The genomic landscape of rare disorders in the Middle East.

BACKGROUND: Rare diseases collectively impose a significant burden on healthcare systems, especially in underserved regions, like the Middle East, which lack access to genomic diagnostic services and the associated personalized management plans. METHODS: We established a clinical genomics and genetic counseling facility, within a multidisciplinary tertiary pediatric center, in the United Arab Emirates to locally diagnose and manage patients with rare diseases. Clinical genomic investigations included exome-based sequencing, chromosomal microarrays, and/or targeted testing. We assessed the diagnostic yield and implications for clinical management among this population. Variables were compared using the Fisher exact test. Tests were 2-tailed, and P < .05 was considered statistically significant. RESULTS: We present data on 1000 patients with rare diseases (46.2% females; average age, 4.6 years) representing 47 countries primarily from the Arabian Peninsula, the Levant, Africa, and Asia. The cumulative diagnostic yield was 32.5% (95% CI, 29.7-35.5%) and was higher for genomic sequencing-based testing than chromosomal microarrays (37.9% versus 17.2%, P = 0.0001) across all indications, consistent with the higher burden of single gene disorders. Of the 221 Mendelian disorders identified in this cohort, the majority (N = 184) were encountered only once, and those with recessive inheritance accounted for ~ 62% of sequencing diagnoses. Of patients with positive genetic findings (N = 325), 67.7% were less than 5 years of age, and 60% were offered modified management and/or intervention plans. Interestingly, 24% of patients with positive genetic findings received delayed diagnoses (average age, 12.4 years; range 7-37 years), most likely due to a lack of access to genomic investigations in this region. One such genetic finding ended a 15-year-long diagnostic odyssey, leading to a life-threatening diagnosis in one patient, who was then successfully treated using an experimental allogenic bone marrow transplant. Finally, we present cases with candidate genes within regions of homozygosity, likely underlying novel recessive disorders. CONCLUSIONS: Early access to genomic diagnostics for patients with suspected rare disorders in the Middle East is likely to improve clinical outcomes while driving gene discovery in this genetically underrepresented population.

A Simple Practical Guide to Genomic Diagnostics in a Pediatric Setting.

With limited access to trained clinical geneticists and/or genetic counselors in the majority of healthcare systems globally, and the expanding use of genetic testing in all specialties of medicine, many healthcare providers do not receive the relevant support to order the most appropriate genetic test for their patients. Therefore, it is essential to educate all healthcare providers about the basic concepts of genetic testing and how to properly utilize this testing for each patient. Here, we review the various genetic testing strategies and their utilization based on different clinical scenarios, and test characteristics, such as the types of genetic variation identified by each test, turnaround time, and diagnostic yield for different clinical indications. Additional considerations such as test cost, insurance reimbursement, and interpretation of variants of uncertain significance are also discussed. The goal of this review is to aid healthcare providers in utilizing the most appropriate, fastest, and most cost-effective genetic test for their patients, thereby increasing the likelihood of a timely diagnosis and reducing the financial burden on the healthcare system by eliminating unnecessary and redundant testing.

Utility of clinical exome sequencing in a complex Emirati pediatric cohort.

Clinical exome sequencing (CES) has become a routine diagnostic tool in several pediatric subspecialties, with a reported average diagnostic yield of ~25% in this patient poulation. The utility of CES in the United Arab Emirates (UAE) has not been previously investigated, most likely due to the lack of the appropriate tertiary pediatric centers and diagnostic genomic facilities in this country. Here, we report, for the first time, CES findings on a multispecialty pediatric cohort in the UAE (N = 51). This cohort, which was mostly Emirati (86%; 44/51), was followed at Al Jalila Children's Hospital (AJCH), the first and only dedicated tertiary pediatric center in the country. CES demonstrates a high diagnostic yield (41%; 21/51) in this cohort, where 55% (28/51) had previous non-diagnostic genetic testing while for the remaining individuals (45%), CES was the first-tier test. Given the reported high consanguinity rate in this population, 48% of the positive cases (10/21) were due to genes associated with recessive conditions. However, 11 out of 21 positive cases (52%) were due to heterozygous pathogenic variants in genes known to cause dominantly inherited disorders, including a case with a dual diagnosis attributed to two different genes (2%; 1/51), and another case with a novel de novo variant and new phenotypic features for a known gene (2%; 1/51). Overall, we have identified 13 novel clinically significant variants and showed that application of CES as a first-tier test plays a significant role in genetic diagnosis and management of Emirati pediatric patients.

Progressive myoclonic epilepsy type 1: Report of an Emirati family and literature review.

PURPOSE: Progressive myoclonic epilepsy type one is a neurodegenerative disorder characterized by action- and stimulus-sensitive myoclonus, tonic-clonic seizures, progressive cerebellar ataxia, preserved cognition, and poor outcome. The authors report clinical, neurophysiological, radiological, and genetic findings of an Emirati family with five affected siblings and review the literature. METHODS: All data concerning familial and clinical history, neurologic examination, laboratory tests, electroencephalogram, brain imaging, and DNA analysis were examined. RESULTS: Genetic testing confirmed the diagnosis of autosomal recessive progressive myoclonic epilepsy type 1 (EPM1) in two males and three females. The median age at onset was three years. Action- or stimulus-sensitive myoclonus and generalized seizures were recorded in 100% of our patients, at median age at onset of 3 and 4 years, respectively. Multisegmental myoclonus and generalized status myoclonicus were observed in 80% of our patients. Dysarthria and ataxia developed in 100% of our patients. Vitamin D deficiency and recurrent viral infections were noticed in 100% of our cohort. Cognitive, learning, and motor dysfunctions were involved in 100% of our patients. The sphincters were affected in 60% of our patients. Abnormal EEG was recorded in 100% of our cohort. Generalized brain atrophy progressively occurred in 60% of our patients. Phenytoin and carbamazepine were used in 60% of our patients with worsening effect. Valproate and levetiracetam were used in 100% of our patients with improving effect. CONCLUSIONS: This is the first to report a family with EPM1 in UAE. Our study emphasized a particular phenotype expressed as earlier disease onset, severe myoclonus, and generalized seizures. Cognitive, cerebellar, motor, and autonomic dysfunctions and brain atrophy were also earlier at onset and more severe than previously reported. Recurrent viral infections are another unique feature. This constellation in tout à fait was not previously reported in the literature.