Next-Generation Sequencing in Pediatric Lipid Disorders: Expanding the Genetic Landscape and Clinical Understanding

This study aimed to assess the utility of next-generation sequencing panels in the molecular evaluation of pediatric lipid metabolism disorders and identifying clinically relevant and novel genetic variants.

Sixty-seven pediatric patients with clinical signs of dyslipidemia were valuated retrospectively. Lipid profiles, clinical findings, and family histories were recorded. Patients were referred for genetic evaluation because of dyslipidemia and/or clinical or familial features suggestive of an inherited lipid disorder. The criteria used for referral differed according to the lipid phenotype and included marked or persistent lipid abnormalities, relevant family history, and characteristic clinical findings. NGS was performed using a 25-gene custom panel related to lipid metabolism.

Genetic variants were identified in 44 patients (65.6%), with 33 distinct variants across multiple genes, including 13 novel variants. Six patients had multiple variants in different genes. Pathogenic or likely pathogenic variants were significantly more common among patients with a positive family history (p = 0.002). Several novel variants showed a potential genotype-phenotype correlation, particularly in patients with severe manifestations such as xanthomas, hepatosteatosis, or atherosclerosis.

In children with clinically suspected inherited lipid disorders, multigene NGS testing may provide clinically useful molecular information and complement careful clinical phenotyping and family history assessment. Genetic testing may be particularly informative in children with a strong or suggestive family history or with phenotypes raising suspicion for a monogenic lipid disorder. However, a negative NGS result does not exclude a genetic etiology, and genetic findings should be interpreted in the context of the clinical phenotype.