Detection of Copy Number Variation by SNP-Allelotyping

Abstract

Charcot-Marie-Tooth disease type 1A (CMT1A) is caused by an abnormal copy number variation (CNV) with a trisomy of chromosome 17p12. The increase of the DNA-segment copy number is expected to alter the allele frequency of single nucleotide polymorphism (SNP) within the duplicated region. We tested whether SNP allele frequency determined by a Sequenom MassArray can be used to detect the CMT1A mutation. Our results revealed distinct patterns of SNP allele frequency distribution, which reliably differentiated CMT1A patients from controls. This finding suggests that this technique may serve as an alternative approach to identifying CNV in certain diseases, including CMT1A.

Prevalence of chromosomal abnormalities identified by copy number variation sequencing in high-risk pregnancies, spontaneous abortions, and suspected genetic disorders

“…Recently, the development of high-throughput sequencing techniques has extended the detection of chromosomal CNV to karyotype analysis, fluorescence in situ hybridization (FISH), chromosomal microarray analysis (CMA) such as array comparative genomic hybridization (a-CGH) and single nucleotide polymorphism (SNP) array, as well as high-throughput-based CNV-sequencing (seq). 5 – 8 Although karyotype analysis is not effective at analyzing small CNV with clinical importance because of its complex procedures and low resolution of 5 Mb, 9 it remains the golden standard for identifying chromosomal abnormality. In contrast, FISH is simpler and more rapid, but the information that can be obtained is limited by probe coverage.…”

Ronin overexpression induces cerebellar degeneration in a mouse model of ataxia

“…CNVs) or non-coding mutations that affect Ronin levels might explain SCA4 disease and possibly other 16q22.1-linked ataxias. Such a scenario would add to the list of genomic rearrangement-related disorders, such as Charcot-Marie-Tooth disease ( Parker et al, 2015 ), which is characterized by CNVs, SCA2, where the increased gene dosage in patients homozygous for the disease-related genetic defect influences the age of disease onset ( Spadafora et al, 2007 ), autosomal dominant early-onset Alzheimer's disease caused by a duplication of the amyloid precursor protein locus ( Rovelet-Lecrux et al, 2006 ; Rumble et al, 1989 ), and familial Parkinson's disease associated with duplications or triplications of α-synuclein (SNCA) ( Chartier-Harlin et al, 2004 ; Ibáñez et al, 2004 ; Singleton et al, 2003 ). Alternatively, simple mutations in the regulatory elements of Ronin (e.g.…”

SCA4 locus-associated gene Ronin (Thap11) increases Ataxin-1 protein levels and induces cerebellar degeneration in a mouse model of ataxia

“…In this case, we predict that genomic rearrangements (e.g., CNVs) might explain SCA4 disease and possibly other 16q22.1-linked ataxias. Such a scenario would add to the list of genomic rearrangement-related disorders, such as Charcot-Marie-Tooth disease (Parker et al, 2015), which is characterized by CNVs, SCA2, where the increased gene dosage in patients homozygous for the disease-related genetic defect influences the age of disease onset (Spadafora et al, 2007), autosomal dominant early-onset AD caused by a duplication of the amyloid precursor protein (APP) locus (Rovelet-Lecrux et al, 2006;Rumble et al, 1989), and familial Parkinson's disease associated with duplications or triplications of α-synuclein (SNCA) (Chartier-Harlin et al, 2004;Ibanez et al, 2004;Singleton et al, 2003). Alternatively, simple mutations in Ronin's regulatory elements (e.g., in one of its enhancers or the promoter) could cause chronic or context-specific misexpression to contribute to the disease.…”