Secondary findings in whole exome sequencing: prevalence and management

Abstract

Whole exome sequencing (WES) is a genomic diagnostic tool widely used to identify genetic variants associated with rare diseases and undiagnosed conditions. In addition to diagnosing the primary condition, WES may also generate secondary findings that are unrelated to the primary indication of testing but have important clinical implications. However, data on the prevalence and clinical management of secondary findings in the Malaysian population remain limited. This study aimed to evaluate the prevalence and clinical management of secondary findings identified through WES at Hospital Kuala Lumpur (HKL) and Hospital Tunku Ampuan Besar Tuanku Aishah Rohani, UKM Children's Specialist Hospital (Hospital TABTAR). A retrospective clinical audit was conducted involving 882 patients who underwent WES between January 2021 and March 2026. Of these, 790 patients consented to receive secondary findings and were included in the secondary findings analysis, while 92 patients opted out and were excluded. Data were obtained from medical records, including demographic characteristics, genetic test results, classification of secondary findings according to the American College of Medical Genetics and Genomics (ACMG) guidelines, and clinical management outcomes. Descriptive statistical analyses were performed. Secondary findings were identified in 33 patients among 790 individuals (4.18%), with a total of 28 secondary findings recorded. One patient harboured two distinct secondary findings. Of the variants identified, 13 (46.43%) were classified as pathogenic and 15 (53.57%) as likely pathogenic. The majority of secondary findings involved genes associated with cardiovascular disorders and hereditary cancer syndromes. Clinical management commonly included genetic counselling and specialist referral, although variability was observed in follow-up adherence and cascade screening uptake among family members. This study provides local evidence on the burden and clinical management of secondary findings identified through WES in Malaysia. The findings highlight the importance of structured follow-up pathways, effective genetic counselling, and improved integration of genomic medicine into routine clinical practice to optimise the clinical utility of secondary findings.