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

Phelan-McDermid syndrome (PMS) is a genetic condition caused by deletions of chromosome 22q13.3 or pathogenic variants in the SHANK3 gene. Neurologic features typically include intellectual disability, autism spectrum disorder, hypotonia, and absent speech, though there is considerable variability even among individuals with the same molecular cause. This prospective study aimed to explore the utility of genome sequencing to identify additional molecular diagnoses that may contribute to variability in a cohort of patients with PMS. Twenty probands diagnosed with PMS (60% with a 22q13 deletion, 40% with a SHANK3 variant) underwent trio or duo genome sequencing and chromosomal microarray. This analysis identified a second molecular finding associated with a neurological condition in 3/20 participants. Molecular diagnoses related to neurological phenotypes included: (1) spinal muscular atrophy, lower extremity-predominant, 2A, autosomal dominant (SMALED2A), (2) spastic paraplegia 7, and (3) 16p11.2 deletion syndrome. Five additional new molecular diagnoses were associated with a clinically actionable secondary or incidental finding. This exploratory study provides early evidence for the potential utility of expanded sequencing among individuals with PMS, even for those without phenotypic features outside of the expected range.

The research of single gene-related disorders or pathogenic copy-number variations (CNVs) has given a significant impetus to the shift from a diagnostic work-up focused on epileptic syndromes to genomic approaches in individuals with severe pediatric-onset epilepsies and in developmental and epileptic encephalopathies. Genome-wide association studies (GWAS) have identified various loci of susceptibility for common epilepsies and highlighted a strong predisposing role of common variants in several genes involved in well-known monogenic diseases. The largest GWAS identified eight major loci with stronger genome-wide significance for epilepsy, regardless the underlying epileptic syndrome: 2q24.3, 2p16.1, 4p15.1, 7q21.11, 8p23.1, 9q21.13, 10q24.32, 16q12.1, 2p16.1 and 2q24.3 occurred more frequently in patients with genetic generalized epilepsies. Loci 4p12, 8q23.1 and 16p11.2 achieved a high genome-wide significance for Juvenile Myoclonic Epilepsy. Childhood Absence Epilepsy was significantly genome-wide associated with 2p16.1 and 2q22.3. The loci 3q25.31, 6q22.31 and 2q24.3 were significantly associated with non-acquired focal epilepsies. Polygenic risk scores (PRS) are used to quantify the cumulative effects of several common genetic variants in a single score, each of which individually contributes minimally to disease susceptibility. The impact of PRS on clinical practice might be relevant for epilepsy risk prediction in groups of patients at high risk of developing epilepsy in the near future. Elevated PRS values have been observed in genetic generalized epilepsies particularly in familial forms, females, and patients with previous seizure events. Among comorbidities associated with epilepsy, depression, psychosis, and attention-deficit/hyperactivity disorder (ADHD) showed significantly elevated PRS.

Trichotillomania (TTM) is a psychiatric condition in which people feel an overwhelming urge to pull out their hair, resulting in noticeable hair loss and significant distress. Twin and family studies suggest that TTM is at least partly genetic, but no genome-wide analyses have been completed. To fill the gap in this field, we have conducted a case–control study of genotype array data from 101 European ancestry TTM cases and 488 ancestry-matched unaffected controls. TTM cases were ascertained in the United States through web-based recruitment, patient support groups, and conferences organized by the Trichotillomania Learning Center. Following clinical confirmation of a TTM diagnosis, patients completed self-report assessments of frequency and duration of hair pulling, other psychiatric symptoms, and family history. Unaffected controls were also ascertained in the United States and were matched to cases by ancestry. In the first formal genome-wide association study of TTM, we did not identify any common variants with a genome-wide significant (p < 5 × 10⁻⁸) association level with case status. We found that cases carry a higher load of common polygenic risk for psychiatric disorders (p = 0.008). We also detected copy number variants previously associated with neuropsychiatric disorders (specifically, deletions in NRXN1, CSMD1, and 15q11.2). These results further support genetics' role in the etiology of TTM and suggest that larger studies are likely to identify risk variation and, ultimately, specific risk genes associated with the condition.

Women with the FMR1 premutation (FXpm) are at heightened genetic vulnerability for depression, with risk compounded by the stressors of parenting a disabled child. Although risk factors persist as FXpm women age, depression in FXpm mothers during midlife and old age is poorly characterized. This study used an accelerated longitudinal design to capture the trajectory of depressive symptoms in 73 FXpm mothers across 20–75 years of age. The FXpm mothers had children with fragile X syndrome or FXpm and contributed 2–11 longitudinal assessments, for a total of 294 observations. Mothers with mid-range CGG expansions (91–110 CGG repeats) exhibited the highest overall symptoms, with a marked increase in depression during early midlife, followed by late midlife trajectories that varied by history of premature menopause. Symptoms of mothers with high CGGs (111–200) peaked during early and late adulthood rather than midlife. At low CGGs (55–90) symptoms were low and stable across age. Parenting stress was associated with increased symptoms during early adulthood, but this effect dwindled with age. Findings illuminate evolving patterns of depression vulnerability across adulthood that are shaped by specific environmental and genetic factors, offering insights for personalized medicine to enhance the health of aging FXpm mothers.

A large proportion of patients undergoing cognitive behavior therapy (CBT) for obsessive-compulsive disorder (OCD) do not respond sufficiently to treatment. Identifying predictors for change in symptom severity after treatment could inform clinical decision-making, allow for better-tailored interventions, and avoid treatment failure. Prior research on predictors for treatment response has, however, yielded inconsistent findings with limited clinical utility. Here, we investigated the predictive power of nine polygenic risk scores (PRSs) for psychiatric and cognitive traits in 1598 OCD patients (1167 adults and 431 children/adolescents) treated with CBT in Sweden and Norway. We fitted linear mixed models adjusted for age, sex, genotyping batch, and the first five ancestry PCs to estimate associations between PRS and symptom severity change from pre- to post-treatment. The PRS for schizophrenia showed a modestly significant association with symptom change (β = 0.013, p = 0.04, R ² = 0.10), indicating that a higher PRS for schizophrenia was associated with a smaller decrease in symptom severity. No other PRS were significantly associated with the outcome. While these results await replication and expansion, current PRS for psychiatric and cognitive phenotypes do not seem to contribute meaningfully to symptom severity change in CBT for OCD.

Brasher, M. S., A. D. Grotzinger, N. P. Friedman, H. R. Smolker, and L. M. Evans. 2024. “Disentangling Differing Relationships Between Internalizing Disorders and Alcohol Use.” American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 195B: e32975. https://doi.org/10.1002/ajmg.b.32975.

In the originally published article, dbGaP phs001672 was not acknowledged properly.

The Acknowledgments section should have included the following: “The authors thank Million Veteran Program (MVP) staff, researchers, and volunteers, who have contributed to MVP, and especially participants who previously served their country in the military and now generously agreed to enroll in the study. (See https://www.research.va.gov/mvp/ for more details). The citation for MVP is Gaziano, J.M. et al. Million Veteran Program: A mega-biobank to study genetic influences on health and disease. J Clin Epidemiol 70, 214–23 (2016). This research is based on data from the Million Veteran Program, Office of Research and Development, Veterans Health Administration, and was supported by the Veterans Administration (VA) Million Veteran Program (MVP) award #000.”

The second sentence in the Methods section should read: “Internalizing phenotypes included the generalized anxiety disorder two item questionnaire (GAD-2) score from (Levey et al., 2020, summary statistics available through dbGaP phs001672), a meta-analysis of lifetime anxiety disorder from (Purves et al., 2020), and a meta-analysis of broad depression from (Howard et al., 2018).”

The Data Availability Statement should have included: “phs001672: Veterans Administration (VA) Million Veteran Program (MVP) Summary Results from Omics Studies.”

We apologize for this error.

People with mosaicism for trisomy 21 have been shown to exhibit many of the same phenotypic traits present in people with non-mosaic Down syndrome, but with varying symptom severity. However, the behavioral phenotype of people with mosaic Down syndrome (mDS) has not been well characterized. This study aimed to examine the prevalence of self-report and caregiver-report symptoms of depression and anxiety among a sample of 62 participants with mDS aged 12–46 and assess their association with the percentage of trisomy 21 in blood and/or buccal mucosa cells. The overall MANCOVA revealed a significant effect of trisomy on the set of internalizing scales, controlling for age and gender (p = 0.038, partial eta² = 0.22). However, follow-up univariate analyses showed that the initial significant effect of trisomy on fear (p = 0.049, partial eta² = 0.08) did not survive correction for multiple comparisons (adjusted p = 0.300). No other effects were significant. This study highlights the high occurrence of depression and anxiety symptoms in individuals with mDS and the need for routine assessment to optimize their care. It also demonstrates the ability of people with mDS to complete these evaluations, thereby supporting their inclusion in research studies/clinical trials.