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Pediatric Healthcare & Pediatric Infections 2017
September 20-22, 2017 | Toronto, Canada
allied
academies
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10
TH
AMERICAN PEDIATRICS HEALTHCARE &
PEDIATRIC INFECTIOUS DISEASES CONGRESS
Yigal Dror
Hospital for Sick Children, Canada
Genetic basis of inherited bone marrow failure syndromes
I
nherited bone marrow failure syndromes (IBMFSs) are
rare disorders with underproductive bone marrow, varying
degrees of low blood counts, physical malformations and risk
of myelodysplastic syndromes, leukemia and solid tumors.
Over 25 different syndromes have been characterized.
Phenotypic overlap among the IBMFSs frequently limits
the ability to establish a diagnosis based solely on clinical
features. Over 80 IBMFS genes have been identified that
functions in fundamental biochemical pathways such as DNA
repair, ribosome biogenesis, telomere maintenance and cell
survival. The large number of syndromes and associated
genes and phenotypic overlap often renders genetic testing
prolonged and costly. Correct diagnosis, treatment, and
cancer surveillance often depend on identifying the mutated
gene. In this presentation, data about the phenotypic
complexity of the IBMFSs and leukemia risk will be described.
The results of applying new genomic methods to facilitate
diagnosis will be discussed. Lastly, genes that were recently
discovered as associated with IBMFS will also be discussed.
Speaker Biography
Dr. Yigal Dror is the Head of the Haematology Section and Director of the Marrow
Failure and Myelodysplasia Program, senior scientist at the Genetics and Genome
Biology Program at The Hospital for Sick Children, Toronto, and a member of the
Institute of Medical Sciences at the University of Toronto. Dr. Dror graduated
from the Hadassah Medical School of the Hebrew University in Jerusalem, and
completed pediatric residency in Kaplan Hospital, Rehovot, Israel. He completed
clinical fellowship in pediatric hematology/oncology and a post-doctoral
research fellowship in the field of hematopoiesis and marrow failure syndromes/
myelodysplasia at SickKids hospital, Toronto. In 2000 Dr. Dror assumed his current
position as a clinician scientist at SickKids.His main clinical interests are in the area
of bone marrow failure and myelodysplastic syndrome. His research focuses on
characterization of stem cells and blood cells in these conditions, genetic etiologies
and clinical outcome. He heads the Canadian Inherited Marrow Failure Registry.
Dr. Dror’s lab showed that Shwachman-Diamond syndrome (SDS) marrow progenitors
are reduced, overexpress Fas and undergo apoptosis through the FAS pathway. SBDS-
deficiency results in abnormal accumulation of functional FAS at the plasma membrane
level. The slow cell growth of SDS cells is associated with increased levels of reactive
oxygen species, and can be reversed by antioxidants. His lab also studied the landscape
of mutations and affected genes in inherited bone marrow failure syndromes using
samples and data from the Canadian Inherited Marrow Failure Regsitry. The lab
identified PARN as a new IBMFS gene and described defects in ribosomes and telomeres
that unravel previously unknown functions of PARN, and suggest a new disease
mechanism in which PARN-deficiency disrupts the polyadenylated state of H/ACA box
RNA molecules that in turn influences ribosome profile and telomere length. The lab
also identified DNAJC21 as the second gene associated with SDS. His lab showed that
IBMFS are associated with high risk (37%) of clones/MDS/AML in childhood, and found
that SDS marrows are characterized by stromal dysfunction, increased angiogenesis
and abnormal leukemia-gene expression in marrow progenitor cells
e:
yigal.dror@sickkids.ca