J Inherit Metab Dis. 2025 Nov;48(6):e70094. doi: 10.1002/jimd.70094.
ABSTRACT
“Genotype-first” approaches, studies that apply genomic sequencing in unselected cohorts of apparently healthy adults or infants, have begun to upend traditional notions about the prevalence and penetrance of inherited metabolic disorders. In this commentary, we discuss how large-scale genomic data from healthy newborns and biobanks of adult research participants, along with clinical testing such as reproductive carrier screening and secondary findings from exome and genome sequencing, have revealed a new category of “genotype positive” cases of IMDs that were previously unrecognized by both clinicians and public health programs. In particular, the prevalence and penetrance of variants linked to IMD have important implications for evaluating the utility of genomic sequencing as a public health screening tool in the newborn period. Although genomic sequencing may allow us to detect treatable disease earlier and identify individuals at risk before irreversible damage occurs, realizing its promise as a screening tool will require an acknowledgment that more genomic data does not always equate to clearer decisions and that disease-associated variants may not universally require intervention.
PMID:41024452 | DOI:10.1002/jimd.70094
