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

2021 ◽  
Vol 22 (24) ◽  
pp. 13189
Author(s):  
Chia-Hsiang Chen ◽  
Yu-Shu Huang ◽  
Ting-Hsuan Fang
Keyword(s):  
Bipolar Disorder ◽  
Autism Spectrum ◽  
Sequencing Analysis ◽  
Missense Mutations ◽  
Multiplex Family ◽  
Rare Mutations ◽  
Congenital Insensitivity ◽  
Congenital Insensitivity To Pain ◽  
Multiplex Families ◽  
Multiple Hit

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.

scholarly journals Identification of a Rare Novel KMT2C Mutation That Presents with Schizophrenia in a Multiplex Family

2021 ◽  
Vol 11 (12) ◽  
pp. 1254
Author(s):  
Chia-Hsiang Chen ◽  
Ailing Huang ◽  
Yu-Shu Huang ◽  
Ting-Hsuan Fang
Keyword(s):  
Genetic Disorder ◽  
Autism Spectrum ◽  
Sequencing Analysis ◽  
Multiplex Family ◽  
Brain Gene Expression ◽  
Rare Mutations ◽  
Whole Exome ◽  
Kleefstra Syndrome ◽  
Lysine Methyltransferase ◽  
Complex Genetic Disorder

Schizophrenia is a complex genetic disorder involving many common variants with modest effects and rare mutations with high penetrance. Rare mutations associated with schizophrenia are highly heterogeneous and private for affected individuals and families. Identifying such mutations can help establish the molecular diagnosis, elucidate the pathogenesis, and provide helpful genetic counseling for affected patients and families. We performed a whole-exome sequencing analysis to search for rare pathogenic mutations co-segregating with schizophrenia transmitted in a dominant inheritance in a two-generation multiplex family. We identified a rare missense mutation H1574R (Histidine1574Arginine, rs199796552) of KMT2C (lysine methyltransferase 2C) co-segregating with affected members in this family. The mutation is a novel deleterious mutation of KMT2C, not reported before in the literature. The KMT2C encodes a histone 3 lysine 4 (H3K4)-specific methyltransferase and involves epigenetic regulation of brain gene expression. Mutations of KMT2C have been found in neurodevelopmental disorders, such as Kleefstra syndrome, intellectual disability, and autism spectrum disorders. Our finding suggests that schizophrenia might be one of the clinical phenotype spectra of KMT2C mutations, and KMT2C might be a novel risk gene for schizophrenia. Nevertheless, the co-segregation of this mutation with schizophrenia in this family might also be due to chance; functional assays of this mutation are needed to address this issue.

scholarly journals Identification of Rare Mutations of Two Presynaptic Cytomatrix Genes BSN and PCLO in Schizophrenia and Bipolar Disorder

2021 ◽  
Vol 11 (11) ◽  
pp. 1057
Author(s):  
Chia-Hsiang Chen ◽  
Yu-Shu Huang ◽  
Ding-Lieh Liao ◽  
Cheng-Yi Huang ◽  
Chia-Heng Lin ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Missense Mutation ◽  
Genetic Factors ◽  
Sequencing Analysis ◽  
Missense Mutations ◽  
Severe Mental Disorders ◽  
Risk Genes ◽  
Rare Mutations ◽  
Related Proteins ◽  
Insight Into

Schizophrenia and bipolar disorder are severe mental disorders with a major component of genetic factors in their etiology. Rare mutations play a significant role in these two disorders, and they are highly heterogeneous and personalized. Identification of personalized mutations is essential for the establishment of molecular diagnosis, providing insight into pathogenesis and guiding the personalized treatment for each affected patient. We conducted whole-genome sequencing analysis of families with schizophrenia and bipolar disorder to search for their genetic underpinnings. This report identified a rare missense mutation Arg1087Gln of BSN (bassoon presynaptic cytomatrix protein) co-segregating with schizophrenia in a family with multiple affected members. Furthermore, we identified the rare missense mutation Ser1535Leu of PCLO (piccolo presynaptic cytomatrix protein) in two sisters with bipolar disorder and another rare missense mutation, His5142Arg in PCLO, in a patient with schizophrenia. These three missense mutations were very rare and were predicted to be pathogenic. The BSN and PCLO genes encode two structurally related proteins of the presynaptic cytomatrix at the active zone that regulates neurotransmission at the presynaptic neuronal terminal. Our findings suggest the involvement of the presynaptic matrix in the pathogenesis of schizophrenia and bipolar disorder, and BSN and PCLO are the risk genes for schizophrenia and bipolar disorder.

scholarly journals Novel NTRK1 mutation in Chinese patient with congenital insensitivity to pain with anhidrosis: A Case Report

2020 ◽  
Author(s):  
Jing Sha ◽  
Zaochun Xu ◽  
Jingfang Zhai ◽  
Bei Zhang ◽  
Yanling Zhang ◽  
...  
Keyword(s):  
Case Report ◽  
Novel Mutation ◽  
Genetic Mutation ◽  
Chinese Patient ◽  
Tyrosine Kinase Receptor ◽  
Sequencing Analysis ◽  
Congenital Insensitivity ◽  
In Silico Studies ◽  
Congenital Insensitivity To Pain ◽  
Insensitivity To Pain

Abstract Objective : Congenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessively inherited disorder characterized by insensitivity to noxious stimuli and inability to sweat. Methods : In this case report, an 18-year-old Chinese boy diagnosed with CIPA with the clinical features of loss of algesthesis, inability to sweat, self-mutilation, developmental delay and dislocation of the left hip joint. Blood samples from the patient was collected and subjected to genetic analysis. Results : Sequencing analysis revealed a novel mutation, c.1769A>G, in the neurotrophic tyrosine kinase receptor type 1 gene (NTRK1). In silico studies suggested that the mutations described are detrimental to the function of the protein encoded by the NTRK1 gene. Conclusions : The novel mutation widen the genetic mutation spectrum of NTRK1 in CIPA patients, and provide more evidence for precise diagnosis of the clinically suspected patients with CIPA.

scholarly journals Novel SCN9A missense mutations contribute to congenital insensitivity to pain: Unexpected correlation between electrophysiological characterization and clinical phenotype

2020 ◽  
Vol 16 ◽  
pp. 174480692092388
Author(s):  
Jiaoli Sun ◽  
Lulu Li ◽  
Luyao Yang ◽  
Guangyou Duan ◽  
Tingbin Ma ◽  
...  
Keyword(s):  
Sodium Current ◽  
Hek293 Cells ◽  
Pain Patient ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Protein Levels ◽  
Congenital Insensitivity ◽  
Congenital Insensitivity To Pain ◽  
Electrophysiological Characterization ◽  
Insensitivity To Pain

Congenital insensitivity to pain (OMIM 243000) is an extremely rare disorder caused by loss-of-function mutations in SCN9A encoding Nav1.7. Although the SCN9A mutations and phenotypes of painlessness and anosmia/hyposmia in patients are previously well documented, the complex relationship between genotype and phenotype of congenital insensitivity to pain remains unclear. Here, we report a congenital insensitivity to pain patient with novel SCN9A mutations. Functional significance of novel SCN9A mutations was assessed in HEK293 cells expressing Nav1.7, the results showed that p.Arg99His significantly decreased current density and reduced total Nav1.7 protein levels, whereas p.Trp917Gly almost abolished Nav1.7 sodium current without affecting its protein expression. These revealed that mutations in Nav1.7 in this congenital insensitivity to pain patient still retained partial channel function, but the patient showed completely painlessness, the unexpected genotypic-phenotypic relationship of SCN9A mutations in our patient may challenge the previous findings “Nav1.7 total loss-of-function leads to painlessness.” Additionally, these findings are helpful for understanding the critical amino acid for maintaining function of Nav1.7, thus contributing to the development of Nav1.7-targeted analgesics.

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