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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
Author(s) -
MartinRodriguez Samuel,
CalvoFerrer Alicia,
OrtegaUnanue Nerea,
SamaniegoJimenez Laura,
SanzIzquierdo Maria Pilar,
BernardoGonzalez Ivan
Publication year - 2019
Publication title -
annals of human genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.537
H-Index - 77
eISSN - 1469-1809
pISSN - 0003-4800
DOI - 10.1111/ahg.12312
Subject(s) - ataxia telangiectasia , multiplex ligation dependent probe amplification , nijmegen breakage syndrome , sanger sequencing , genetics , biology , gene duplication , copy number variation , exon , compound heterozygosity , gene , microbiology and biotechnology , mutation , dna damage , dna , genome
Abstract 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.