Mystery Patients: Using genomic tools to help diagnose and treat rare disease Stuart Turvey MBBS DPhil FRCPC Director of Clinical Research, CFRI Aubrey J. Tingle Professor of Pediatric Immunology Professor, Department of Pediatrics, UBC

15yo female child with a unique disease Defining clinical features include: –severe eczema –recurrent pneumonia with lung damage –inflammatory bowel disease –severe gum disease –failure to thrive –multiple fractures after minor trauma The Patient

Family Tree

Growth Failure

Pathological Fractures

Extensive GI Inflammation

Profound Lymphocytic Infiltration Patient

Diagnosis?

Working diagnosis = undefined immunodeficiency Treatment = try to address various symptoms

Current Candidate Approach to Genetic Diagnosis

Our genome

Human genome = 3 billion nucleotides. Only ~1.5% are actually translated into proteins.

Exome sequencing and bioinformatic filtering strategy

Exome Sequencing Results

The Mutation single base pair substitution in the MALT1 gene (NM_006785:c.1739G>C) predicted to convert a tryptophan to serine (NP_ :p.Trp580Ser) in the C terminal domain of the MALT1 protein

MALT1: dual functions as a scaffold protein and caspase-like protease Paracapsase activity cleaving: BCL10, A20, NIK (NF-κB-inducing kinase), CYLD, and RelB Turvey SE, et al. (2014) J Allergy Clin Immunol 134(2):

MALT1 mutation results in very low expression of MALT1 protein

Rare Diseases and the Power of Genomics Rare diseases affect 1-in-12 Canadians Most rare diseases present in childhood –1/3 rd of patients at BC Children’s Hospital have a rare disease New genomic technology is allowing us to diagnose many children Diagnosis empowers ‘precision medicine’