Psychiatric Genetics最新文献

Background: Major depressive disorder (MDD) is among the leading causes of disability worldwide and treatment efficacy is variable across patients. Polymorphisms in cytochrome P450 2C19 (CYP2C19) play a role in response and side effects to medications; however, they interact with other factors. We aimed to predict treatment outcome in MDD using a machine learning model combining CYP2C19 activity and nongenetic predictors.

Methods: A total of 1410 patients with MDD were recruited in a cross-sectional study. We extracted the subgroup treated with psychotropic drugs metabolized by CYP2C19. CYP2C19 metabolic activity was determined by the combination of *1, *2, *3, and *17 alleles. We tested if treatment response, treatment-resistant depression, and side effects could be inferred from CYP2C19 activity in combination with clinical-demographic and environmental features. The model used for the analysis was based on a decision tree algorithm using five-fold cross-validation.

Results: A total of 820 patients were treated with CYP2C19 metabolized drugs. The predictive performance of the model showed at best.70 accuracy for the classification of treatment response (average accuracy = 0.65, error = ±0.047) and an average accuracy of approximately 0.57 across all the tested outcomes. Age, BMI, and baseline depression severity were the main features influencing prediction across all the tested outcomes. CYP2C19 metabolizing status influenced both response and side effects but to a lower extent than the previously indicated features.

Conclusion: Predictive modeling could contribute to precision psychiatry. However, our study underlines the difficulty in selecting variables with sufficient impact on complex outcomes.

Objective: This position article discusses current major ethical and social issues related to genetic counseling and testing in clinical psychiatry (PsyGCT).

Methods: To address these complex issues in the context of clinical psychiatry relevant to PsyGCT, the interdisciplinary and pan-European expert Network EnGagE (Enhancing Psychiatric Genetic Counseling, Testing, and Training in Europe; CA17130) was established in 2018. We conducted an interdisciplinary, international workshop at which we identified gaps across European healthcare services and research in PsyGCT; the workshop output was summarized and systematized for this position article.

Results: Four main unresolved ethical topics were identified as most relevant for the implementation of PsyGCT: (1) the problematic dualism between somatic and psychiatric disorders, (2) the impact of genetic testing on stigma, (3) fulfilling professional responsibilities, and (4) ethical issues in public health services. We provide basic recommendations to inform psychiatrists and other healthcare professionals involved in the clinical implementation of PsyGCT and conclude by pointing to avenues of future ethics research in PsyGCT.

Conclusion: This article draws attention to a set of unresolved ethical issues relevant for mental health professionals, professionals within clinical genetics, patients and their family members, and society as a whole and stresses the need for more interdisciplinary exchange to define standards in psychiatric counseling as well as in public communication. The use of PsyGCT may, in the future, expand and include genetic testing for additional psychiatric diagnoses. We advocate the development of pan-European ethical standards addressing the four identified areas of ethical-practical relevance in PsyGCT.

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.

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.

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.

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.

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.

The role of genetic factors in cluster headache etiology, suggested by familial and twin studies, remains ill-defined, with the exact pathophysiological mechanisms still largely elusive. This systematic review aims to synthesize current knowledge on cluster headache genetics and explore its implications for personalized treatment and prediction of treatment response. Thus, we searched PubMed, Scopus, and the Cochrane Library databases and reference lists of identified research articles, meta-analyses, and reviews to identify relevant studies up to 10 July 2024. The quality of the evidence was assessed using Newcastle-Ottawa Scale for case control studies and NIH Quality Assessment tool for Observational Cohort and Cross-Sectional Studies. The protocol of this study was registered via the Open Science Framework ( https://osf.io/cd4s3 ). Fifty-one studies were selected for the qualitative synthesis: 34 candidate gene studies, 5 GWAS, 7 gene expression studies, 4 pharmacogenetic association studies, and 1 whole genome sequencing study. The bulk of genetic evidence in cluster headache underscores the involvement of genes associated with chronobiological regulation. The most studied gene in cluster headache is the HCRTR2 , which is expressed in the hypothalamus; however, findings across studies continue to be inconclusive. Recent GWAS have uncovered novel risk loci for cluster headache, marking a significant advancement for the field. Nevertheless, there remains a need to investigate various genes involved in specific mechanisms and pathways.

Rubinstein-Taybi syndrome (RSTS) is an autosomal dominant genetic disease characterized by growth retardation, psychomotor retardation, and distinctive facial features. It is primarily caused by mutations in CREBBP or EP300. In this study, we aimed to describe the clinical manifestations and genetic analyses of two cases with RSTS. Clinical analysis was performed on two cases with RSTS. Molecular diagnoses were made via whole exome sequencing, and potential pathogenic variants were filtered and selected. PCR followed by Sanger sequencing was used to verify candidate variants in the family members. Case 1 involved a 7-year-old boy (patient 1) who exhibited delayed language development, growth retardation, and intellectual disability. We did not find any other characteristics of RSTS, such as thumb or hallux abnormalities. Case 2 involved a fetus who had severe congenital heart disease, low conus medullaris, and a large gallbladder. Whole exome and Sanger sequencing results revealed that a missense mutation c.5120G>A (p. Cys1707Tyr) was present in patient 1 and that the fetus carried a heterozygous nonsense mutation c.1984C>T (p. Gln662Ter). In conclusion, whole exome sequencing combined with Sanger sequencing revealed that c.5120G>A (p. Cys1707Tyr) and c.1984C>T (p. Gln662Ter) are two new mutation sites that cause RSTS. This study expands the clinical phenotypes and is helpful in identifying gene-phenotype correlations in RSTS.

Autism spectrum disorder (ASD) is a genetically heterogeneous neurobehavioral disorder. The etiology and the inheritance pattern are usually multifactorial. The index case is a 3-year-old male, whose family applied to the child psychiatry outpatient clinic due to failure to speak at 30 months. He had mild dysmorphic features. He is diagnosed with ASD according to DSM-V criteria. Chromosomal analysis revealed mos 48,XYYY[28]/47,XYY[72] karyotype. In FISH analysis, nuc ish (DXZ1x1, DYZ1x3)[44]/(DXZ1x1, DYZ1x2)[156] was detected. WES results displayed a heterozygous missense variant of uncertain significance c.3545G>A in the CACNA1E gene. XYY syndrome is one of the most common sex chromosome aneuploidies, and ASD is detected 20 times more likely than males in general population. To the best of our knowledge, the first case with the coexistence of mosaic 48,XYYY/47,XYY karyotype and CACNA1E variant together may contribute to phenotypic heterogeneity. Further investigation into the functionality of the variant in CACNA1E is needed.