%0 Case Reports
%T 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.
%A Maroilley T
%A Wright NAM
%A Diao C
%A MacLaren L
%A Pfeffer G
%A Sarna JR
%A Billie Au PY
%A Tarailo-Graovac M
%A Maroilley T
%A Wright NAM
%A Diao C
%A MacLaren L
%A Pfeffer G
%A Sarna JR
%A Billie Au PY
%A Tarailo-Graovac M
%A Maroilley T
%A Wright NAM
%A Diao C
%A MacLaren L
%A Pfeffer G
%A Sarna JR
%A Billie Au PY
%A Tarailo-Graovac M
%J Front Genet
%V 13
%N 0
%D 2022
%M 35145552
%F 4.772
%R 10.3389/fgene.2022.815210
%X 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.