Case Report: Biallelic Loss of Function ATM due to Pathogenic Synonymous and Novel Deep Intronic Variant c.1803-270T > G Identified by Genome Sequencing in a Child With Ataxia-Telangiectasia.

Autor:	Maroilley T; Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.; Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada., Wright NAM; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada.; Section of Pediatric Hematology-Immunology, Department of Pediatrics, Alberta Children's Hospital, University of Calgary, Calgary, AB, Canada., Diao C; Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.; Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada., MacLaren L; Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada., Pfeffer G; Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.; Department of Clinical Neurosciences and Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada., Sarna JR; Department of Clinical Neurosciences and Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada., Billie Au PY; Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada., Tarailo-Graovac M; Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.; Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada.
Jazyk:	angličtina
Zdroj:	Frontiers in genetics [Front Genet] 2022 Jan 25; Vol. 13, pp. 815210. Date of Electronic Publication: 2022 Jan 25 (Print Publication: 2022).
DOI:	10.3389/fgene.2022.815210
Abstrakt:	Ataxia-telangiectasia (AT) is a complex neurodegenerative disease with an increased risk for bone marrow failure and malignancy. AT is caused by biallelic loss of function variants in ATM , which encodes a phosphatidylinositol 3-kinase that responds to DNA damage. Herein, we report a child with progressive ataxia, chorea, and genome instability, highly suggestive of AT. The clinical ataxia gene panel identified a maternal heterozygous synonymous variant (NM_000051.3: c.2250G > A), previously described to result in exon 14 skipping. Subsequently, trio genome sequencing led to the identification of a novel deep intronic variant [NG_009830.1(NM_000051.3): c.1803-270T > G] inherited from the father. Transcript analyses revealed that c.1803-270T > G results in aberrant inclusion of 56 base pairs of intron 11. In silico tests predicted a premature stop codon as a consequence, suggesting non-functional ATM; and DNA repair analyses confirmed functional loss of ATM. Our findings highlight the power of genome sequencing, considering deep intronic variants in undiagnosed rare disease patients. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2022 Maroilley, Wright, Diao, MacLaren, Pfeffer, Sarna, Billie Au and Tarailo-Graovac.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu