Case series of four psychiatric patients with copy number variations in the neurexin 1 gene

NRXN1 encodes a presynaptic cell adhesion protein, neurexin 1, and plays an important role in the formation of synapses release neurotransmitters.1, 2 Rare copy number variations (CNVs) have been shown to be associated with schizophrenia (SCZ), autism spectrum disorder (ASD), bipolar (BD).1-4 Here, we report first case series four Japanese patients CNVs. These CNVs were identified using array comparative genomic hybridization our previous studies5, 6 (see details Supporting Information). This study was approved by ethics committee Nagoya University. Written informed consent obtained from participants. Figure 1A summarizes clinical data Patient 1 69-year-old female treatment-resistant SCZ (TRS). Her developmental milestones unremarkable. She graduated junior high school average grade moved one job another. At 28 years age, she developed bizarre delusions auditory hallucinations. treated antipsychotics, but experienced repeated relapses. Over time, her cognitive function deteriorated, lost ability live independently, eventually required long-term hospitalization. 69 hallucinations persisted despite treatment doses antipsychotics (olanzapine 10 mg/day, aripiprazole 24 risperidone 12 mg/day). 46-year-old TRS. had family history intellectual disability mother. father died when 13 old placed foster care. After graduating school, worked diligently as cashier at store. 26 disorganized speech Thereafter, multiple relapses hospitalizations. psychotic symptoms became refractory antipsychotics. time this study, not controlled olanzapine mg/day. 3 14-year-old girl ASD mild disability. As preschooler, could participate group activities tended play alone. only interested very selected things hypersensitive sounds smells. Around obsessive thoughts harming others persecution observation, accompanied mood swings. Sertraline, aripiprazole, valproate prescribed for these symptoms. IQ age years. 4 30-year-old male BD-II. He born 36 gestational weeks low birth weight (2250 g). In elementary he exhibited ASD- attention-deficit/hyperactivity (ADHD)-like symptoms: unable understand social situations, interpreted language literally, touch. forgetful frequently things. 23 suffered depressive moods insomnia psychiatric clinic. 29 hypomanic symptoms, including elevated mood, talkativeness, spending sprees, which improved lithium. again depressed hospitalized. stable lithium 400 His 87. 1B shows patients. Patients 1–3 exonic deletions disrupting NRXN1. intragenic duplication, likely disrupts transcript reading frame The inheritance pattern unknown because DNA parents available any None other pathogenic inter-individual variability manifestations has highlighted CNVs.1-4 On hand, less attention paid intra-individual their manifestations. present also presentations. teens. BD-II ADHD-like his childhood. addition, two deletion Although there are few reports TRS CNVs, reported TRS.5 Taken together, may more complex severe Further will needed establish significance limitations are: (1) retrospective evaluation phenotypes (2) lack objective assessment standardized instruments. Longitudinal, prospective studies quantitative assessments further elucidate natural Itaru Kushima designed performed experiments, analyzed data, wrote draft manuscript. authors commented on refined Toshiya Inada, Kazutaka Ohi, Jun Egawa, Norio Ozaki recruited participants and/or collected samples or phenotype data. All carefully read manuscript final version submission. We thank participating study. Mami Yoshida, Kiyori Monta, Yukari Mitsui technical assistance. research supported grants Ministry Education, Culture, Sports, Science Technology Japan (MEXT) Health, Labour Welfare Japan; Agency Medical Research Development (AMED) under Grant Nos. JP20dm0107087, JP21wm0425007, JP21dm0207075, JP21ak0101113, JP21dk0307075, JP20dk0307081, JP21dk0307103, JP21ek0109488, JP21km0405216, JP21ek0109411; Society Promotion (JSPS) KAKENHI 17H05090, 18H04040, 21K07543, 21H00194, 21H04815, 18K07590, 15K19720; SENSHIN Foundation. I. K., T. I., K. O., J. E. declare no conflict interest. N. O. received support speakers' honoraria from, served consultant to, Sumitomo Dainippon, Eisai, Otsuka, Kaiteki, Mitsubishi Tanabe, Shionogi, Eli Lilly, Mochida, Daiichi Sankyo, Nihon Medi-Physics, Takeda, Meiji Seika Pharma, EA Pfizer, MSD, Lundbeck Japan, Tsumura, Novartis, Boehringer Ingelheim, Viatris, Kyowa, Janssen, Yoshitomi Yakuhin, Kyowa Kirin, Ono, Astellas, UCB, Taisho Toyama, Review, Woolsey, outside submitted work. all N/A that findings corresponding author upon reasonable request. Please note: publisher is responsible content functionality supporting information supplied authors. Any queries (other than missing content) should directed article.