Genomic Insights into Inherited Bone Marrow Failure

Abstract

Hematopoiesis is a tightly regulated hierarchical differentiation process where hematopoietic stem cells differentiate into lineage-specific progenitors and in time, mature blood cells. Hematopoiesis takes place in the bone marrow. Bone marrow failure occurs when the marrow has either impaired hematopoietic cellularity or problems in differentiation into at least one lineage. Inherited forms of bone marrow failure can present in either syndromic fashion or restricted to complications from defective hematopoiesis. Although many genes have been identified that, when mutated, cause inherited bone marrow failure, the genetic basis of a subset of patients remains unresolved. We hypothesized that these patients harbor previously uncharacterized mutations in genes that would help us better understand why specific mutations are deleterious and help elucidate the importance of these genes in cell function and hematopoiesis. We utilized massively-parallel sequencing to sequence the genomes of patients and informative family members. We then identified candidate mutations likely to explain the cause of bone marrow failure. In this dissertation, we highlight key insights made in four genes: FAM111B, THPO, BRCA1, and GALE. We expanded the phenotype associated with FAM111B to include marrow failure and exocrine pancreatic dysfunction. We identified homozygous loss-of-function mutations in THPO that cause a hematopoietic extrinsic marrow failure but is treatable with a THPO receptor agonist. We provide a mechanism for survival of homozygous nonsense mutations in BRCA1. Finally, we report a homozygous missense mutation in GALE, an important enzyme for glycosylation, as the cause of inherited thrombocytopenia in a large Bedouin family. Our findings highlight the importance of studying the genetic basis of rare hematopoietic diseases to inform clinical management, provide accurate genetic counseling, and better understand molecular pathways and interactions important for hematopoiesis.