Children (Basel). 2026 Sep 04. pii: 1194. [Epub ahead of print]13(9):
BACKGROUND: Rare diseases collectively affect millions of children worldwide and are a major cause of pediatric morbidity, mortality, and lifelong disability. Although most have a genetic basis, obtaining a timely molecular diagnosis remains challenging because of substantial clinical and genetic heterogeneity. Advances in genomic medicine are transforming rare disease diagnosis and establishing genomics as the center of precision medicine.
METHODS: This review summarizes current evidence on genomic approaches for pediatric rare diseases, including established and emerging sequencing technologies, their clinical applications, implementation challenges, and future directions.
RESULTS: Whole-genome sequencing is increasingly being adopted as a first-line genomic test for suspected rare genetic disorders, particularly when the phenotype is heterogeneous or does not point to a specific diagnosis. Conventional cytogenetic and targeted molecular techniques remain important complementary approaches for selected phenotypes, variant classes, and orthogonal confirmation. Gene panels are effective for well-defined phenotypes, whereas whole-exome sequencing remains a high-yield approach for genetically heterogeneous disorders, particularly when whole-genome sequencing is not available or is not clinically indicated. Long-read whole-genome sequencing expands diagnostic capacity by detecting structural variants, repeat expansions, complex rearrangements, and non-coding pathogenic variants that frequently escape short-read technologies. Emerging multi-omics approaches further improve variant interpretation and help resolve previously unsolved cases. Beyond diagnosis, molecular findings guide personalized clinical management, genetic counselling, reproductive planning, and access to targeted therapies and genotype-driven clinical trials. However, broad implementation is constrained by challenges in variant interpretation, ethical and legal considerations, data governance, workforce capacity, cost, and inequitable access to genomic services. Artificial intelligence, international data-sharing initiatives, and coordinated healthcare networks are helping overcome these barriers and improve diagnostic equity.
CONCLUSIONS: Whole-genome sequencing is increasingly emerging as a first-line genomic strategy for pediatric rare diseases, while complementary technologies, expert phenotyping, and iterative data interpretation remain essential for comprehensive and accurate diagnosis and equitable access to genomic medicine.
Keywords: genome sequencing; genomic medicine; molecular diagnosis; precision medicine; rare diseases