Genome Sequencing Identifies Monogenic Causes in Adults with Metabolic Diseases

PurposeA subset of metabolic diseases is caused by rare monogenic variants. Next generation sequencing (NGS)-based testing offers a promising approach for identifying such variants. However, its application in clinical diagnostics for metabolic diseases is limited, and the diagnostic yield is unknown. MethodsWe performed clinical genome sequencing (GS) on 560 adults seen in New York clinical practices between August 2020 and December 2023. Participants presented with hyperlipidemia/hypertriglyceridemia (HLD/HTG), pre-diabetes, Type 2 diabetes mellitus (T2DM), and metabolic dysfunction-associated fatty liver disease/steatohepatitis (MAFLD/MASH). Variants in a curated set of 90 genes associated with monogenic forms of these conditions were classified as Pathogenic (P), Likely Pathogenic (LP), and Variant of Uncertain Significance (VUS) using ACMG and ClinGen Sequence Variant Interpretation Working Group guidelines. P/LP variants in ACMG secondary findings (v3.1) genes were also reported with participant consent. ResultsThe cohort included a female-to-male ratio of 1.7, with 18.6% African American and 22.6% Latino participants. The most common primary enrollment diagnoses were HLD/HTG (25%), T2DM (9%), pre-diabetes (7%), and MAFLD/MASH (4%). Many participants had multiple conditions (42% with two, 12% with three). Approximately one-third had reportable variants with 6% classified as P/LP. The most common P/LP variants were in APOB and LDLR. ConclusionsThe prevalence of clinically significant (P/LP) variants related to primary metabolic disease in this cohort was 6%. An additional 5.5% of participants had P/LP variants in genes recommended for return as ACMG secondary findings. Future studies should focus on refining participant selection for genome sequencing to optimize its diagnostic and clinical value.