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

Chia-Hsiang Chen,Ting-Hsuan Fang,Yu-Shu Huang

doi:10.3390/ijms222413189

Chia-Hsiang Chen, Ting-Hsuan Fang + Show 1 more

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https://doi.org/10.3390/ijms222413189

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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.

Highlights

Schizophrenia (SZ) and bipolar disorder (BD) are two devastating chronic mental disorders, with the pathogenesis remaining to be elucidated
Our findings suggest that SZ and BD might be part of the clinical phenotype spectra of SCN9A mutations
Identifying common variants and rare mutations associated with SZ and BD has increased our understanding of the neurobiology of these two disorders [3,4,5]

Summary

Introduction

Schizophrenia (SZ) and bipolar disorder (BD) are two devastating chronic mental disorders, with the pathogenesis remaining to be elucidated. Genetic factors play a significant role in the etiology of these two disorders [1,2]. The genetic bases of these two disorders are complex, involving common variants with modest effects and rare mutations with high clinical penetrance in multiple genes. Identifying common variants and rare mutations associated with SZ and BD has increased our understanding of the neurobiology of these two disorders [3,4,5]. SZ and BD are two psychiatric diagnoses from the clinical aspect, there is a significant overlap of symptoms between these two disorders [6]. Genetic studies showed overlaps of genetic variants between these two disorders, indicating these two disorders share some common heritability [7,8,9,10]

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