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Whole Exome Sequencing of Adult and Pediatric Cohorts of the Rare Vascular Disorder Systemic Capillary Leak Syndrome

Pierce, Richard*; Ji, Weizhen*; Chan, Eunice C.; Xie, Zhihui; Long, Lauren M.; Khokha, Mustafa*,‡; Lakhani, Saquib*; Druey, Kirk M.

doi: 10.1097/SHK.0000000000001254
Clinical Aspects (Human Subjects): PDF Only

Objective: Systemic capillary leak syndrome (SCLS) is a rare disorder that presents with episodes of hypovolemic shock. The extent to which genetic abnormalities contribute to SCLS is unknown. We identified pediatric and adult cohorts with characteristic clinical courses. We sought to describe the clinical characteristics of both cohorts, identify a possible genetic contribution to SCLS, and demonstrate that whole exome sequencing (WES) may be conducted by critical care providers.

Design: Prospective observational study of WES of nine adult and eight pediatric SCLS patients and available unaffected first-degree relatives.

Setting: Tertiary children's hospitals and referral research laboratory.

Patients: Children and adults with SCLS.

Interventions: None.

Measurements: Patients and available first-degree relatives underwent WES. Data were analyzed for rare homozygous, bi-allelic, de novo and heterozygous variants with allelic enrichment and metabolic pathway analyses.

Main Results: Children with SCLS presented at a younger age with episodes similar to those experienced by adults. All patients and available relatives underwent satisfactory WES. No overlapping gene variants or metabolic pathways were identified across all SCLS patients. Multiple candidate genes with homozygous or bi-allelic mutations were identified in individual subjects with SCLS. There was no significant enrichment of genes with rare heterozygous variants.

Conclusions: The clinical characteristics of children and adults with SCLS are similar. We did not identify a uniform germline exomic genetic etiology for SCLS. WES identified several candidate genes in individual patients for future research. WES is a viable way for critical care providers to investigate the etiology of diseases with presumed genetic contributions.

*Yale University Pediatric Genomic Discovery Program, Department of Pediatrics

Molecular Signal Transduction Section, Laboratory of Allergic Diseases, National Institute of Health, Institute of Allergy and Infectious Disease

Yale University Department of Genetics

Address reprint requests to Richard Pierce, MD, MS, 333 Cedar Street, PO Box 208064, New Haven, CT 06520. E-mail:

Received 22 June, 2018

Revised 16 July, 2018

Accepted 15 August, 2018

Supplemental digital content is available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal's Web site (

This study utilized financial support to the Pediatric Genomic Discovery Program from Yale New Haven Hospital. Funding support was also provided by the Intramural Research Program, NIAID/NIH (Z00001983 to K.M.D.) and NICHD/NIH (T32HD068201 to R.P.).

The authors report no conflicts of interest

© 2019 by the Shock Society