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

Abstract

IMPORTANCENewborn 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 firsttier 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. RESULTSIn 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 RELEVANCEThe 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.

Estimating the impact of Angelman syndrome on parental productivity in Australia using productivity-adjusted life years

“…At present, the supports available to persons with AS and their families include sleep aids and behavioural therapy (Wheeler et al, 2017). In future, supports may also include specific therapeutic treatments for AS, with trials underway at present investigating the efficacy and effectiveness of gene therapies for AS (Godler et al, 2022). Therefore, evidence regarding the total socioeconomic impact, including the parental productivity burden, attributable to AS is needed to inform future funding decisions.…”

“…Furthermore, limitations in the granularity of data available to support the estimation of the parental productivity index meant that the parental productivity impact associated with the ‘lengthy diagnostic odyssey’ commonly experienced by the families of persons with AS was not to be estimated (Wheeler et al, 2017). However, it is anticipated that diagnostic approaches which support reducing the time to a diagnosis of AS could have a flow-on benefit of reducing a component of the parental stress associated with having a child with AS (Baker et al, 2021; Doble et al, 2020; Godler et al, 2022).…”

“…The lower prevalence estimate was obtained from a retrospective registry review in Denmark, which identified 80 patients with AS out of the 6.90 million patients in the Danish National Patient Registry (DNPR) from 1994 to 2015, corresponding to a prevalence of 1:86,250 (0.001%) (Jørgensen et al, 2019a). The upper prevalence estimate was obtained from a study evaluating the feasibility of screening for chromosome 15 imprinting disorders in infants born in Victoria, Australia which reported a prevalence of 1:8,290 (0.012%) for infants born in 2011 (Godler et al, 2022).…”

“…Few studies reporting the population prevalence of AS in Australia were identified and variation across the reported estimates in other countries was significant (Al Salloum et al, 2015; Godler et al, 2022; Jørgensen et al, 2019a; Luk & Lo, 2016; Mertz et al, 2013; Õiglane-Shlik et al, 2006; Petersen et al, 1995; Thomson et al, 2006). As such, results were estimated for a lower, base-case, and upper prevalence scenario to account for the underlying uncertainty in the prevalence of AS within Australia.…”

“…Specifically, the absence of a newborn screening program for AS to allow for estimates on cohorts of unbiased ascertainment, overlapping phenotypic characteristics with other syndromes, issues pertaining to the accuracy of diagnostic methods, the lack of genetic confirmation for approximately 10% of cases, and historically low levels of awareness among clinicians (Õiglane-Shlik et al, 2006; Thomson et al, 2006; Tones et al, 2018; Wheeler et al, 2017). Many of these factors mean that children with AS, and their families, are often subject to a ‘lengthy diagnostic odyssey’ with most only receiving a diagnosis between the ages of one and five years (Godler et al, 2022; Wheeler et al, 2017).…”