Genetics of ataxia telangiectasia in a highly consanguineous population

Abstract

Ataxia telangiectasia (AT) is a rare autosomal recessive multisystemic disorder. It usually presents in toddler years with progressive ataxia and oculomotor apraxia, or less commonly, in the late-first or early-second decade of life with mixed movement disorders. Biallelic mutations in ataxia telangiectasia mutated gene (ATM) cause AT phenotype, a disease not well documented in Saudi Arabia, a highly consanguineous society. We studied several Saudi AT patients, identified ATM variants, and investigated associated clinical features. We included 17 patients from 12 consanguineous families. All patients had comprehensive clinical and radiological assessment, and most were examined through whole-exome sequencing (WES). Selected individuals were analyzed using various genetic approaches. We identified five different ATM variants in our patients: three previously reported mutations, and two novel variants.Nearly all patients had classical AT presentation except for two patients with a milder phenotype. Among the three known variants, a deletion causing truncation (c.381delA resulting in p.(Val128Ter)) was identified in 13 patients. Two patients harboured the other two truncating variants, (c.9001_9002delAG resulting in p.Ser3001Phefs*6) and (c.9066delA resulting in p.Glu3023Alafs*10) and two patients had novel compound heterozygous variants (NM_000051.3:Paternal

A Novel GEMIN4 Variant in a Consanguineous Family Leads to Neurodevelopmental Impairment with Severe Microcephaly, Spastic Quadriplegia, Epilepsy, and Cataracts

“…We performed WES to identify plausible disease-causing variant(s). Our analysis, coupled with previously published variant filtering processes [ 30 , 31 , 32 , 33 , 34 ], yielded a novel homozygous missense variant in exon 2 of GEMIN4 (NM_015721: c.440A>G:p.His147Arg) as the only candidate underlying the disease. Then we used Sanger sequencing for the segregation analysis and confirmation of the variant in the family.…”

A Novel Homozygous Founder Variant of RTN4IP1 in Two Consanguineous Saudi Families

“…Using this, we calculated the recombination rates to calculate a predicted age for the variant. The calculation was performed using published protocols [1,19,32]. This analysis predicted that the variant could To investigate the potential consequence of the missense variant on protein expression, we performed immunoblotting experiments using the index patient's (F1-II-2) fibroblasts.…”

“…Using this, we calculated the recombination rates to calculate a predicted age for the variant. The calculation was performed using published protocols [1,19,32]. This analysis predicted that the variant could be traced back 56 generations.…”

Clinical, radiological, and genetic characterization of SLC13A5 variants in Saudi families: Genotype phenotype correlation and brief review of the literature

“…After library preparation, captured fragments were run on an Illumina HiSeq 2500 Sequencer and mapped against UCSC hg19 (Illumina, Inc., San Diego, CA, United States). Comprehensive filtering of the detected variants was done as previously published (8)(9)(10)(11). Especially, variants based on homozygosity, coding, and splicing features, being within the autozygome of the affected individuals in the families, were prioritized during filtering analysis.…”

“…Additionally, publicly available databases and local resources, such as the program for Saudi Human Genome-based data outputs, were also screened during filtering. In silico pathogenicity was carried out as reported before (8)(9)(10)(11).…”