Two novel variants in the ATM gene causing ataxia-telangiectasia, including a duplication of 90 kb: Utility of targeted next-generation sequencing in detection of copy number variation
| Autor: | Ivan Bernardo-Gonzalez, Laura Samaniego-Jimenez, Alicia Calvo-Ferrer, Maria Pilar Sanz-Izquierdo, Samuel Martin-Rodriguez, Nerea Ortega-Unanue |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
DNA Copy Number Variations
Genotype Ataxia Telangiectasia Mutated Proteins Biology Compound heterozygosity Polymorphism Single Nucleotide 03 medical and health sciences symbols.namesake Ataxia Telangiectasia Gene Duplication Gene duplication Genetics medicine Humans Genetic Predisposition to Disease Multiplex ligation-dependent probe amplification Copy-number variation Genetics (clinical) Alleles Genetic Association Studies 030304 developmental biology Sanger sequencing 0303 health sciences 030305 genetics & heredity Genetic Variation High-Throughput Nucleotide Sequencing medicine.disease Magnetic Resonance Imaging Nibrin Pedigree Phenotype Child Preschool Ataxia-telangiectasia symbols Female Nijmegen breakage syndrome Biomarkers |
| Zdroj: | Annals of human genetics. 83(4) |
| ISSN: | 1469-1809 |
| Popis: | Ataxia-telangiectasia (A-T) is a rare autosomal recessive neurodegenerative disorder characterized by progressive cerebellar ataxia, ocular apraxia, immunodeficiency, telangiectasia, elevated serum α-fetoprotein concentration, radiosensitivity and cancer predisposition. Classical A-T is caused by biallelic variants on ATM (ataxia telangiectasia mutated) gene, leading to a loss of function of the protein kinase ATM, involved in DNA damage repair. Atypical presentations can be found in A-T-like disease or in Nijmegen breakage syndrome, caused by deficiency of mre11 or nibrin proteins, respectively. In this report, we present the genetic characterization of a 4-year-old female with clinical diagnosis of A-T. Next-generation sequencing (NGS) revealed two novel heterozygous mutations in the ATM gene: a single-nucleotide variant (SNV) at exon 47 (NM_000051.3:c.6899G > C; p.Trp2300Ser) and ∼90 kb genomic duplication spanning exons 17-61, NG_009830.1:g.(41245_49339)_(137044_147250)dup. These findings were validated by Sanger sequencing and MLPA (multiplex ligation-dependent probe amplification) analysis respectively. Familial segregation study confirmed that the two variants are inherited, and the infant is a compound heterozygote. Thus, our study expands the spectrum of ATM pathogenic variants and demonstrates the utility of targeted NGS in the detection of copy number variation. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text