Integrated Whole Genome Sequencing Approach Resolving Diagnostic Challenges in Pediatric Huntington Disease

Abstract

Pediatric patients with progressive neurological symptoms often face prolonged diagnostic journeys as clinical presentations overlap with multiple conditions or occur without informative family history. Traditional diagnostic approaches including chromosomal microarray, targeted gene panels, and whole exome sequencing have limitations that can delay or prevent accurate diagnosis. Whole genome sequencing provides comprehensive genomic coverage without gene preselection. However, short-read technologies struggle to characterize complex genomic features such as large repeat expansions. This study presents four pediatric cases of Huntington disease diagnosed through an integrated sequencing approach combining short-read and long-read whole genome sequencing technologies. Patients ranged from 10 to 12 years of age and presented with diverse symptoms including autism, intellectual disability, developmental regression, seizures, and movement abnormalities. Two patients had no family history suggestive of Huntington disease. The integrated approach enabled diagnosis when clinical presentations provided insufficient guidance for targeted testing, eliminated delays from sequential testing strategies, and provided clinically meaningful quantification of CAG repeat expansions. In three of four cases, long-read sequencing revealed discrepancies of 19 to 32 repeats compared to short-read predictions, fundamentally altering clinical interpretation and prognosis. These cases demonstrate how comprehensive genomic evaluation addresses diagnostic challenges in childhood-onset genetic disorders with nonspecific presentations.