Germline Genetics

Background:

Human herpesvirus (HHV)-8-negative, idiopathic multicentric Castleman disease (iMCD) is a deadly hematologic illness involving progressive flares of systemic inflammation, polyclonal lymphoproliferation, and multiple organ system dysfunction. Approximately 600-1000 individuals of all ages are diagnosed annually in the USA; 35% die within 5 years. Poor outcomes are related to the limited mechanistic understanding of iMCD. The etiology, dysregulated signaling pathway, and cell type in iMCD are completely unknown. Very limited research has been performed into genetic risk factors and/or pathogenic variants. In UCD, somatic mutations in N666S in PDGFRB were found in 10% of patients by Li et a (https://paperpile.com/app/p/8bd7424a-00bc-0089-bef8-67e1c974386f). In iMCD, somatic mutations in L261F in NCOA4 were found in 23% (5 out of 22) of idiopathic multicentric CD (iMCD) cases (https://paperpile.com/app/p/1ba0fad3-7102-080e-845a-8a05f86ed81c). A family with germline FAS mutations in a patient with iMCD and one with UCD has been reported (https://paperpile.com/app/p/348eeea1-d42a-0a27-b8ce-c208a6019107). A review of limited genetic sequencing data inferred that mutations in genes affecting chromatin organization and abnormalities in methylation are seen more commonly in iMCD and abnormalities within the mitogen-activated protein kinase (MAPK) and interleukin signaling pathways are more frequent in UCD. 

To identify genetic risk factors and/or pathogenic variants for iMCD, we have assembled a pilot cohort of 26 iMCD patients. We are planning to perform whole exome sequencing (WES) on an additional 125-150 iMCD patients by the end of 2022. Whole exome sequencing was performed (as well as SNP chip with <300,000 SNPs) on the pilot cohort and sequencing reads were mapped to GRCh38 reference. Variant calling was performed utilizing GATK and multiple screening criteria were used including filtering for exon variants with a frequency of <1% in public available databases (Exome aggregation consortium, ExAC and genome aggregation database, gnomAD), and predicted to be damaging by deleterious prediction software platforms (SIFT, MutationAssesor, etc.).

Research Questions:

  1. Are there patients with homozygous or compound heterozygous mutations in CABIN1 in the pilot dataset? 

  2. Are there variants in genes involved in CABIN1-related pathways?

  3. Are there mutations/variants in other genes that have been previously associated with CD?

  4. Are there patients with monogenic, clearly pathogenic mutations in the pilot dataset?