The genomic landscape of pediatric rheumatology disorders in the Middle East

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.

Genetics in inborn errors of immunity: pediatric autoinflammatory phenotypes and the underlying genetic causes in 125 families

“…This rate supports other studies focusing on the genetic diagnosis of AID [5,13,[36][37][38][39][40][41]. Cohorts of equal size [5,13,36] and larger cohorts [41] were both evaluated in these studies, and some only included pediatric patients [12,39,42,43], while others also included adults [36-38, 41, 44, 45]. A higher positive yield was reported in studies with a more selective choice in the patient cohort, e.g.…”

“…Demirkaya et al published a severity score for familial Mediterranean fever (ISSF) based on chronic sequelae, organ dysfunction, organ failure, frequency of attacks, and increases in acute phase reactants [56]; however, the diagnosis of FMF is usually based on a combination of clinical and genetic factors. High allele frequencies of MEFV PVs have been observed in certain ethnicities [42].…”

Genetic and Clinical Characteristics of Patients in the Middle East With Multisystem Inflammatory Syndrome in Children

“…High-quality variants with read depths greater than 10, genotypic quality greater than 30, and mapping quality greater than 60 were retained for downstream analysis. 20 We prioritized rare variants in 186 signature genes (eTable 2 in the Supplement ) that may be implicated in disease progression of MIS-C, mainly genes that are associated with immune responses, including cellular response to cytokine, cell mediation of immunity, and immune and interferon signaling pathways from reported literature. 21 , 22 , 23 , 24 We used 3 filters to retain (1) truncating or loss of function (LoF) variants in the 186 inflammatory- or immune-related genes with deleterious effect on Reference Sequence database canonical transcripts and allele frequency less than 1% in the Genome Aggregation Database (gnomAD); (2) homozygous missense or LoF variants across the 186 genes and allele frequency less than 1% in gnomAD; and (3) missense variants in a subset of genes (n = 14) recently associated with severe COVID-19 21 , 22 (eTable 2 in the Supplement ) and gnomAD allele frequency less than 0.5%.…”

The Genomic Landscape of Rare Disorders in the Middle East

“…All testing was performed in a College of American Pathologists (CAP)-accredited genomics facility. Sample preparation and analyses were performed as previously described 10 and summarized in Supplementary Methods 11–13 (available upon request).…”