Case Reports
 
2022 Jan 25;13:815210.
 doi: 10.3389/fgene.2022.815210. eCollection 2022.

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

Affiliations 

Affiliations

  • 1Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
  • 2Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
  • 3Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada.
  • 4Section of Pediatric Hematology-Immunology, Department of Pediatrics, Alberta Children's Hospital, University of Calgary, Calgary, AB, Canada.
  • 5Department of Clinical Neurosciences and Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada.
    • PMID: 35145552
    Free PMC article

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.