LAUSR

To the Editor: In 2006, Watson et al. recommended, during their participation in an American College of Medical Genetics (ACMG) Newborn Screening Expert Group, a uniform panel of conditions for inclusion in state newborn screening programs. The experts conducted 3949 evaluations for 84 conditions and categorized them based on their clinical characteristics; analytical test features; and diagnosis, treatment, and management of the acute or chronic condition. The conditions were ranked based on a quantified expert opinion analysis. Medium-chain acyl-CoA dehydrogenase deficiency, congenital hypothyroidism, and phenylketonuria were the highest ranked conditions and lysosomal storage diseases, Pompe disease, and Krabbe disease were ranked the lowest. Since then, modern medicine has evolved rapidly and the clinical integration of genomic information has increased. We therefore question if the moment has arrived to discuss and update the ACMG’s list of uniform conditions to substantially reflect relevant evidence over the past decade. This is to help ensure that use of genome and exome sequencing (GS and ES) in newborns is based on (1) clinical utility or actionability and (2) disease prevalence and penetrance among the general newborn population. ES and GS should be implemented in ways that consider their clinical utility or actionability in newborns. For instance, Stark showed that early ES could have benefitted a child with normal features at birth before clinical signs of Kabuki syndrome (e.g., microcephaly and developmental delay) manifested by age 18 months. Kabuki syndrome was not considered or included among the 84 conditions in the 2006 ACMG recommendations. Since 2006, evidence supporting the clinical actionability of genetic testing for Kabuki syndrome (secondary complication prevention, treatment or intervention, and surveillance and guidelines) has surfaced. In another example, Choi et al. identified via ES a novel pathogenic variant in a 4-day-old newborn with carbamoyl phosphate synthetase 1 deficiency (CPS1D) who showed no phenotypic abnormalities at birth but later presented treatable symptoms of hypothermia, poor feeding, lethargy, and respiratory depression. The 2006 ACMG expert panel, however, placed CPS1D at the 17th percentile. Since some state-directed newborn screening programs have incorporated testing for immunodeficiency based on the ACMG’s 2006 guidance, Pavey et al. explored the clinical utility of GS in population screening for immunodeficiency-related conditions in newborns. They analyzed clinical and GS data from an ethnically and racially diverse cohort of 1349 newborn–parent trios in California. Results showed that 396 trios, or 29% of their newborn cohort, carried a single pathogenic or likely pathogenic variant in an immunodeficiency-related gene(s). A manual review of all the variants identified only one affected newborn with a high probability of a true immunodeficiency called complement component 9 (C9) deficiency. Pavey et al. recommended that the child undergo clinical confirmation of the disease and receive unconjugated and conjugated forms of the pneumococcal and meningococcal vaccinations, including serogroup B. The ACMG placed severe combined immunodeficiency at the 33rd percentile, yet C9, being a true immunodeficiency, was not discussed or included in the 2006 recommendations. Use of ES and GS in newborns should also consider disease prevalence or penetrance within the population. Kabuki syndrome has an estimated prevalence of 1 in 32,000 in Japan and among the general population, although estimates of 1 in 86,000 have been reported for Australia and New Zealand. Choi et al. explained that estimating the prevalence and incidence of CPS1D in the Korean population is very difficult because, to their knowledge, their reported CPS1D case was the first reported case in Korea. CPS1D is a rare condition with an estimated prevalence of 1 in 800,000 newborns in Japan (unknown incidence among the general population). Although reportedly rarer than Kabuki syndrome, ACMG experts appear to prioritize testing for CPS1D versus Kabuki syndrome in the 2006 ACMG guidelines. Also, C9 deficiency is reported as high among Korean and Japanese populations but was not among the conditions considered in the 2006 ACMG guidelines. In 2019, Milko et al. developed a tool that can be used to carefully select conditions for inclusion in ES and GS newborn screening. They created an age-based semiquantitative metric (ASQM) that can classify gene–disease pairs into categories based on age-based factors and facilitate decision-making about incorporating genomic sequencing into newborn care. Their result was a curation of 822 gene–disease pairs, through which 466 were classified as having childhood onset and high actionability based on expert committee scores against five core characteristics of clinical actionability (severity, likelihood, efficacy of the intervention, burden of the intervention, and knowledge base), and 755 categorized gene–disease pairs. Milko