The Clinical Impact of Chromosomal Microarray on Paediatric Care in Hong Kong

Abstract

ObjectiveTo evaluate the clinical impact of chromosomal microarray (CMA) on the management of paediatric patients in Hong Kong.MethodsWe performed NimbleGen 135k oligonucleotide array on 327 children with intellectual disability (ID)/developmental delay (DD), autism spectrum disorders (ASD), and/or multiple congenital anomalies (MCAs) in a university-affiliated paediatric unit from January 2011 to May 2013. The medical records of patients were reviewed in September 2013, focusing on the pathogenic/likely pathogenic CMA findings and their “clinical actionability” based on established criteria.ResultsThirty-seven patients were reported to have pathogenic/likely pathogenic results, while 40 had findings of unknown significance. This gives a detection rate of 11% for clinically significant (pathogenic/likely pathogenic) findings. The significant findings have prompted clinical actions in 28 out of 37 patients (75.7%), while the findings with unknown significance have led to further management recommendation in only 1 patient (p<0.001). Nineteen out of the 28 management recommendations are “evidence-based” on either practice guidelines endorsed by a professional society (n = 9, Level 1) or peer-reviewed publications making medical management recommendation (n = 10, Level 2). CMA results impact medical management by precipitating referral to a specialist (n = 24); diagnostic testing (n = 25), surveillance of complications (n = 19), interventional procedure (n = 7), medication (n = 15) or lifestyle modification (n = 12).ConclusionThe application of CMA in children with ID/DD, ASD, and/or MCAs in Hong Kong results in a diagnostic yield of ∼11% for pathogenic/likely pathogenic results. Importantly the yield for clinically actionable results is 8.6%. We advocate using diagnostic yield of clinically actionable results to evaluate CMA as it provides information of both clinical validity and clinical utility. Furthermore, it incorporates evidence-based medicine into the practice of genomic medicine. The same framework can be applied to other genomic testing strategies enabled by next-generation sequencing.

Chromosomal Microarray Analysis of Consecutive Individuals with Autism Spectrum Disorders Using an Ultra-High Resolution Chromosomal Microarray Optimized for Neurodevelopmental Disorders

“…CMA yields significant rates of pathogenic or potentially pathogenic (VOUS) results [2,11,12,13,14,15,16,17,18,19,20], which have clinical utility for the case-by-case clinical management of individuals with these individually rare disorders [23,24,25,26,27,28,29,30,31,32,33,34]. …”

“…Collectively this trend has resulted in corresponding increases in the clinical value of CMA testing [11,12,13,14,15,16,17,18,19,20,21,24,25,26,27,28,29,30,31,32,33,34]. In addition to guidelines on the clinical indications for CMA, the American College of Medical Genetics and Genomics (ACMG) has issued guidance on the appropriate content and design of such arrays and specifically opined that, “It is desirable to have enrichment of probes targeting dosage-sensitive genes known to result in phenotypes consistent with common indications for a genomic screen (e.g., intellectual disability, developmental delays, autism, and congenital anomalies)” [22].…”

“…Such critical regions that did not contain >1 probe/1000 bp on the baseline array were supplemented with additional probe content to provide improved detection of smaller deletions and duplications. Additional probe enrichment was of genomic regions identified by our prior studies and elsewhere in the medical literature of published copy number variants and individual genes associated with DD/ID/ASD [23,24,25,26,27,28,29,30,31,32,33,34,35,36]. The increase in analytical sensitivity resulting from this additional 3.3% probe content has been calculated to be 2.6% [21].…”

A meta-analysis of the diagnostic sensitivity and clinical utility of genome sequencing, exome sequencing and chromosomal microarray in children with suspected genetic diseases

“…The proportion of children receiving a change in clinical management by WGS results was 0.27 (95% Cl 0.17-0.40, I 2 =54%, four studies of 136 children), compared with 0.18 (95% Cl 0.13-0.24, I 2 -77%,twelve studies of 992 children) by WES, and 0.06 (95% Cl 0.05-0.07, I 2 =42%, eight studies of 4,271 children) by CMA (Figure 5). Meta-analysis of WGS and CMA groups, for which heterogeneity was not significant ( P =.09 and P =.10, respectively), demonstrated that the rate of clinical utility of WGS was higher than CMA ( P <.0001) 25,32,34,35,37,45,59-61 . Meta-analysis of four studies that reported comparisons of rates of clinical utility by WGS/WES and CMA within cohorts 25,32,37,45 .…”

Use of clinical chromosomal microarray in Chinese patients with autism spectrum disorder—implications of a copy number variation involving DPP10

“…The diagnostic yield of our cohort in Hong Kong is 3.5% but direct comparison is difficult as our study is the only one among the three that uses a clinical aCGH platform and reports only pathogenic/likely pathogenic CNVs using stringent clinical laboratory criteria [13]. We did not identify many known ASD-associated CNVs, perhaps due to the limited sample size of the cohort.…”