Rapid Whole-Genomic Sequencing and a Targeted Neonatal Gene Panel in Infants With a Suspected Genetic Disorder

Abstract

ImportanceGenomic testing in infancy guides medical decisions and can improve health outcomes. However, it is unclear whether genomic sequencing or a targeted neonatal gene-sequencing test provides comparable molecular diagnostic yields and times to return of results.ObjectiveTo compare outcomes of genomic sequencing with those of a targeted neonatal gene-sequencing test.Design, Setting, and ParticipantsThe Genomic Medicine for Ill Neonates and Infants (GEMINI) study was a prospective, comparative, multicenter study of 400 hospitalized infants younger than 1 year of age (proband) and their parents, when available, suspected of having a genetic disorder. The study was conducted at 6 US hospitals from June 2019 to November 2021.ExposureEnrolled participants underwent simultaneous testing with genomic sequencing and a targeted neonatal gene-sequencing test. Each laboratory performed an independent interpretation of variants guided by knowledge of the patient’s phenotype and returned results to the clinical care team. Change in clinical management, therapies offered, and redirection of care was provided to families based on genetic findings from either platform.Main Outcomes and MeasuresPrimary end points were molecular diagnostic yield (participants with ≥1 pathogenic variant or variant of unknown significance), time to return of results, and clinical utility (changes in patient care).ResultsA molecular diagnostic variant was identified in 51% of participants (n = 204; 297 variants identified with 134 being novel). Molecular diagnostic yield of genomic sequencing was 49% (95% CI, 44%-54%) vs 27% (95% CI, 23%-32%) with the targeted gene-sequencing test. Genomic sequencing did not report 19 variants found by the targeted neonatal gene-sequencing test; the targeted gene-sequencing test did not report 164 variants identified by genomic sequencing as diagnostic. Variants unidentified by the targeted genomic-sequencing test included structural variants longer than 1 kilobase (25.1%) and genes excluded from the test (24.6%) (McNemar odds ratio, 8.6 [95% CI, 5.4-14.7]). Variant interpretation by laboratories differed by 43%. Median time to return of results was 6.1 days for genomic sequencing and 4.2 days for the targeted genomic-sequencing test; for urgent cases (n = 107) the time was 3.3 days for genomic sequencing and 4.0 days for the targeted gene-sequencing test. Changes in clinical care affected 19% of participants, and 76% of clinicians viewed genomic testing as useful or very useful in clinical decision-making, irrespective of a diagnosis.Conclusions and RelevanceThe molecular diagnostic yield for genomic sequencing was higher than a targeted neonatal gene-sequencing test, but the time to return of routine results was slower. Interlaboratory variant interpretation contributes to differences in molecular diagnostic yield and may have important consequences for clinical management.

Expanding the phenotypic spectrum for CDK8‐related disease: A case report

“…We describe the first documented occurrence of an inherited CDK8 ‐associated disease variant in a child–parent pair (child: NM_001260.3; parent: NM_001260.2). All documented cases of CDK8 ‐related syndromes to date have arisen de novo (Table S1) (Aggarwal et al, 2020; Calpena et al, 2019; Halfmeyer et al, 2023; Maron et al, 2023; Miyamoto et al, 2021; Uehara et al, 2020); 13 different heterozygous variants have been identified in 18 unrelated patients. This case documents parental inheritance of a CDK8 pathogenic variant which can affect genetic counseling and recurrence risk in other family members.…”

Clinical Genetic and Genomic Testing in Congenital Heart Disease and Cardiomyopathy

“…In these studies, rapid genome sequencing in select cohorts of CHD patients identified clinically actionable results, in 27-46% of patients, and surpassed CMA in head-to-head comparisons [57][58][59]. However, other studies highlight limitations, including the burden of interpreting variants of uncertain significance, with differences in variant interpretation up to 43% [60]. Furthermore, while the coverage of genome sequencing is superior to exome sequencing, there are still gaps in genome sequencing coverage [55,61].…”

The Critical Role of Technologies in Neonatal Care

“…Whole genome sequencing and targeted neonatal gene panels can support rapid diagnosis, with turnaround times being as short as 4 days [95,96]. A point-of-care, swab-based genetic test device has recently been developed, which can detect the m.1555 A > G variant implicated in development of deafness in babies who are treated with gentamicin.…”