Hospital-wide access to genomic data advanced pediatric rare disease research and clinical outcomes

Abstract

Boston Children's Hospital has established a genomic sequencing and analysis research initiative to improve clinical care for pediatric rare disease patients. Through the Children's Rare Disease Collaborative (CRDC), the hospital offers CLIA-grade exome and genome sequencing, along with other sequencing types, to patients enrolled in specialized rare disease research studies. The data, consented for broad research use, are harmonized and analyzed with CRDC-supported variant interpretation tools. Since its launch, 66 investigators representing 26 divisions and 45 phenotype-based cohorts have joined the CRDC. These studies enrolled 4653 families, with 35% of analyzed cases having a finding either confirmed or under further investigation. This accessible and harmonized genomics platform also supports additional institutional data collections, research and clinical, and now encompasses 13,800+ patients and their families. This has fostered new research projects and collaborations, increased genetic diagnoses and accelerated innovative research via integration of genomics research with clinical care.

Fig. 1. Key features of the CRDC.

This chart displays the six key features of the CRDC across the top and how they contribute to its research (red) and clinical (blue) goals. This figure was created in Microsoft PowerPoint.

Fig. 2. Overview of participants and data included in the CRDC.

Overview of participants and data included in the CRDC. A Distribution of type of sequencing performed. B Distribution of age at enrollment. C Distribution of sequencing of parents. For (A–C), the pie chart includes patients for all CRDC-sequenced cohorts combined and the bar chart includes individual CRDC-sequenced cohorts with at least 20 patients. D Average number of HPO (Human Phenotype Ontology) terms collected per patient for individual CRDC-sequenced cohorts with at least 20 patients. Top: HPO terms collected manually by research teams. Bottom: HPO terms extracted from the electronic health record by Clinithink. SUDP sudden unexpected death in pediatrics, SIDS sudden infant death syndrome, ADHD attention deficit/hyperactivity disorder, DSD disorders of sex development, MIS-C multisystem inflammatory syndrome in children, HSP hereditary spastic paraplegia, ASD autism spectrum disorder, CHD congenital heart defect. This figure was created in R with ggplot.

Fig. 3. Growth of the CRDC since launch.

These plots track the increase in total number of (A) families receiving genomic sequencing through the collaborative under a broad-use research consent and (B) disease cohorts enrolling such families. Enrollment slowed slightly in the early months of the COVID-19 pandemic as researchers transitioned to remote consenting and sample collection, as marked on the plot. This figure was created in R with ggplot.

Fig. 4. Additional projects supported by the CRDC.

A number of samples were included in additional projects performed to increase access to sequencing (ES, GS) and evaluate orthogonal methods for identifying the genetic basis of a rare disease presentation: RNA-seq, single-cell RNA-seq (scRNA-seq), long-read genome sequencing (LR-seq), high-depth exome sequencing to detect somatic mosaic variants (Deep-seq) and proteomics. This figure was created in Microsoft Excel.

Fig. 5. The research-to-clinical loop.

The research-to-clinical loop involves taking advantage of the benefits and flexibility of research studies to close the gap on unmet health needs and then evolve the standard of care by bringing the results back to the clinic. This figure was created in Microsoft PowerPoint.