members by Sanger sequencing. Simulation analysis was done on one novel CLRN1 variant to characterize its effect on mRNA processing. Clinical evaluation included history, slit-lamp biomicroscopy, and indirect ophthalmoscopy. Results: We identified two novel variants in CLRN1 [(c.433+1G>A) and (c.323T>C, p.Leu108Pro)], and two recurrent variants in ABCA4 [(c.1648G>A, p.Gly550Arg) and (c.5460+1G>A)]. Two families with the same DCV were found to have different phenotypes and another family was shown to have sector RP. Moreover, simulation analysis for the CLRN1 splice donor variant (c.433+1G>A) showed that the variant might affect mRNA processing resulting in the formation of an abnormal receptor. Also, a family that was previously diagnosed with nonsyndromic RP was found to have Usher syndrome based on their genetic assessment and audiometry. Conclusion: Our findings extend the spectrum of CLRN1- and ABCA4-associated IRDs and describe new phenotypes for these genes. We also highlighted the importance of combining molecular and clinical data to correctly diagnose IRDs and the utility of simulation analysis to predict the effect of splice donor variants on protein formation and function. https://pubmed.ncbi.nlm.nih.gov/31968401/