Article Text
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
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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.
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