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The genomic landscape of pediatric rheumatology disorders in the Middle East
Basil M Fathalla1, Ali Alsarhan2, Samina Afzal3
1Rheumatology Department, Al Jalila Children's Specialty Hospital, Dubai, UAE.
Insights
Genomic testing in Middle Eastern children with rheumatic diseases yielded a 46.5% positive diagnosis rate. These genetic findings significantly guided clinical management and revealed new insights into disease susceptibility.
Area of Science:
- Pediatric Rheumatology
- Clinical Genomics
- Genetic Medicine
Background:
- Comprehensive genomic investigations for pediatric rheumatic disorders remain underexplored in the Middle East.
- Understanding the genetic basis of these conditions is crucial for accurate diagnosis and management.
Purpose of the Study:
- To characterize the landscape and clinical utility of genomic investigations in pediatric rheumatic diseases in the Middle East.
- To identify genetic variations associated with these disorders in a diverse Arab pediatric cohort.
Main Methods:
- Clinical and genetic assessment of 71 pediatric patients with rheumatic diseases.
- Utilized next-generation sequencing-based gene panels, whole-exome sequencing, and rapid sequencing.
- Analysis included identification of gene alterations and copy number variants (CNVs).
Main Results:
- A 46.5% positive diagnostic yield was achieved, with dual diagnoses in 3% of cases.
- The MEFV gene was the most frequent finding (64%), followed by 11 other genes/loci.
- Copy number variants (CNVs) accounted for 15.2% of positive findings; rapid sequencing proved effective.
- Genetic findings guided clinical management in 81.8% of positive cases.
Conclusions:
- Genomic testing is clinically valuable for diagnosing pediatric rheumatic disorders in the Middle East.
- Identified novel genetic insights, including heterozygous loss of function in IFIH1 increasing susceptibility to recurrent fevers.
- Highlights the importance of genetic variation landscape in understanding pediatric rheumatic diseases.
Abstract:
The landscape and clinical utility of comprehensive genomic investigations for a wide range of pediatric rheumatic disorders have not been fully characterized in the Middle East. Here, 71 pediatric patients, of diverse Arab origins, were clinically and genetically assessed for a spectrum of rheumatology-related diseases at the only dedicated tertiary children's hospital in the United Arab Emirates. Clinical genomic investigations included mainly (76%) next-generation sequencing-based gene panels and whole-exome sequencing, along with rapid sequencing in the intensive care unit and urgent setting. The overall positive yield was 46.5%, whereas dual diagnoses were made in two cases (3%). Although the majority (21/33, 64%) of positive findings involved the MEFV gene, the remaining (12/33, 36%) alterations were attributed to 11 other genes/loci. Copy number variants (CNVs) contributed substantially (5/33, 15.2%) to the overall diagnostic yield. Sequencing-based testing, specifically rapid sequencing, had a high positive rate and delivered timely results. Genetic findings guided clinical management plans and interventions in most cases (27/33, 81.8%). We highlight unique findings and provide additional evidence that heterozygous loss of function of the IFIH1 gene increases susceptibility to recurrent fevers. Our study provides new insights into the pathogenic variation landscape in pediatric rheumatic disorders.
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