Identifying Novel Genomic Variants in Hemophagocytic Lymphohistiocytosis in Adults
CitationCeremsak, John. 2021. Identifying Novel Genomic Variants in Hemophagocytic Lymphohistiocytosis in Adults. Doctoral dissertation, Harvard Medical School.
AbstractHemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening disorder of immune system overactivation that occurs in familial (primary) and acquired (secondary) forms. While primary HLH is caused by inherited mutations in genes that regulate cellular immunity, secondary HLH usually occurs in the setting of infection, malignancy, or autoimmune disease and may be diagnosed at any age, including well into adulthood. Although these two forms of HLH have historically been regarded as distinct entities, evidence suggests that a subset of adults with HLH may in fact harbor an underlying genetic predisposition. In this study, a cohort of 88 adult patients with HLH were interrogated for germline genetic variants associated with primary HLH as well as somatic variants associated with clonal hematopoiesis (CH). Among the 17 germline genes sequenced, 7 variants in 18 patients were considered to be disruptive based on in silico model predictions. Among the 80 patients for whom somatic variant analysis was performed, CH with a variant allele frequency (VAF) greater than 0.02 was identified in 21 patients. The rate of disruptive germline variants and somatic variants associated with CH were found to be enriched relative to control populations. Overall, the results suggest that germline variants likely do not drive HLH in adults and that CH is more common in adults with HLH, although whether this represents a causal relationship remains unclear.
Citable link to this pagehttps://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37367725