Using Long-Term Follow-Up Data to Classify Genetic Variants in Newborn Screened Conditions

Abstract

With the rapid increase in publicly available sequencing data, healthcare professionals are tasked with understanding how genetic variation informs diagnosis and affects patient health outcomes. Understanding the impact of a genetic variant in disease could be used to predict susceptibility/protection and to help build a personalized medicine profile. In the United States, over 3.8 million newborns are screened for several rare genetic diseases each year, and the follow-up testing of screen-positive newborns often involves sequencing and the identification of variants. This presents the opportunity to use longitudinal health information from these newborns to inform the impact of variants identified in the course of diagnosis. To test this, we performed secondary analysis of a 10-year natural history study of individuals diagnosed with metabolic disorders included in newborn screening (NBS). We found 564 genetic variants with accompanying phenotypic data and identified that 161 of the 564 variants (29%) were not included in ClinVar. We were able to classify 139 of the 161 variants (86%) as pathogenic or likely pathogenic. This work demonstrates that secondary analysis of longitudinal data collected as part of NBS finds unreported genetic variants and the accompanying clinical information can inform the relationship between genotype and phenotype.

Current Status of Newborn Bloodspot Screening Worldwide 2024: A Comprehensive Review of Recent Activities (2020–2023)

“…A companion report identified at least one model to overcome each of the four challenges to RUSP implementation identified in the first report: (1) screening panel variability; (2) information limitations from short pilots; (3) expansion of NBS definitions by screening new conditions; and (4) capacity constraints in the RUSP review process [ 48 ]. In an effort to speed the expansion process, the NBSTRN developed web-based tools and resources that enabled NBS stakeholders to advance their research and potentially improve clinical care for patients and their families [ 49 , 50 , 51 ]. Reports in 2020 and 2023 provided aggregate data and reviewed the NBS experiences of the USA states and two territories for conditions on the RUSP from 2015–2017 [ 52 ] and 2018–2020 [ 53 ], and a separate 2023 report reviewed the rate of implementation of the added conditions from 2010–2018 [ 54 ].…”

Variant curation and interpretation in hereditary cancer genes: An institutional experience in Latin America

“…Population‐specific biobanks with repositories of genetic variants and health information are a valuable resource for supporting genotype–phenotype analyses and conclusion on clinical actionability. This was demonstrated by Whilhelm K., et al, when performing a secondary analysis of 161 genetic variants not reported in ClinVar complemented with longitudinal clinical data collected as part of a newborn screening program, which allowed the reclassification of 139 (86%) of these as P/LP (Wilhelm et al, 2022). It is noteworthy that an Institutional Biobank and a Program registry support our work with local genetic data and associated clinical information from cancer patients participating in the Hereditary Cancer Program at the INC‐C; in addition, these patients are being followed up by the Institutional Genetics Clinic.…”

NBSTRN Tools to Advance Newborn Screening Research and Support Newborn Screening Stakeholders

“…The LPDR contains the Inborn Errors of Metabolism Information System (IBEM-IS) data repository for IBEMC longitudinal natural history data [14,15]. A recent study used IBEM-IS data available in the LPDR to characterize and classify novel variants across 32 diseases [16]. The researchers aggregated data from 982 IBEM-IS participants (51.6%) who had confirmatory genotyping analysis to assess the novelty of the recorded variants.…”