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.
Glossary
- ATLD=
- ataxia-telangiectasia-like disorder;
- ATM=
- ataxia telangiectasia mutated;
- MMC=
- mitomycin C;
- NBS=
- Nijmegen breakage syndrome;
- NBSLD=
- Nijmegen breakage syndrome-like disorder;
- NGS=
- Next-generation sequencing;
- NMD=
- nonsense-mediated mRNA decay;
- NSES=
- neuromuscular sub-exomic sequencing;
- WES=
- whole exome sequencing
Footnotes
Funding information and disclosures are provided at the end of the article. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/NG.
The Article Processing Charge was funded by Swedish Research Council.
- Received May 25, 2018.
- Accepted in final form August 22, 2018.
- Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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