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

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.

Single variant, yet “double trouble”: TSC and KBG syndrome because of a large de novo inversion

“…In our C OMB G ENE research study—approved by the Conjoint Health Research Ethics Board at the University of Calgary (REB19-0245)—where we also include patients with well-defined clinical diagnoses, yet no genetic variants in known genes ( Maroilley et al, 2022 ), we enrolled a female patient with a clear clinical diagnosis of TSC presenting with subependymal nodules and cortical tubers, refractory epilepsy and infantile spasms, bilateral astrocytic retinal hamartomas, multiple cardiac rhabdomyomas, bilateral renal angiomyolipmas, hypomelanotic macules, angiofibromas, and moderate to severe intellectual disability (non-verbal). She had additional clinical features not typical for TSC; specifically, hypotonia, short stature (third centile), and dysmorphic features.…”

“…To further seek for the genetic origin of the condition, genome sequencing of the proband’s blood-derived DNA was performed using the Illumina TruSeq PCR-free DNA library and the Illumina NovaSeq 6000. Singleton srWGS was analysed as in Maroilley et al (2022 , 2023a) and as described in Methods. As no rare SNVs or indels were detected affecting the TSC1 or TSC2 , we expanded the gene-centric analyses to include more complex variants ( Maroilley et al, 2021 ; 2023a ; 2023b ).…”

“…The first stage of data analyses for patients with well-defined clinical features is gene-centric ( Maroilley et al, 2022 ), guided by a hypothesis and focused on a single locus ( Shu et al, 2023 ). After quality check with FAST-QC ( Andrews, 2010 ) and trimming with Trimmomatic v0.35 ( Bolger et al, 2014 ), reads were aligned along the human reference genome GRCh37 with BWA-MEM v0.7.15 ( Li, 2013 Preprint ), sorted by coordinates using Samtools v1.3.1 ( Li et al, 2009 ) and marked for duplicates using MarkDuplicates Picard tool ( Picard Tools - By Broad Institute, 2023 ).…”

“…It is not rare for patients to receive a clinical diagnosis of a well-defined syndrome—so far known to be caused only by variants in one or couple of genes—yet no or partial genetic diagnosis after multiple genetic tests failing to identify a pathogenic variant, or in case of recessive disease, finding only one variant. With improved analytical methods on sequencing datasets, it has been shown that genome sequencing may help to resolve genetic mechanisms in such cases ( Wahlster et al, 2021 ; Maroilley et al, 2022 ).…”

A novel FAME1 repeat configuration in a European family identified using a combined genomics approach

“…The average depth of coverage achieved was 36 for individual II‐2 and 41 for II‐3. The data were analyzed to detect potentially causative single nucleotide variants (SNVs; as in Maroilley et al, 2022 11 ) and structural variants (SVs; based on a semi‐automated pipeline first developed using model organism genomes, and later adapted to human genomes 12 ). The ancestry of both individuals was assessed using the R package EthSeq 13 .…”