Spectrum of autosomal recessive pediatric cancer predisposition syndromes in a population with high consanguinity.

Abstract

e22637 Background: Most studies of pediatric cancer predisposition syndromes (CPS) are derived from Western populations, resulting in limited understanding of CPS spectra in low- and middle-income countries. We aimed to characterize the genetic landscape of CPS among children of Arab ancestry treated at King Hussein Cancer Center (KHCC), with a particular focus on the impact of consanguinity. Methods: We conducted a retrospective review of children (<18 years) referred to the KHCC Pediatric Cancer Predisposition Clinic between January 2020 and October 2025. Germline testing was performed using targeted next-generation sequencing panels (Invitae) covering cancer predisposition, immunodeficiency, and bone marrow failure syndromes. Patients were stratified based on reported parental consanguinity. Results: A total of 230 pediatric cancer patients underwent germline testing. Median age at cancer diagnosis was 5 years (range, 0.2–18), and 55% were male. The most common indications for CPS evaluation were a family history of cancer (59%), followed by tumor types suggestive of an underlying predisposition syndrome (46%). The overall consanguinity rate was 26%, increasing to 35% among patients with a positive family history. Overall, 76 patients were diagnosed with 24 distinct CPSs. Among children from consanguineous families, 27 of 30 (90%) had autosomal recessive (AR) CPSs, while 3 of 30 (10%) had autosomal dominant (AD) conditions. In the non-consanguineous group, 45 of 46 (98%) had AD CPSs, and one child (2%) had a mitochondrial disorder due to a heteroplasmic variant. The most frequent CPSs were constitutional mismatch repair deficiency (CMMRD, n=11), RB1-related predisposition (n=10), neurofibromatosis (n=8), and Li-Fraumeni syndrome (n=6). Variants of uncertain significance (VUS) considered likely contributory were identified in 17 patients. Genetic testing was negative in 54 of 230 patients (23%). Conclusions: Consanguinity profoundly shapes the spectrum of pediatric CPS in Arab populations, with a marked predominance of autosomal recessive syndromes. These findings underscore the need for population-specific genetic evaluation strategies. Future efforts should prioritize systematic reclassification of VUS through integrated tumor–germline analyses, trio-based testing, and functional studies. Broader implementation of whole-exome and whole-genome sequencing is essential for clinically high-risk patients with negative panel testing, particularly in highly consanguineous populations.