Cetica Valentina, Cavallin Mara, Ricci Maria Luisa, Mandorlini Claudia, Bartolini Emanuele, Parrini Elena, Guerrini Renzo
Paediatric Neurology Unit and Laboratories, Neuroscience Department, Member of ERN Epicare and ITHACA, Meyer Children's Hospital IRCCS, Florence, Italy.
Department of Developmental Neuroscience, IRCCS Foundation Stella Maris, Pisa, Italy.
J Med Genet. 2024 Sep 24;61(10):999-1002. doi: 10.1136/jmg-2024-110101.
We aim to describe double gonosomal mosaicism in the 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 (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.
