Clinical and genetic spectrum of dual rare genetic diseases revealed by whole-exome sequencing in 14 pediatric patients.

backgroundDual molecular diagnoses, defined as the coexistence of pathogenic variants in two distinct disease-causing genes, challenge the traditional single-gene model of Mendelian inheritance. With the advent of whole-exome sequencing (WES), such complex genotypes are increasingly recognized.

objectiveTo investigate the clinical and genetic spectrum of dual rare genetic diseases in pediatric patients and to assess the diagnostic utility of WES in detecting diverse variant types.

methodsA retrospective analysis was conducted on 872 children with suspected rare genetic disorders who underwent proband or trio-based WES from January 2019 to February 2025. Variants were classified according to American College of Medical Genetics and Genomics(ACMG) guidelines. Dual diagnoses were confirmed when two independent pathogenic or likely pathogenic variants, each explaining part of the phenotype, were identified.

resultsAmong 872 patients, 370 (42.4%) received a molecular diagnosis, and 14 (3.8%) were confirmed with dual molecular diagnoses. Autosomal dominant (AD) disorders were most frequent (85.7%), de novo variants represented 57.14% (8 out of 14 cases). Six patients (42.9%) harbored combinations of single nucleotide variant (SNV) and other variant types, including exon deletions, paternal uniparental disomy (UPD15). Clinically, 14.3% of cases were phenotypically distinct, while 85.7% were phenotypically overlapping.

conclusionDual molecular diagnoses occur in approximately 3.8% of molecularly diagnosed patients and frequently involve de novo dominant variants. WES effectively detects multiple variant types (including SNV, CNV, exon deletions, UPD, and mosaicism) providing crucial insights for precise diagnosis, management, and genetic counseling in children with complex phenotypes.