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Analysis of genetic mutations contributing to congenital heart defects in an ENU induced mouse model

Smith, Laura (2014) Analysis of genetic mutations contributing to congenital heart defects in an ENU induced mouse model. Master's Thesis, University of Pittsburgh. (Unpublished)

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Congenital heart defects (CHD) are the most common birth malformation affecting about 8 infants per 1,000 live births and is responsible for the majority of prenatal deaths. Currently, the fundamental cause of most CHD cases remains unknown. Congenital heart defects pose a serious public health concern due to the high incidence and mortality among the population. By improving the understanding of causation of CHD, we may better understand the pathological basis of the disease and find disease risk for patients and their families.
We conducted a forward genetic screen using ENU-induced mice in order to find the majority of disease-causing genes for congenital heart defects. We were able to recover a total of 88 mutations within 62 disease-causing genes that contribute to both cardiac and non-cardiac mutant phenotypes from 146 mouse lines. Of these variants, 59 were missense, 16 were splicing, and 13 were nonsense.
There are 21 mutations from our screen that were found to be in the same domain as published human mutations. The mutations are similar in the sense that they occur in the same protein domain, but not necessarily the same exon. These mutations also present similar phenotypes in both mice and humans. Three of these mutations are incredibly similar to published human mutations due to the fact that they are within one or two amino acids or nucleotides from each other.
All in all, we can conclude that the 88 disease-causing mutations recovered from our genetic screen are mostly damaging. Three-fourths (75%) of the mutations were completely damaging. About 17% were possibly damaging, 2% were possibly tolerated, and 1% was tolerated. The remaining 5% are splicing mutations that were more than two base pairs from the exon and therefore did not have a definitive conservation call. Overall, there is only one mutation in our screen that is tolerated. This information proves that mutations which are disease causing occur in highly conserved locations. Mutations from our screen, especially those that are similar to published human mutations, are important in determining the genotype-phenotype relationship in congenital heart defects.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorLo, Ceciliacel36@pitt.eduCEL36
Committee ChairKamboh, M Ilyaskamboh@pitt.eduKAMBOH
Committee MemberKammerer, Candacecmk3@pitt.eduCMK3
Date: 29 January 2014
Date Type: Publication
Defense Date: 5 December 2013
Approval Date: 29 January 2014
Submission Date: 3 December 2013
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 99
Institution: University of Pittsburgh
Schools and Programs: School of Public Health > Human Genetics
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: master's thesis
Date Deposited: 29 Jan 2014 17:16
Last Modified: 15 Nov 2016 14:16


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