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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

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 progr...

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Autores principales: Maroilley, Tatiana, Wright, Nicola A. M., Diao, Catherine, MacLaren, Linda, Pfeffer, Gerald, Sarna, Justyna R., Billie Au, Ping Yee, Tarailo-Graovac, Maja
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8822238/
https://www.ncbi.nlm.nih.gov/pubmed/35145552
http://dx.doi.org/10.3389/fgene.2022.815210
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author Maroilley, Tatiana
Wright, Nicola A. M.
Diao, Catherine
MacLaren, Linda
Pfeffer, Gerald
Sarna, Justyna R.
Billie Au, Ping Yee
Tarailo-Graovac, Maja
author_facet Maroilley, Tatiana
Wright, Nicola A. M.
Diao, Catherine
MacLaren, Linda
Pfeffer, Gerald
Sarna, Justyna R.
Billie Au, Ping Yee
Tarailo-Graovac, Maja
author_sort Maroilley, Tatiana
collection PubMed
description 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.
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spelling pubmed-88222382022-02-09 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 Maroilley, Tatiana Wright, Nicola A. M. Diao, Catherine MacLaren, Linda Pfeffer, Gerald Sarna, Justyna R. Billie Au, Ping Yee Tarailo-Graovac, Maja Front Genet Genetics 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. Frontiers Media S.A. 2022-01-25 /pmc/articles/PMC8822238/ /pubmed/35145552 http://dx.doi.org/10.3389/fgene.2022.815210 Text en Copyright © 2022 Maroilley, Wright, Diao, MacLaren, Pfeffer, Sarna, Billie Au and Tarailo-Graovac. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Genetics
Maroilley, Tatiana
Wright, Nicola A. M.
Diao, Catherine
MacLaren, Linda
Pfeffer, Gerald
Sarna, Justyna R.
Billie Au, Ping Yee
Tarailo-Graovac, Maja
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
title 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_short 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
title_sort 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
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8822238/
https://www.ncbi.nlm.nih.gov/pubmed/35145552
http://dx.doi.org/10.3389/fgene.2022.815210
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