Genome sequencing identifies monogenic causes in adults with metabolic diseases

A subset of metabolic diseases is caused by rare monogenic variants. Next-generation sequencing offers a promising approach for identifying such variants, but its application in clinical diagnostics for metabolic disease is limited and the diagnostic yield is unknown.

To determine the diagnostic yield of clinical genome sequencing (GS) in adults presenting with common metabolic diseases.

We performed clinical 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/or 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), or Variant of Uncertain Significance (VUS) using ACMG/ClinGen guidelines. P/LP variants in ACMG secondary findings (v3.1) genes were also reported with participant consent.

The cohort had a female-to-male ratio of 1.7, with 18.6% African American and 22.6% Latino participants. The most common 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.

The 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 ACMG secondary findings genes. Future studies should refine participant selection for genome sequencing to optimize its diagnostic and clinical value.