Psychiatric Genetics最新文献

Objective: Genome-wide association studies (GWAS) implicate psychiatric, metabolic, and anthropometric factors in anorexia nervosa. We developed an 'experiential genetics' design, layering qualitative methodology atop GWAS to capture the subjective experience of anorexia nervosa.

Method: We randomly selected GWAS participants with anorexia nervosa from the highest ( n  = 10) and lowest ( n  = 10) anorexia nervosa polygenic risk scores (PRS). Clinicians blind to PRS group conducted semi-structured interviews exploring the perception of symptoms, onset, course, and physical and psychological experience of negative energy balance (NEB) (i.e. the pathognomonic anorexia nervosa symptom of expending more energy than one consumes). Blind raters rated transcripts; experiential themes and subthemes were identified through thematic analysis.

Results: Themes indicated that the high-PRS group reported more lifetime psychiatric problems, described the descent into anorexia nervosa as a purposeful progression of preexisting preoccupations, experienced NEB as more positive and energizing, and were more often symptomatic at interview; for them anorexia nervosa seemed to represent the apex of a life trajectory centered on eating disorder traits and symptoms. The low-PRS group reported fewer lifetime psychiatric problems, a more environmentally determined illness onset, fewer extreme symptoms, and were less symptomatic at interview; for them anorexia nervosa seemed to constitute a transient interruption of their life trajectory. Interviewers correctly guessed group membership less frequently than chance (43%), questioning whether the dimensions commonly associated with anorexia nervosa capture the genetic essence of anorexia nervosa.

Conclusion: Qualitative research can capture the phenotypic expression of genetic risk, enrich GWAS, characterize heterogeneity, and inform development of genetically informed interventions.

Objective: The aim herein was to investigate mitochondrial cytochrome B (MT-CYB) mutations in individuals with bipolar disorder. Stanniocalcin-1 ( STC1 ) and uncoupling protein 2 ( UCP2 ) mRNA expressions and their relationship with clinical data and each other were also investigated.

Method: The blood samples of 100 individuals were included in this study. Real-time PCR was used to evaluate mRNA expressions of STC1 and UCP2 . Genetic alterations were investigated via Sanger DNA sequencing. An in silico analysis was performed to reveal the phenotypic effects of MT-CYB mutations.

Results: In the MT-CYB gene of the bipolar disorder patients, the most seen mutations were the T194A A>G mutation at position 1532, G deletion at position 15498, and C>A L236I mutation at position 15452. Most of the mutations appeared to be neutral or benign. The UCP2 and STC1 mRNA expression levels were significantly higher in the patients than in the healthy controls ( P  = 0.0124 and P  < 0.0001, respectively). The area under the curve values of the receiver operating characteristic curve analysis for UCP2 and STC1 were 0.6631 ( P  = 0.0123) and 0.8059 ( P  < 0.0001), respectively. No significant relationship was observed between the gene expressions and the routine laboratory findings. There was a positive correlation between the UCP2 and STC1 mRNA expressions in the bipolar disorder patients ( r  = 0.03559, P  = 0.0306).

Conclusion: Expression of UCP2 and STC1 may be important parameters in bipolar disorder. MT-CYB mutations may be related to gene expressions. Comprehensive studies on bipolar disorder will help better understand UCP2 and STC1 gene functions.

Background: Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder caused by the deficiency of arylsulfatase A (ARSA). Accumulation of sulfatide, substrate of ARSA, in the central and peripheral nervous system causes neurodegeneration, which leads to neurologic and psychiatric symptoms. Adult-onset MLD is the least frequent type of MLD and shows both genetic and clinical heterogeneity. The clinical presentation differs according to pathogenic variants in the ARSA gene. Therefore, establishing genotype-phenotype correlation is crucial for the diagnosis and management of patients with adult-onset MLD.

Methods: A family of multiple individuals with adult-onset psychomotor deterioration was assessed. The patients had behavioral disturbances initially, and neurological deficits had developed in the later stages of the disease. The family was analyzed using karyotype analysis, Sanger sequencing, custom next-generation sequencing (NGS) panel of the genes related to dementia, and whole exome sequencing (WES).

Results: Karyotype analysis and NGS dementia panel showed no pathogenic aberration. However, WES analysis revealed heterozygous variants in the ARSA gene: c.542T>G (p.Ile181Ser) and c.661T>A (p.Phe221Ile). Segregation analysis, performed by Sanger sequencing, showed that all individuals with the same clinical findings were compound heterozygous for c.542T>G and c.661T>A substitutions.

Conclusion: The compound heterozygosity of c.542T>G and c.661T>A variants of the ARSA gene cause adult-onset MLD. The genotype detected in the patients was not reported before in the literature. Moreover, the clinical course of the patients followed a similar pattern with dominantly psychiatric symptoms at the initial stage of the disease, indicating a distinct phenotype caused by the two pathogenic variants of the ARSA gene.

Although psychotic symptoms have occasionally been associated with pathogenic CHD2 variants, few articles have provided phenotypic information in this respect or described treatment response. We describe an 18-year-old female with a 15q26.1 interstitial deletion that disrupts CHD2, who at age 12 developed a variety of psychotic symptoms that responded well to quetiapine therapy. She also exhibited improvement in her cognitive functioning, language skills, and social responsiveness, which coincided with the initiation of metformin. This is only the third report to characterize antipsychotic treatment response in an individual harboring a pathogenic CHD2 variant, and the first to do so in relation to quetiapine. Although anecdotal, psychotic symptoms that develop in relation to pathogenic CHD2 variants may respond to atypical antipsychotic therapy, and metformin may have additional benefits in this population with respect to behavioral/social deficits. However, more evidence is needed before any firm conclusions can be drawn.

Heterozygous variants in the Early B cell factor 3 ( EBF3 ) have been reported in individuals presenting with hypotonia, ataxia and delayed development syndrome (HADDS) (MIM#617330). However, individuals with pathogenic variants in EBF3 show phenotypic heterogeneity and very few variants in the C-terminal domain have been described. We report on a heterozygous de-novo variant in the EBF3 gene in an individual with neurodevelopmental delay and behavioural problems. The proband presented with speech delay, learning disability and behavioural problems that suggest an oppositional defiant disorder. He also has hyperactivity, irritability, hetero-aggressiveness, visual hallucinations, insomnia and decreased pain sensitivity. Whole exome sequencing revealed a de-novo heterozygous nonsense variant - c.1408C>T (p.Arg470*) - in the EBF3 gene, classified as pathogenic. The patient herein described, with a truncating variant in the C-terminal domain of EBF3 , supports the clinical variability of this condition and contributes to genotype-phenotype correlation of this rare disorder.

Background: Copy number variants (CNVs) are an important source of normal and pathogenic genome variations. Chromosomal microdeletions and microduplications have long been associated with abnormal developmental outcomes. Recently, the application of CNV sequencing (CNV-seq) is rapidly identifying new recurrent microdeletion and microduplication syndromes and a previously unsuspected level of copy number variation which needs to be distinguished from pathogenic change.

Materials and methods: In this research, a 26-year-old, gravida 1, para 0, woman underwent amniocentesis at 18 weeks of gestation. Cytogenetic analysis of the cultured amniocytes and CNV-seq on uncultured amniocytes was performed. After that, we performed trio whole-exome sequencing (WES) on the family.

Results: CNV-seq detected three chromosomal microduplications in the fetus, respectively are 2p16.1p15, 6q27, and 9p22.3. The microduplication of 2p16.1p15 is inherited from the mother, and the microduplication of 6q27 and 9p22.3 comes from the father. After genetic counseling, the parents decided to continue the pregnancy.

Conclusion: We present a rare case of a Chinese family with inherited multiple chromosomal microduplications with normal phenotype. Our case can be helpful for prenatal diagnosis and genetic counseling. Chromosomal microdeletions and microduplications are difficult to detect by conventional cytogenetics. Combination of prenatal ultrasound, karyotype analysis, CNV-seq, trio-WES, and genetic counseling is helpful for the prenatal diagnosis of chromosomal microdeletions/microduplications.

Although numerous copy number variants (CNVs) are considered pathogenic with respect to the development of schizophrenia, only eight loci have reached genome-wide significance. Reviews/studies characterizing antipsychotic use in this context exist for only three corresponding CNV syndromes. As these disorders also predispose to neurodevelopmental anomalies and various medical comorbidities, affected individuals may be particularly sensitive to the side effects of antipsychotic medications. As such, this review sought to identify and describe all reports of antipsychotic use among individuals with the other genome-wide significant schizophrenia risk CNVs (2p16.3 deletions/ NRXN1 variants, 15q13.3 and 16p11.2 deletions, 7q11.23 duplications, and 1q21.1 deletions or duplications). Only 10 eligible articles describing 29 individuals were included. While treatment response was reasonably good for most individuals, despite variability existing across the specific CNV syndromes, side effects were rarely reported. Above all, this review highlights the need for more case reports/series to be published.