American Journal of Medical Genetics Part B: Neuropsychiatric Genetics最新文献

In 1939, Hans Luxenburger published a detailed overview of the current status of schizophrenia genetics research, reaching six major conclusions. First, schizophrenia is clearly a hereditary disease. Second, however, schizophrenia is not the hereditary trait itself but rather the consequences of a slowly developing biological progress, the nature of which remains entirely unknown. Third, the full manifestation of the disorder requires certain environmental influences that must come into play. In around 30% of cases, the environment can inhibit hereditary factors so that the predisposition does not manifest in schizophrenia. Fourth, the mode of inheritance of schizophrenia remains unknown, although recessivity is more likely than dominance and monomerism is more likely than polymerism. Fifth, current evidence suggests that schizophrenia is likely etiologically homogenous. Sixth, schizophrenia is part of a hereditary circle that includes “normal” variants of the human personality (schizothymia), a pathological version of this dimension (schizoidia), and other schizophrenia-like delusional syndromes. Luxenburger is skeptical of efforts to clarify further Mendelian transmission models in the absence of pathophysiological markers because schizophrenia cannot serve as a typical phenotype for genetic analysis. By contrast, he strongly supports empirical work on hereditary prognosis, which does not depend on assumptions about any particular phenotype–genotype relationship.

Since 2008, FOXG1 haploinsufficiency has been linked to a severe neurodevelopmental phenotype resembling Rett syndrome but with earlier onset. Most patients are unable to sit, walk, or speak. For years, FOXG1 sequencing was only prescribed in such severe cases, limiting insight into the full clinical spectrum associated with this gene. Next-generation sequencing (NGS) now enables unbiased diagnostics. Through the European Reference Network for Rare Malformation Syndromes, Intellectual and Other Neurodevelopmental Disorders, we gathered data from patients with heterozygous FOXG1 variants presenting a mild phenotype, defined as able to speak and walk independently. We also reviewed data from three previously reported patients meeting our criteria. We identified five new patients with pathogenic FOXG1 missense variants, primarily in the forkhead domain, showing varying nonspecific intellectual disability and developmental delay. These features are not typical of congenital Rett syndrome and were rarely associated with microcephaly and epilepsy. Our findings are consistent with a previous genotype–phenotype analysis by Mitter et al. suggesting the delineation of five different FOXG1 genotype groups. Milder phenotypes were associated with missense variants in the forkhead domain. This information may facilitate prognostic assessments in children carrying a FOXG1 variant and improve the interpretation of new variants identified with genomic sequencing.

Pathogenic variants in DDX3X are associated with neurodevelopmental disorders. Communication impairments are commonly reported, yet specific speech and language diagnoses have not been delineated, preventing prognostic counseling and targeted therapies. Here, we characterized speech and language in 38 female individuals, aged 1.69–24.34 years, with pathogenic and likely pathogenic DDX3X variants (missense, n = 13; nonsense, n = 12; frameshift, n = 7; splice site, n = 3; synonymous, n = 2; deletion, n = 1). Standardized speech, language, motor, social, and adaptive behavior assessments were administered. All participants had gross motor deficits in infancy (34/34), and fine motor deficits were common throughout childhood (94%; 32/34). Intellectual disability was reported in 86% (24/28) of participants over 4 years of age. Expressive, receptive, and social communication skills were, on average, severely impaired. However, receptive language was significantly stronger than expressive language ability. Over half of the assessed participants were minimally verbal (66%; 22/33; range = 2 years 2 months–24 years 4 months; mean = 8 years; SD = 6 years) and augmented speech with sign language, gestures, or digital devices. A quarter of the cohort had childhood apraxia of speech (25%; 9/36). Despite speech and language impairments, social motivation was a relevant strength. Many participants used augmentative and alternative communication (AAC), underscoring the need for early, tailored, and comprehensive AAC intervention.

Compared to the large body of maternal mental health research for other pediatric disorders, we know far less about the experience of mothers of children with 22q11DS. This study investigates the coping methods, protective factors, and mental health of this population. These findings might lead to better support for 22q11DS maternal mental health. An international sample of 71 mothers (M = 40.5 years) of children with 22q11DS (M = 9.2 years) was recruited and completed an online survey assessing maternal mental health (symptoms of depression, anxiety, traumatic stress, general stress, and alcohol consumption), coping methods, and mental health protective factors (social support, dyadic adjustment, parenting competence). Maternal ratings of child mental health symptoms were also obtained. Mothers' self-report revealed a high percentage who screened positive for elevated levels of general stress (69%), hazardous alcohol consumption (30.9%), traumatic stress (33.8%), anxiety (26.8%), and depression (26.8%). After controlling for demographic variables and child mental health symptoms, maternal self-reported maladaptive coping methods were positively associated with maternal symptoms of depression, anxiety, stress, and traumatic stress. Reducing maladaptive coping methods may be a promising intervention for improving mental health in mothers of children with 22q11DS.

Loss-of-function CHD2 (chromodomain helicase DNA-binding protein 2) mutations are associated with a spectrum of neurodevelopmental disorders often including early-onset generalized seizures, photosensitivity, and epileptic encephalopathies. Patients show psychomotor delay/intellectual disability (ID), autistic features, and behavior disorders, such as aggression and impulsivity. Most reported cases are sporadic with description of germline mosaicism only in two families. We detect the first case of parental gonosomal CHD2 mosaicism disclosed by two brothers showing mild ID, born to healthy parents. The eldest brother has a history of drug-controlled generalized tonic–clonic seizures and displays sleep disorder and aggressive behavior suggestive of Smith–Magenis syndrome (SMS). Analysis of brothers’ DNAs by next-generation sequencing (NGS) custom gene panel for pediatric epilepsy and/or ID disclosed in both the same pathogenic CHD2 variant. Additional NGS experiment on genomic DNA from parents’ peripheral blood and from buccal swab raised the suspicion of low-grade gonosomal mosaicism in the unaffected mother subsequently confirmed by digital polymerase chain reaction (dPCR). This report underlines as worthwhile CHD2 screening in individuals presenting ID/developmental delay, with/without epilepsy, and behavior and sleep disorders suggestive of SMS. Detecting a CHD2 variant should prime testing probands' parents by NGS coupled to dPCR on different tissues to exclude/confirm gonosomal mosaicism and define the recurrence risk.

Both internalizing disorders and alcohol use have dramatic, wide-spread implications for global health. Previous work has established common phenotypic comorbidity among these disorders, as well as shared genetic variation underlying them both. We used genomic structural equation modeling to investigate the shared genetics of internalizing, externalizing, and alcohol use traits, as well as to explore whether specific domains of internalizing symptoms mediate the contrasting relationships with problematic alcohol use compared to alcohol consumption. We also examined patterns of genetic correlations between similar traits within additional Finnish and East Asian ancestry groups. When the shared genetic influence of externalizing psychopathology was accounted for, the genetic effect of internalizing traits on alcohol use was reduced, suggesting the important role of common genetic factors underlying multiple psychiatric disorders and their genetic influences on comorbidity of internalizing and alcohol use traits. Individual internalizing domains had contrasting effects on frequency of alcohol consumption, which demonstrate the complex system of pleiotropy that exists, even within similar disorders, and can be missed when evaluating only relationships among formal diagnoses. Future work must consider the broad effects of shared psychopathology along with the fine-scale effects of heterogeneity within disorders to more fully understand the biology underlying complex traits.

Despite recent progress in the genetics of suicidal behavior, the pathway by which genetic liability increases suicide attempt risk is unclear. We investigated the mediational pathways from family/genetic risk for suicide attempt (FGRS_SA) to suicide attempt by considering the roles of psychiatric illnesses. In a Swedish cohort, we evaluated time to suicide attempt as a function of FGRS_SA and the mediational effects of alcohol use disorder, drug use disorder, attention-deficit/hyperactivity disorder, major depression, anxiety disorder, bipolar disorder, and non-affective psychosis. Analyses were conducted by sex in three age periods: 15–25 years (N_females = 850,278 and N_males = 899,366), 26–35 years (N_females = 800,189 and N_males = 861,774), and 36–45 years (N_females = 498,285 and N_males = 535,831). The association between FGRS_SA and suicide attempt was mediated via psychiatric disorders. The highest mediation effects were observed for alcohol use disorder in males (15–25 years, HR_total = 1.60 [1.59; 1.62], mediation = 14.4%), drug use disorder in females (25–36 years, HR_total = 1.46 [1.44; 1.49], mediation = 11.2%), and major depression (25–36 years) in females (HR_total = 1.46 [1.44; 1.49], mediation = 7%) and males (HR_total = 1.50 [1.47;1.52], mediation = 4.7%). While the direct effect of FGRS_SA was higher at ages of 15–25, the mediation via psychiatric disorders was more prominent in later adulthood. Our study informs about the psychiatric illnesses via which genetic liability operates to impact suicide attempt risk, with distinct contributions according to age and sex.

Schizophrenia is a chronic, debilitating mental illness caused by both genetic and environmental factors. Genetic factors play a major role in schizophrenia development. Early growth response 3 (EGR3) is a member of the EGR family, which is associated with schizophrenia. Accumulating studies have investigated the relationship between EGR3 and schizophrenia. However, the role of EGR3 in schizophrenia pathogenesis remains unclear. In the present review, we focus on the progress of research related to the role of EGR3 in schizophrenia, including association studies between EGR3 and schizophrenia, abnormal gene expressional analysis of EGR3 in schizophrenia, biological function studies of EGR3 in schizophrenia, the molecular regulatory mechanism of EGR3 and schizophrenia susceptibility candidate genes, and possible role of EGR3 in the immune system function in schizophrenia. In summary, EGR3 is a schizophrenia risk candidate factor and has comprehensive regulatory roles in schizophrenia pathogenesis. Further studies investigating the molecular mechanisms of EGR3 in schizophrenia are warranted for understanding the pathophysiology of this disorder as well as the development of new therapeutic strategies for the treatment and control of this disorder.

Schizophrenia (SCZ) is influenced by a combination of genetic and environmental factors. Although several studies have been conducted to identify the causative loci and genes, few of these loci or genes can be repeated due to the high phenotypic and genetic heterogeneity of disease, and their mechanisms are not fully understood. There may be some “missing heritability” that has not yet been found. In order to investigate the deleterious heritable mutations, whole-exome sequencing (WES) in pedigrees with SCZ was used in the current work. Two unrelated pedigrees with SCZ were recruited to perform WES. Genetic analysis was next performed to find potential variants in accordance with the prioritized strategy. Followed by genetic analysis to detect candidate variants according to the prioritized strategy. Next, a series of algorithms was used to predict the pathogenicity of variants. Sanger sequencing was finally conducted to verify the co-segregation. Recessive mutations in six genes (TFEB, SNAI2, TFAP2B, PRKDC, ST18 in Pedigree 1 and PKHD1L1 in Pedigree 2) that co-segregated with SCZ in two families were discovered through genetic analysis by WES. Sanger sequencing verified that all of the mutations in the affected siblings were homozygous. These results corroborated the hypothesis that SCZ exhibits strong heterogeneity and complex inheritance patterns. The newly discovered homozygous variations deepen our understanding of the mutation spectrum and offer more proof for the involvement of TFEB, SNAI2, TFAP2B, PRKDC, ST18, and PKHD1L1 in the development of SCZ.