Long-term Penetrance of Disease Variants in Genes Prioritized for Genomic Newborn Screening: Evidence from Adult...

Genomic newborn screening (gNBS) is a potential public health intervention, but its positive predictive value (PPV) remains uncertain. Estimating the prevalence and penetrance of pathogenic and likely pathogenic (P/LP) variants in genes prioritized for screening may clarify the long-term PPV and clinical utility of gNBS.

To compare ICD-based ascertainment, electronic medical record (EMR) review, and clinical assessment of genetic disorders in adults with P/LP variants in 54 genes prioritized for gNBS.

Two-cohort observational study with EMR review and clinical assessment in the hospital-based cohort.

The U.K. Biobank (UKB) and Mass General Brigham Biobank (MGBB).

451,877 adults from the UKB and 53,371 from the MGBB, all with exome sequencing data.

P/LP variants in 54 genes prioritized through expert consensus for gNBS, in genotypes consistent with each gene's inheritance pattern.

The primary outcome was the absolute difference in the proportion of MGBB participants identified as affected by ICD versus EMR ascertainment. Secondary outcomes included findings from clinical assessments of undiagnosed MGBB participants, corrected UKB penetrance estimates, and extrapolation to U.S.. annual birth cohorts and living adults.

P/LP variants were identified in 665 UKB participants (0.15%) and 82 MGBB participants (0.15%), approximately 1 in 650. In MGBB, EMR review revealed that 58/82 individuals (70.7%) were undiagnosed, although 25 of 58 (43.1%) had documented symptoms. Disease-associated ICD codes were found in 39.0% (32/82) of participants, whereas EMR review identified symptoms in 59.8% (49/82, McNemar P<.001). Applied to UKB, this correction yielded a penetrance of 28.4% (95% CI, 18.6% to 38.2%), implying that 73 to 203 participants beyond the 51 identified by ICD codes may have clinical features of disease. Extrapolated to U.S. birth cohorts, 4,900 to 5,700 newborns per year may harbor P/LP variants in these genes and survive into adulthood. Approximately 355,000 to 410,000 U.S. adults may have P/LP variants in these genes.

Penetrance of P/LP variants in genes prioritized for gNBS is substantially higher than ICD estimates suggest. Many adults with P/LP variants are symptomatic but undiagnosed, supporting inclusion of these genes in gNBS.

Question: What proportion of adults with genomic variants linked to treatable genetic diseases develop symptoms and what does this imply for genomic newborn screening (gNBS)?Findings: Among 505,222 adults, disease-associated variants in 54 gNBS genes were found in approximately 1 in 650 participants. In a hospital biobank cohort, only 29.3% of participants had been diagnosed, but electronic medical record review and targeted phenotyping identified symptoms in 59.8%.Meaning: Individuals with treatable genetic disorders that are identifiable through genomic screening are symptomatic but undiagnosed into adulthood, highlighting the importance of genomic newborn screening.