Article Dans Une Revue Frontiers in Genetics Année : 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

Linda Maclaren
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Gerald Pfeffer
  • Fonction : Auteur
Justyna R Sarna
  • Fonction : Auteur
Ping Yee Billie Au
  • Fonction : Auteur
Maja Tarailo-Graovac

Résumé

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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hal-04416718 , version 1 (25-01-2024)

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Tatiana Maroilley, Nicola a M Wright, Catherine Diao, Linda Maclaren, Gerald Pfeffer, et al.. 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. Frontiers in Genetics, 2022, 13, ⟨10.3389/fgene.2022.815210⟩. ⟨hal-04416718⟩
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