Genetic variation and complex disease: the examination of an X-linked disorder and a multifactorial disease

 
 
 
 

Genetic variation and complex disease: the examination of an X-linked disorder and a multifactorial disease

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Title: Genetic variation and complex disease: the examination of an X-linked disorder and a multifactorial disease
Author: Cottrell, Catherine E
Description: Improved treatment strategies in pediatric Hodgkin Lymphoma (HL) have resulted in a cure rate approaching 95%, yet the development of a second primary malignant neoplasm (SMN) is a risk for survivors. Oxidative stress has been linked to the development of cancer due to the damaging effects of reactive species on DNA, lipids, and proteins. The aim of this study was to assess the associations of antioxidant gene alleles and the risk of developing a SMN in HL patients. Polymorphisms were chosen from antioxidant-related genes including; SOD GPX, CAT, and NOS. Statistical analysis was completed using tests of association, haplotype, and multiple regression modeling. Out of the 36 SNPs that were included in the final analysis, 4 SNPs in the GPX1, GPX3, GPX4, and SOD2 genes, were potentially suggestive (p<0.05) of an association between genotype and the development of a SMN. Replication studies are necessary, though it is notable that polymorphisms within the GPX family may be associated with the development SMN in our cohort. X-chromosome inactivation (XCI) is an epigenetic process used to regulate gene dosage in mammalian females by silencing one X-chromosome. While the pattern of XCI is typically random in normal females, abnormalities of the X-chromosome may result in skewing due to disadvantaged cell growth. We describe a female patient with an X;1 translocation [46,X, t(X;1)(q28;q21)dn] and unusual pattern of XCI who was clinically diagnosed with Otopalatodigital syndrome (OPD) type 1. There was complete skewing of XCI in the patient, along with the atypical findings of an active normal X-chromosome and an inactive derivative X. OPD1 is characterized by skeletal abnormalities, craniofacial defects, and hearing loss. Mutations within the FLNA gene (Xq28) are known to cause OPD, though none were detected in our patient. Characterization of the translocation revealed that the patient’s Xq28 breakpoint interrupts the DKC1 gene, located 400kB distal to FLNA. Analysis of the breakpoint region revealed functional disomy of Xq28 genes distal to DKC1. Possible explanations for the patient’s phenotype include a position effect due to the translocation breakpoint, an undetected FLNA-related mutation, or altered gene dosage due to consequences of atypical XCI.
Permanent Link: http://rave.ohiolink.edu/etdc/view?acc_num=osu1196182829
http://hdl.handle.net/2374.OX/6225
Date: 2007

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