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Neurogenetics
Short report
Double gonosomal mosaicism as an unusual hereditary mechanism in familial GRIN2A-related disorder
  1. Valentina Cetica1,
  2. Mara Cavallin1,
  3. Maria Luisa Ricci1,
  4. Claudia Mandorlini1,
  5. Emanuele Bartolini2,
  6. Elena Parrini1,
  7. Renzo Guerrini1,3
  1. 1 Paediatric Neurology Unit and Laboratories, Neuroscience Department, Member of ERN Epicare and ITHACA, Meyer Children's Hospital IRCCS, Florence, Italy
  2. 2 Department of Developmental Neuroscience, IRCCS Foundation Stella Maris, Pisa, Italy
  3. 3 University of Florence, Florence, Italy
  1. Correspondence to Professor Renzo Guerrini; renzo.guerrini{at}meyer.it

Abstract

We aim to describe double gonosomal mosaicism in the GRIN2A gene in a mother who passed on two different pathogenic variants at the same nucleotide to her two affected children. We studied a boy with epilepsy and intellectual disability, along with his sister and mother who exhibited language impairment and learning difficulties without epilepsy. We identified in the proband a splice-site variant in GRIN2A (c.1008–1G>A) inherited from his mother. Subsequent testing of his sister revealed a different change at the same nucleotide c.1008–1G>T, which was also present in the mother’s DNA at 3.9% allele frequency. The co-occurrence of two mutational events at the same nucleotide is extremely rare. Since a chance occurrence is unlikely, we hypothesise that a base mismatch may introduce instability triggering a second event. In this family, the mother carries three alleles, of which one is at very low frequency. This complex genetic landscape poses diagnostic challenges since low-level mosaicism may escape detection via conventional methods. Applying specific technology becomes crucial, as double mosaicism might prove to be more prevalent than anticipated severely impacting diagnostic accuracy and genetic counselling.

  • Neurology
  • Genetics
  • Pediatrics

https://doi.org/10.1136/jmg-2024-110101

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    Footnotes

    • Contributors Study concept and design: VC, MC, and RG. Acquisition, analysis, and interpretation of data: VC, MC, MLR, CM, EP and RG, All authors critically reviewed the manuscript and approved the final version for publication. RG is responsible for the overall content and acts as guarantor.

    • Funding This work was supported by the Regione Toscana under the Call for Health 2018 [grant DECODE-EE] (to RG), the Brain Project' by Fondazione Cassa di Risparmio di Firenze (to RG) and the Current Research 2023 Funding of the Italian Ministry of Health (to VC, MC, MLR, CM, EP and RG).

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.