Involvement of Rare Mutations of SCN9A, DPP4, ABCA13, and SYT14 in Schizophrenia and Bipolar Disorder

Abstract

Rare mutations associated with schizophrenia (SZ) and bipolar disorder (BD) usually have high clinical penetrance; however, they are highly heterogeneous and personalized. Identifying rare mutations is instrumental in making the molecular diagnosis, understanding the pathogenesis, and providing genetic counseling for the affected individuals and families. We conducted whole-genome sequencing analysis in two multiplex families with the dominant inheritance of SZ and BD. We detected a G327E mutation of SCN9A and an A654V mutation of DPP4 cosegregating with SZ and BD in one three-generation multiplex family. We also identified three mutations cosegregating with SZ and BD in another two-generation multiplex family, including L711S of SCN9A, M4554I of ABCA13, and P159L of SYT14. These five missense mutations were rare and deleterious. Mutations of SCN9A have initially been reported to cause congenital insensitivity to pain and neuropathic pain syndromes. Further studies showed that rare mutations of SCN9A were associated with seizure and autism spectrum disorders. Our findings suggest that SZ and BD might also be part of the clinical phenotype spectra of SCN9A mutations. Our study also indicates the oligogenic involvement in SZ and BD and supports the multiple-hit model of SZ and BD.

Association of <i>ABCA13</i> Gene Variants with Autism Spectrum Disorder and Other Neuropsychiatric Disorders

“…These symptoms and diagnoses were ADHD, anxiety disorder, ID, delay in speech, and febrile convulsion (Table 1). Our results in the same line with the previous studies showing the association between variants in the ABCA13 gene and different psychiatric disorders such as bipolar disorder, schizophrenia, major depressive disorder, ADHD, and ASD [Yoshida et al, 2016;Chen et al, 2021aChen et al, , 2021bLiu et al, 2021;Nakato et al, 2021]. Martin et al investigated the pathways in the etiopathogenesis of ADHD and ASD using CNV analysis and found a deletion involving the ABCA13 gene in a patient with ASD [Martin et al, 2014].…”

“…There are large scale sequencing studies as well as genome-wide association studies of schizophrenia, bipolar disorder, and ASD-detecting effects of the ABCA13 gene interacting partners on NDDs [Satterstrom et al, 2020]. These accumulating data support the involvement of the ABCA13 gene and interacting partner genes in etiopathogenesis of the NDDs [Chen et al, 2021a[Chen et al, , 2021bLiu et al, 2023]. The aim of this study was to elucidate the role of ABCA13 gene single-nucleotide variants (SNVs) in the etiopathogenesis of autism by investigating the impact of ABCA13 gene variants under psychiatric conditions.…”

Two Genetic Mechanisms in Two Siblings with Intellectual Disability, Autism Spectrum Disorder, and Psychosis

“…Nevertheless, a large part of neuropsychiatric patients’ genetic landscape is still missing. Several studies have indicated that oligemic involvement is part of the genetic landscape of neurodevelopmental disorders [ 32 , 88 , 89 , 90 , 91 ]. Notably, in a recent study, John and colleagues reported the detection of five rare heterozygous variants in a schizophrenia multiplex family.…”

“…Some studies suggested using NGS as a first-tier genetic test for neurodevelopmental disorders [ 29 , 30 ]. Our group also identified several rare genetic mutations associated with ID and psychiatric conditions using NGS [ 31 , 32 , 33 ]. Our studies support that NGS helps establish a personalized molecular diagnosis for neurodevelopmental and psychiatric disorders [ 34 ].…”