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Ataxia-Telangiectasia-Like Disorder in a Family Deficient for Mre11a, Caused by a Mre11 Variant Publisher



Sedghi M1, 2 ; Salari M1 ; Moslemi AR3 ; Kariminejad A4 ; Davis M5 ; Goullee H6 ; Olsson B7 ; Laing N6 ; Tajsharghi H6, 8
Authors
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Authors Affiliations
  1. 1. Medical Genetics Laboratory, Alzahra University Hospital, Isfahan University of Medical Sciences, Isfahan, Iran
  2. 2. Department of Neurology, Shahid Beheshti University of Medical Science, Tehran, Iran
  3. 3. Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, Sweden
  4. 4. Kariminejad-Najmabadi Pathology and Genetics Center, Tehran, Iran
  5. 5. Department of Diagnostic Genomics, Pathwest, QEII Medical Centre, Iran
  6. 6. Centre for Medical Research, University of Western Australia, Harry Perkins Institute for Medical Research, Nedlands, Australia
  7. 7. School of Bioscience, University of Skovde, Sweden
  8. 8. Division Biomedicine, School of Health and Education, University of Skovde, Sweden

Source: Neurology: Genetics Published:2018


Abstract

Objective We report 3 siblings with the characteristic features of ataxia-telangiectasia-like disorder associated with a homozygous MRE11 synonymous variant causing nonsense-mediated mRNA decay (NMD) and MRE11A deficiency. Methods Clinical assessments, next-generation sequencing, transcript and immunohistochemistry analyses were performed. Results The patients presented with poor balance, developmental delay during the first year of age, and suffered from intellectual disability from early childhood. They showed oculomotor apraxia, slurred and explosive speech, limb and gait ataxia, exaggerated deep tendon reflex, dystonic posture, and mirror movement in their hands. They developed mild cognitive abilities. Brain MRI in the index case revealed cerebellar atrophy. Next-generation sequencing revealed a homozygous synonymous variant in MRE11 (c.657C>T, p.Asn219=) that we show affects splicing. A complete absence of MRE11 transcripts in the index case suggested NMD and immunohistochemistry confirmed the absence of a stable protein. Conclusions Despite the critical role of MRE11A in double-strand break repair and its contribution to the Mre11/Rad50/Nbs1 complex, the absence of MRE11A is compatible with life. © 2018 The Author(s).
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