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Children with medical complexity (CMC) are a priority population in paediatric medicine.1–3 CMC have at least one chronic condition, technology dependence, multiple subspecialist involvement and substantial healthcare utilisation.2 3 They account for >30% of all paediatric healthcare spending despite comprising <1% of the total paediatric population.3 In a prior retrospective study (2010–2014), uptake of genetic testing was high.4 Rare genetic conditions are collectively common5 and often associated with medical complexity and/or serious neurological impairment.1 5 The contemporary aetiological landscape of childhood medical complexity is uncharted however.
We conducted a retrospective chart review of CMC enrolled in a local Complex Care Program over a >10-year period (01 January 2010–01 November 2020) (online supplemental figure 1).6 We extracted and critically reviewed phenotype and genetic testing data (online supplemental methods).
For 802 CMC, the median year of birth was 2013 (range 1999–2020) and 56% were male. At least one genetic test was performed in 88% (n=706). An additional 4% (n=31) met current clinical criteria for genetic testing because of unexplained major congenital anomalies or growth/development differences. Putative non-genetic causes accounted for the remaining 8% (n=65; online supplemental figure 1).
Over half the CMC had a primary genetic diagnosis (53.9%, 95% CI: 50.3% to 57.4%) (online supplemental table 1). In nine cases, this was a partial genetic diagnosis (online supplemental table 1). Eleven children each had two genetic diagnoses contributing to their phenotype (online supplemental table 1). These counts do not include CMC with clinical diagnoses of genetic conditions for which there is no confirmatory test (eg, Aicardi syndrome), or genetic diagnoses likely unrelated to their major morbidities (eg, Klinefelter syndrome).
There were 265 different primary genetic diagnoses, arising from all major categories of genetic variation (figure 1A and online supplemental figure 2). Only nine conditions were present in five or more CMC (figure 1B), and 211 conditions were each observed in a single individual/family (online supplemental table 1). Aside from Down syndrome, all conditions were rare diseases. Genome sequencing1 as a single genetic test could have detected an estimated 99% of the diagnoses (online supplemental table 1). Recurrence risks for parents varied from <1% to 50% or higher (figure 1C), underscoring the potential importance of identifying the precise molecular genetic cause(s) of their child’s medical complexity. A minority of conditions had specialised treatments either already available or in clinical trials (figure 1D). Genetic therapies were available clinically for two conditions (spinal muscular atrophy and metachromatic leukodystrophy; figure 1D).
Most children in this cohort of 802 Canadian CMC had a known or suspected underlying genetic condition. Studies relying solely on diagnostic codes from administrative or health systems data can underestimate the collective burden of rare genetic diseases. For example, a recent population-scale study estimated prevalence rates in CMC of ‘genetic conditions’ or ‘congenital/genetic (disorders)’ ranging from 4.5% to 36.4%.2 The diversity of genetic diagnoses in the CMC population appears unmatched by any other clinically defined group in paediatrics. One limitation of our study is that ascertainment was via structured Complex Care Clinics in a large urban setting, in a high-income country with a publicly funded healthcare system. Detailed phenotyping and access to advanced genetic testing were necessary to reveal the breadth of genetic disease in this cohort. Conversely, more comprehensive genetic testing like genome-wide sequencing was not performed in many children in this study cohort (online supplemental figure 1). Those CMC who remained undiagnosed after one or more genetic tests may ultimately be found to have rare or novel genetic conditions detectable by genome-wide sequencing.1
In summary, these findings provide a detailed picture of the aetiological landscape of childhood medical complexity. Diagnostic and therapeutic odysseys are common in the CMC population. Recognising the collective impact of rare genetic diseases is important when setting healthcare and research priorities.
Patient consent for publication
The study was approved by our institutional Research Ethics Board,with an accompanying patient consent waiver (#1000073142).
We thank the many individuals involved in the diagnosis and care of these CMC.
Contributors BH collected data, carried out the analyses, drafted the initial manuscript, and critically reviewed and revised the manuscript. TK, IU, MC, AP and WW designed the data collection instruments, collected data, and critically reviewed and revised the manuscript. JO designed the study, collected data, and critically reviewed and revised the manuscript. GC conceptualised and designed the study, coordinated and supervised data collection, drafted the initial manuscript, and critically reviewed and revised the manuscript.
Funding Funding was provided by the SickKids Research Institute, a Canadian Institutes of Health Research Canada Graduate Scholarship (to BH), a SickKids Starbucks Research Studentship Award (to AP), a Lunenfeld Summer Studentship (to WW) and the University of Toronto McLaughlin Centre.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.