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The Contribution of Whole Gene Deletions and Large Rearrangements to the Mutation Spectrum in Inherited Tumor Predisposing Syndromes
- Source :
- Human Mutation. 37:250-256
- Publication Year :
- 2016
- Publisher :
- Hindawi Limited, 2016.
-
Abstract
- Heterozygous whole gene deletions (WGDs), and intragenic microdeletions, account for a significant proportion of mutations underlying cancer predisposition syndromes. We analyzed the frequency and genotype-phenotype correlations of microdeletions in 12 genes (BRCA1, BRCA2, TP53, MSH2, MLH1, MSH6, PMS2, NF1, NF2, APC, PTCH1, and VHL) representing seven tumor predisposition syndromes in 5,897 individuals (2,611 families) from our center. Overall, microdeletions accounted for 14% of identified mutations. As expected, smaller deletions or duplications were more common (12%) than WGDs (2.2%). Where a WGD was identified in the germline in NF2, the mechanism of somatic second hit was not deletion, as previously described for NF1. For neurofibromatosis type 1 and 2, we compared the mechanism of germline deletion. Unlike NF1, where three specific deletion sizes account for most germline WGDs, NF2 deletion breakpoints were different across seven samples tested. One of these deletions was 3.93 Mb and conferred a severe phenotype, thus refining the region for a potential NF2 modifier gene to a 2.04-Mb region on chromosome 22. The milder phenotype of NF2 WGDs may be due to the apparent absence of chromosome 22 loss as the second hit. These observations of WGD phenotypes will be helpful for interpreting incidental findings from microarray analysis and next-generation sequencing.
- Subjects :
- 0301 basic medicine
Genetics
congenital, hereditary, and neonatal diseases and abnormalities
Mutation
Biology
BRCA2 Protein
MLH1
medicine.disease_cause
Germline
03 medical and health sciences
030104 developmental biology
0302 clinical medicine
Germline mutation
MSH2
030220 oncology & carcinogenesis
Genotype
medicine
Chromosome 22
Genetics (clinical)
Subjects
Details
- ISSN :
- 10597794
- Volume :
- 37
- Database :
- OpenAIRE
- Journal :
- Human Mutation
- Accession number :
- edsair.doi...........32089126f0bd94d74e8d049fca6c501a