GENETIC MUTATIONS CAUSING INHERITED RETINAL DYSTROPHIES IN THE PALESTINIAN POPULATION
Alaa Al Talbishi (1,2), Yahia AlSweity (1), Kholoud Ayesh (1), Fathiya Abu Turky (2), Prasanthi Namburi (2), Frans P.M. Cremers (3), Muhammad Imran Khan (3), Gerry Clare (1), Eyal Banin (2), Dror Sharon (2), St. John Eye Hospital, Jerusalem, (2), Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem (2), Department of Human Genetics, Radboud University Nijmegen Medical Center, The Netherlands (3).
Inherited retinal dystrophies (IRDs) are a diverse group of genetic disorders associated with visual impairment due to loss of function of photoreceptor cells (rods and cones). These dystrophies cause visual impairment in more than 2 million people worldwide and are characterised by considerable clinical and genetic heterogeneity (1).
Consanguineous mating between two individuals who are heterozygotes carrying the same recessive mutant allele increases the likelihood of having offspring with autosomal recessive disorders (2). According to the Palestinian Central Bureau of Statistics, 45.1% of marriages in Palestine are between consanguineous partners.
Thus, Palestinians carry an increased risk of developing autosomal recessive conditions, including IRDs. For example, we have calculated the prevalence of congenital stationary night blindness (CSNB) among Jerusalemite Palestinians to be 1 in 4,725 (unpublished data), far higher than the estimated 1 in 294,000 of the world’s population (3). Another example is the prevalence of non-syndromic RP which was estimated to be 1 in 1,798 Palestinian Muslims living in Jerusalem, almost three times the estimated prevalence in America and Europe (4).
In this paper, we include data from our cohort of West Bank and Jerusalemite Palestinian families in which there was a clinical diagnosis of IRD, and whose members agreed to provide a blood sample as part of their participation in a genetic research. Our aim was to diagnose the most common IRDs in the Palestinian community and to identify the most common causative genetic mutations.
Patient Recruitment and Clinical Evaluation
The tenets of the Declaration of Helsinki were followed and informed consent was obtained from patients and family members who provided blood samples for DNA analysis. Palestinian families with family members diagnosed with an IRD were recruited between 1999 and 2017 at Hadassah or St. John Eye Hospital. All participants underwent a comprehensive clinical, electrophysiological and imaging evaluation.
Initially, Sanger sequencing was used to screen for founder mutations known to cause IRDs in the Palestinian population. Samples negative for the founder mutations were analysed by the Molecular Inversion Probe (MIP) method. In certain cases, whole exome sequencing (WES) was performed as part of an extended search for the genetic diagnosis.
- 386 families (including 612 patients with IRDs) were recruited from different regions of the West bank, Gaza strip and Jerusalem.
- The percentage of consanguineous marriages in our study was at least 74.3%.
- The mean age of the participants was 27.8 ± 15 years (ranging from 3-77 years).
- The genetic cause of disease has been identified in 202 families (52%) using Sanger sequencing of founder mutations (56%), MIPs (30%), and WES (14%).
- The most common genetically diagnosed IRDs were retinitis pigmentosa (RP), Stargardt disease, and achromatopsia (ACHM).
- Autosomal recessive mode of inheritance was genetically found in 189 (94% of genetically diagnosed cases ) families).
Chart shows percentage of genetically diagnosed among the clinical cases.
Pictures show fundus photos, FAF and OCT of the example case.
Example Case: 11 years old female, a product of consanguineous marriage. Visual acuity 6/30 both eyes. BEST1 (p.Leu128His c.383 T>A) Homozygous mutation, parents are heterozygous.
In this study, we report 35 novel mutations in 21 IRD genes. The genes harbouring the largest number of novel mutations are ABCA4 and BEST1.
Some of the mutations are very common among Palestinians, including the TRPM1, p.Lys294* mutation (causing disease in 45 affected individuals with CSNB) and ABCA4, IVS28-15del23bp mutation (causing disease in 23 affected individuals with Stargardt).
Chart shows the most common IRD-causing genes in Palestinians.
To the best of our knowledge, this is the first clinical and genetic report of a Palestinian cohort with IRDs. The analysis revealed a large genetic heterogeneity with a relatively high level of private mutations, therefore a thorough genetic analysis using different methods and advanced techniques is needed for an efficient analysis.
1.Wright AF, Chakarova CF, Abd El-Aziz MM, Bhattacharya SS. Photoreceptor degeneration: genetic and mechanistic dissection of a complex trait. Panel-Based Clinical Genetic Testing in 85 Children with Inherited Retinal Disease .Nat Rev Genet. 2010;11(4):273-284.
2.Tadmouri GO, Nair P, Obeid T, Al Ali MT, Al Khaja N, Hamamy HA (2009) Consanguinity and reproductive health among Arabs.Reprod Health 6:17.
3.Haim M (1986). Congenital stationary night blindness. Acta ophthalmologica. 64:192-198.
4.Sharon D, Banin E (2015). Nonsyndromic Retinitis Pigmentosa is Highly Prevalent in the Jerusalem Region with a high Frequency of Founder Mutations. Mol Vis. 2015 Jul 17;21:783-92. eCollection 2015.