A novel partial de novo duplication of JARID2 gene causing a neurodevelopmental phenotype

Abstract Deletions covering the entire or partial JARID2 gene as well as pathogenic single nucleotide variants leading to haploinsufficiency of JARID2 have recently been shown to cause a clinically distinct neurodevelopmental syndrome phenotype. Here, we present a previously undescribed partial de novo duplication of the JARID2 gene in a patient displaying a phenotype associated with known JARID2 loss-of-function variant carriers. The phenotype of the index patient included coordination problems, clumsiness, language delay, unclear speech, problems with behavior and attention as well as difficulties with social contacts and daily activities. The patient has markedly dark infraorbital circles and slightly prominent supraorbital ridges. The phenotype shares a notable resemblance to previously characterized JARID2 deletion patients. Genetic analyses from the samples of the index patient and the parents were performed. Whole-genome sequencing and array comparative genomic hybridization revealed a novel disease-causing variant type, a partial tandem duplication of JARID2, covering the exons 1-7. Furthermore, RNA sequencing validated increased expression of these exons. Expression alterations were also detected in the target genes of PRC2 complex, in which JARID2 acts as an essential member. Our data adds to the variety of different pathogenic variants causing the JARID2 specific neurodevelopmental syndrome phenotype.