Feasibility of Screening for Chromosome 15 Imprinting Disorders in 16 579 Newborns by Using a Novel Genomic Workflow

Importance  Newborn screening for Angelman syndrome (AS), Prader-Willi syndrome (PWS), and chromosome 15 duplication syndrome (Dup15q) may lead to benefit from early diagnosis and treatment.

Objective  To examine the feasibility of newborn screening for these chromosome 15 imprinting disorders at population scale.

Design, Setting, and Participants  In this diagnostic study, the validation data set for the first-tier SNRPN test, called methylation-specific quantitative melt analysis (MS-QMA), included 109 PWS, 48 AS, 9 Dup15q, and 1190 population control newborn blood spots (NBS) and peripheral tissue samples from participants recruited from January 2000 to December 2016. The test data set included NBS samples from 16 579 infants born in 2011. Infants with an NBS identified as positive for PWS, AS, or Dup15q by the first-tier test were referred for droplet digital polymerase chain reaction, real-time polymerase chain reaction, and low-coverage whole-genome sequencing for confirmatory testing. Data analyses were conducted between February 12, 2015, and August 15, 2020.

Results  In the validation data set, the median age for the 77 patients with PWS was 3.00 years (IQR, 0.01-44.50 years); for the 46 patients with AS, 2.76 years (IQR, 0.028 to 49.00 years); and for the 9 patients with Dup15q, 4.00 years (IQR, 1.00 to 28.00 years). Thirty-eight patients (51.4%) in the PWS group, 20 patients (45.5%) in the AS group, and 6 patients (66.7%) in the Dup15q group who had sex reported were male. The validation data set showed MS-QMA sensitivity of 99.0% for PWS, 93.8% for AS, and 77.8% for Dup15q; specificity of 100% for PWS, AS, and Dup15q; positive predictive and negative predictive values of 100% for PWS and AS; and a positive predictive value of 87.5% and negative predictive value of 100% for Dup15q. In the test data set of NBS samples from 16 579 infants, 92 had a positive test result using a methylation ratio cut-off of 3 standard deviations from the mean. Of these patients, 2 were confirmed to have PWS; 2, AS; and 1, maternal Dup15q. With the use of more conservative PWS- and AS-specific thresholds for positive calls from the validation data set, 9 positive NBS results were identified by MS-QMA in this cohort. The 2 PWS and 2 AS calls were confirmed by second-tier testing, but the 1 Dup15q case was not confirmed. Together, these results provided prevalence estimates of 1 in 8290 for both AS and PWS and 1 in 16 579 for maternal Dup15q, with positive predictive values for first-tier testing at 67.0% for AS, 33.0% for PWS, and 44.0% for combined detection of chromosome 15 imprinting disorders for the validation data set.

Conclusions and Relevance  The findings of this diagnostic study suggest that it is feasible to screen for all chromosome 15 imprinting disorders using SNRPN methylation analysis, with 5 individuals identified with these disorders out of 16 579 infants screened.