Novel Variant Findings and Challenges Associated With the Clinical Integration of Genomic Testing

Abstract

IMPORTANCEA targeted genomic sequencing platform focused on diseases presenting in the first year of life may minimize financial and ethical challenges associated with rapid whole-genomic sequencing.OBJECTIVE To report interim variants and associated interpretations of an ongoing study comparing rapid whole-genomic sequencing with a novel targeted genomic platform composed of 1722 actionable genes targeting disorders presenting in infancy. DESIGN, SETTING, AND PARTICIPANTSThe Genomic Medicine in Ill Neonates and Infants (GEMINI) study is a prospective, multicenter clinical trial with projected enrollment of 400 patients. The study is being conducted at 6 US hospitals. Hospitalized infants younger than 1 year of age suspected of having a genetic disorder are eligible. Results of the first 113 patients enrolled are reported here. Patient recruitment began in July 2019, and the interim analysis of enrolled patients occurred from March to June 2020.INTERVENTIONS Patient (proband) and parents (trios, when available) were tested simultaneously on both genomic platforms. Each laboratory performed its own phenotypically driven interpretation and was blinded to other results. MAIN OUTCOMES AND MEASURESVariants were classified according to the American College of Medical Genetics and Genomics standards of pathogenic (P), likely pathogenic (LP), or variants of unknown significance (VUS). Chromosomal and structural variations were reported by rapid whole-genomic sequencing.RESULTS Gestational age of 113 patients ranged from 23 to 40 weeks and postmenstrual age from 27 to 83 weeks. Sixty-seven patients (59%) were male. Diagnostic and/or VUS were returned for 51 patients (45%), while 62 (55%) had negative results. Results were concordant between platforms in 83 patients (73%). Thirty-seven patients (33%) were found to have a P/LP variant by 2 or both platforms and 14 (12%) had a VUS possibly related to phenotype. The median day of life at diagnosis was 22 days (range, 3-313 days). Significant alterations in clinical care occurred in 29 infants (78%) with a P/LP variant. Incidental findings were reported in 7 trios. Of 51 positive cases, 34 (67%) differed in the reported result because of technical limitations of the targeted platform, interpretation of the variant, filtering discrepancies, or multiple causes. CONCLUSIONS AND RELEVANCEAs comprehensive genetic testing becomes more routine, these data highlight the critically important variant detection capabilities of existing genomic sequencing technologies and the significant limitations that must be better understood.

Genome Analysis in Sick Neonates and Infants: High-yield Phenotypes and Contribution of Small Copy Number Variations

“…This result was in line with findings from recent studies of critically ill newborns: molecular diagnosis had an impact on clinical management in 42%-78% of diagnosed patients. 3,7,18,33 The present observation supports that at least half of critically ill infants are likely to receive improved clinical care if a molecular diagnosis can be made.…”

“…16 Previous studies of whole genome sequencing in critically ill newborn infants did not report pathological small CNVs that J o u r n a l P r e -p r o o f contributed to the final molecular diagnosis. 5,17,18 Therefore, we conducted the present study to delineate the diagnostic efficacy of medical exome, whole exome, and whole genome sequencing according to the primary symptoms that prompted genetic testing, the contribution of small CNVs to the molecular diagnosis, and the impact on clinical management.…”

Insights into the perinatal phenotype of Kabuki syndrome in infants identified by genome‐wide sequencing

“…Eight infants included in this series (8/15; cases 4, 8, 9, 10, 11, 13, 14, 15) Medi-Cal recipients in several California Children's Hospitals). These infants were reported as part of the study results and are listed in summary tables (Dimmock et al, 2021;Kingsmore et al, 2019;Maron et al, 2021). The present study provides detailed, condition-focused phenotypic characterization not previously reported.…”

“…Eight infants included in this series (8/15; cases 4, 8, 9, 10, 11, 13, 14, 15) received WGS or WES as part of a trial of genomic sequencing (second Newborn Sequencing in Genomic Medicine and Public Health study or NSIGHT2, NCT03211039, or Genomic Medicine for Ill Infants and Infants or GEMINI, NCT03890679) or other prospective studies of genomic sequencing (Project Baby Bear‐ a multi‐centered study of whole genome sequencing in critically ill Medi‐Cal recipients in several California Children's Hospitals). These infants were reported as part of the study results and are listed in summary tables (Dimmock et al, 2021; Kingsmore et al, 2019; Maron et al, 2021). The present study provides detailed, condition‐focused phenotypic characterization not previously reported.…”

“…Genome-wide sequencing (whole exome sequencing [WES] or whole genome sequencing [WGS]) removes clinician bias from test selection and can also help differentiate Kabuki from chromosomal anomalies or alternate monogenic etiologies such as CHARGE syndrome, and others. Several studies have demonstrated the diagnostic efficacy and clinical utility of genome-wide sequencing in hospitalized infants and infants, including those with major congenital anomalies (Dimmock et al, 2020(Dimmock et al, , 2021French et al, 2019;Kingsmore et al, 2019;Maron et al, 2021;Meng et al, 2017;Wang et al, 2020) and has resulted in changes in medical management and parental understanding.…”