Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test.

PurposeGenetic testing is an integral diagnostic component of pediatric medicine. Standard of care is often a time-consuming stepwise approach involving chromosomal microarray analysis and targeted gene sequencing panels, which can be costly and inconclusive. Whole-genome sequencing (WGS) provides a comprehensive testing platform that has the potential to streamline genetic assessments, but there are limited comparative data to guide its clinical use.MethodsWe prospectively recruited 103 patients from pediatric non-genetic subspecialty clinics, each with a clinical phenotype suggestive of an underlying genetic disorder, and compared the diagnostic yield and coverage of WGS with those of conventional genetic testing.ResultsWGS identified diagnostic variants in 41% of individuals, representing a significant increase over conventional testing results (24%; P = 0.01). Genes clinically sequenced in the cohort (n = 1,226) were well covered by WGS, with a median exonic coverage of 40 × ±8 × (mean ±SD). All the molecular diagnoses made by conventional methods were captured by WGS. The 18 new diagnoses made with WGS included structural and non-exonic sequence variants not detectable with whole-exome sequencing, and confirmed recent disease associations with the genes PIGG, RNU4ATAC, TRIO, and UNC13A.ConclusionWGS as a primary clinical test provided a higher diagnostic yield than conventional genetic testing in a clinically heterogeneous cohort.

Molecular characterization of NRXN1 deletions from 19,263 clinical microarray cases identifies exons important for neurodevelopmental disease expression.

PURPOSE: The purpose of the current study was to assess the penetrance of NRXN1 deletions. METHODS: We compared the prevalence and genomic extent of NRXN1 deletions identified among 19,263 clinically referred cases to that of 15,264 controls. The burden of additional clinically relevant copy-number variations (CNVs) was used as a proxy to estimate the relative penetrance of NRXN1 deletions. RESULTS: We identified 41 (0.21%) previously unreported exonic NRXN1 deletions ascertained for developmental delay/intellectual disability that were significantly greater than in controls (odds ratio (OR) = 8.14; 95% confidence interval (CI): 2.91-22.72; P < 0.0001). Ten (22.7%) of these had a second clinically relevant CNV. Subjects with a deletion near the 3' end of NRXN1 were significantly more likely to have a second rare CNV than subjects with a 5' NRXN1 deletion (OR = 7.47; 95% CI: 2.36-23.61; P = 0.0006). The prevalence of intronic NRXN1 deletions was not statistically different between cases and controls (P = 0.618). The majority (63.2%) of intronic NRXN1 deletion cases had a second rare CNV at a prevalence twice as high as that for exonic NRXN1 deletion cases (P = 0.0035). CONCLUSIONS: The results support the importance of exons near the 5' end of NRXN1 in the expression of neurodevelopmental disorders. Intronic NRXN1 deletions do not appear to substantially increase the risk for clinical phenotypes.Genet Med 19 1, 53-61.

Relationship of asthma management, socioeconomic status, and medication insurance characteristics to exacerbation frequency in children with asthma.

BACKGROUND: less than 25% of asthmatic children are well controlled. OBJECTIVE: to identify factors associated with asthma exacerbation causing emergency department (ED) visits or hospitalizations related to health status, socioeconomic status (SES), and drug insurance. METHODS: in this retrospective cohort study, complete data were collected on 490 asthmatic children regarding demographics, SES, drug plan characteristics, health status, health resource use, and symptoms. Interview data were linked to administrative data on asthma ED visits and hospitalizations occurring in the following year. Multiple Poisson regression identified independent variables associated with ED visits or hospitalizations in the full cohort and in a subgroup with prescription drug insurance. RESULTS: younger age, previous emergency visits, nebulizer use, pet ownership, and receipt of asthma education but not an action plan were significantly associated with more frequent exacerbations. In the full cohort, children with high income adequacy had 28% fewer exacerbations than did children with low income adequacy. In the subgroup with drug insurance, girls had 26% fewer exacerbations than did boys, and children with food, drug, or insect allergies had 52% more exacerbations than did children without allergies. Children of families with annual insurance deductibles greater than $90 had 95% fewer exacerbations. Every percentage increase in the proportion of income spent out-of-pocket on asthma medications was associated with a 14% increase in exacerbations. CONCLUSIONS: asthma history, disease management factors, and SES were associated with exacerbations requiring urgent care. In families with drug plans, the magnitude of asthma medication cost-sharing as a proportion of household income, rather than income alone, was significantly associated with exacerbations.