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

Tatiana Maroilley; Nicola A M Wright; Catherine Diao; Linda MacLaren; Gerald Pfeffer; Justyna R Sarna; Ping Yee Billie Au; Maja Tarailo-Graovac

doi:10.3389/fgene.2022.815210

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

Front Genet. 2022 Jan 25:13:815210. doi: 10.3389/fgene.2022.815210. eCollection 2022.

Authors

Tatiana Maroilley^{1

2

3}, Nicola A M Wright^{3

4}, Catherine Diao^{1

2

3}, Linda MacLaren^{2

3}, Gerald Pfeffer^{2

5}, Justyna R Sarna⁵, Ping Yee Billie Au^{2

3}, Maja Tarailo-Graovac^{1

2

3}

Affiliations

¹ Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
² Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
³ Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada.
⁴ Section of Pediatric Hematology-Immunology, Department of Pediatrics, Alberta Children's Hospital, University of Calgary, Calgary, AB, Canada.
⁵ Department of Clinical Neurosciences and Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada.

Abstract

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.

Keywords: ATM; case report; deep intronic variant; missing heritability; splicing; synonymous variant; whole-genome sequencing.

Publication types

Case Reports