Learning disability and myoclonic epilepsy associated with apparently synonymous but splice‐disrupting JMJD1C variant that led to 21 bp deletion of the transcript

To the Editor, Pathogenic variants in the Jumonji domain-containing protein 1C (JMJD1C) gene, which encodes a histone modifier that confers a histone demethylase activity, have also been suggested to cause intellectual disability (Saez et al., 2016). One patient with a phenotype resembling Rett syndrome had heterozygous Pro163Leu variant which caused abnormal subcellular localization and reduced binding to MECP2, the causative gene for Rett syndrome (Saez et al., 2016). Prior to this report, two patients with truncating variants have been reported, without clinical detail, in large cohort studies on autism spectrum disorder (Iossifov et al., 2014; Neale et al., 2012). Recently, seven patients with heterozygous variants, either with nonsynonymous or frameshift variants, were reported (Slavotinek et al., 2020) through international collaboration by GeneMatcher (Sobreira, Schiettecatte, Valle, & Hamosh, 2015). The clinical features included learning delays, attention deficit hyperactivity disorder, autism spectrum disorder and seizures. Nonetheless, all the seven patients had either mosaic variants or accompanying variants in intellectual disability-associated genes other than JMJD1C, or a variant that was present in a public database. The authors concluded that further reports of patients and functional studies are required for a more definitive implication of JMJD1C (Slavotinek et al., 2020). Here, we report a patient with learning disability and myoclonic epilepsy who had apparently synonymous but splice-disrupting variant that led to 21 bp deletion of the transcript. The patient was a 11-year-old boy who was born at 39 and 5/7 weeks of gestation to non-consanguineous parents with no significant family medical history. His birth weight was 3,295 g (+0.7 SD), his length was 49.0 cm (−0.1 SD), and his head circumference was 32.5 cm (−0.6 SD). The patient began to exhibit a tremor at the age of 4 years. At the age of 6 years, he had special educational needs, because he had a difficulty in reading and writing. His full-scale intelligence quotient on Wechsler Intelligence Scale for Children (WISC)-IV score was 87, which was within normal range. He was diagnosed as having learning disorder. At the age of 10 years, he began to have epileptic seizures and myoclonus at rest. His weight was 37.3 kg (−0.60 SD) and his height was 142.2 cm (−0.21 SD) at the age of 11 years. There were no dysmorphic features. Approval from the local institutional review board was obtained for the molecular studies. After written informed consent was obtained from the patient and his parents, peripheral blood samples were collected from the patient. An exome analysis was performed as previously reported (Takenouchi et al., 2015). Genomic DNA was extracted from peripheral blood samples from both the patient and his parents. Whole exome analyses of the samples from the patient and his parents were performed using the NovaSeq platform (Illumina, San Diego, California) and SureSeletctXT Human All Exon V6 (Agilent Technologies, Santa Clara, California). Mapping of the sequence reads to the human reference genome (GRCh37) was performed according to the best-practice guidelines for Burrows-Wheeler Aligner (BWA) (Li & Durbin, 2009) and the Genome Analysis Tool Kit (GATK) (McKenna et al., 2010), as packaged in the integrated analysis suite variant tools (San Lucas, Wang, Scheet, & Peng, 2012). The called variants were annotated with SnpEff (Cingolani et al., 2012). RNA-seq Received: 23 July 2020 Revised: 26 August 2020 Accepted: 14 September 2020