Pathogenic Germline Variants in 10,389 Adult Cancers.

We conducted the largest investigation of predisposition variants in cancer to date, discovering 853 pathogenic or likely pathogenic variants in 8% of 10,389 cases from 33 cancer types. Twenty-one genes showed single or cross-cancer associations, including novel associations of SDHA in melanoma and PALB2 in stomach adenocarcinoma. The 659 predisposition variants and 18 additional large deletions in tumor suppressors, including ATM, BRCA1, and NF1, showed low gene expression and frequent (43%) loss of heterozygosity or biallelic two-hit events. We also discovered 33 such variants in oncogenes, including missenses in MET, RET, and PTPN11 associated with high gene expression. We nominated 47 additional predisposition variants from prioritized VUSs supported by multiple evidences involving case-control frequency, loss of heterozygosity, expression effect, and co-localization with mutations and modified residues. Our integrative approach links rare predisposition variants to functional consequences, informing future guidelines of variant classification and germline genetic testing in cancer.

A Mild PUM1 Mutation Is Associated with Adult-Onset Ataxia, whereas Haploinsufficiency Causes Developmental Delay and Seizures.

Certain mutations can cause proteins to accumulate in neurons, leading to neurodegeneration. We recently showed, however, that upregulation of a wild-type protein, Ataxin1, caused by haploinsufficiency of its repressor, the RNA-binding protein Pumilio1 (PUM1), also causes neurodegeneration in mice. We therefore searched for human patients with PUM1 mutations. We identified eleven individuals with either PUM1 deletions or de novo missense variants who suffer a developmental syndrome (Pumilio1-associated developmental disability, ataxia, and seizure; PADDAS). We also identified a milder missense mutation in a family with adult-onset ataxia with incomplete penetrance (Pumilio1-related cerebellar ataxia, PRCA). Studies in patient-derived cells revealed that the missense mutations reduced PUM1 protein levels by ∼25% in the adult-onset cases and by ∼50% in the infantile-onset cases; levels of known PUM1 targets increased accordingly. Changes in protein levels thus track with phenotypic severity, and identifying posttranscriptional modulators of protein expression should identify new candidate disease genes.

A general calculus of fitness landscapes finds genes under selection in cancers.

Genetic variants drive the evolution of traits and diseases. We previously modeled these variants as small displacements in fitness landscapes and estimated their functional impact by differentiating the evolutionary relationship between genotype and phenotype. Conversely, here we integrate these derivatives to identify genes steering specific traits. Over cancer cohorts, integration identified 460 likely tumor-driving genes. Many have literature and experimental support but had eluded prior genomic searches for positive selection in tumors. Beyond providing cancer insights, these results introduce a general calculus of evolution to quantify the genotype-phenotype relationship and discover genes associated with complex traits and diseases.

Prenatal mental health and emotional experiences during the pandemic: associations with infant neurodevelopment screening results.

BACKGROUND: This study determined whether parental mental health and emotional experiences during the prenatal period were linked to infant developmental outcomes through the Ages and Stages Questionnaire (ASQ-3) at 8-10 months. METHODS: Participants included 133 individuals who were living in the US and were pregnant or had given birth within 6 months prior to enrollment. Respondents were majority White with high education and income levels. Online surveys were administered from May 2020 to September 2021; follow-up surveys were administered from November 2020 to August 2022. RESULTS: Parent generalized anxiety symptoms were positively associated with infant communication (ß = 0.34, 95% CI [0.15, 1.76], p < 0.05), while parent-fetal bonding was positively associated with infant communication (ß = 0.20, 95% CI [0.05, 0.76], p < 0.05) and personal-social performance (ß = 0.20, 95% CI [0.04, 0.74], p < 0.05). COVID-19-related worry was negatively associated with infant communication (ß = -0.30, 95% CI [-0.75, -0.12], p < 0.05) and fine motor performance (ß = -0.25, 95% CI [-0.66, -0.03], p < 0.05). CONCLUSION: Parent mental health and emotional experiences may contribute to infant developmental outcomes in high risk conditions such as a pandemic. IMPACT STATEMENT: Maternal SARS-CoV-2 infection has been evaluated in relation to child outcomes, however, parent psychosocial experiences should not be overlooked when considering pandemic risks to child development. Specific prenatal mental health and pandemic-related emotional experiences are associated with infant developmental performance, as assessed by the Ages and Stages. Questionnaire (ASQ-3) at 8 to 10 months old. Findings indicate that parental prenatal anxiety and emotional experiences from the pandemic should be assessed when evaluating child developmental delays.

Patterns of peripartum depression screening and detection in a large, multi-site, integrated healthcare system.

The purpose of this study was to examine peripartum depression (PD) screening patterns within and across the prenatal and postpartum periods and assess the incidence of new positive screens during standard screening protocol timepoints to inform practice, particularly when limited screenings can be conducted.This is a retrospective observational study of women screened for PD through a large, integrated health system using the Edinburgh Postnatal Depression Scale (EPDS) within their obstetrics and pediatric practices. Pregnancies with an EPDS score for at least one obstetric and one pediatric appointment between November 2016 and October 2019 were included (n = 3240). The data were analyzed using chi-squared test, Student's t-test, and binary logistic regression analyses. An EPDS score of 10 or higher was considered a positive screen.The positive screening rate for this cohort was 18.5%, with a prenatal positive rate of 9.9% and a postpartum positive rate of 8.6%. Single relationship status showed a higher rate of PD overall. Two thirds of women were not screened until their third trimester, resulting in delayed detection for an estimated 28% of women who ultimately screened positive. Few new positive screens (1.3%) were detected after 9 weeks postpartum in women who had completed all recommended prior screens.Obstetric providers should screen for PD as early in pregnancy as possible and continue to screen as often as feasible regardless of previous negative EPDS scores. Prioritizing screening more often in pregnancy and before 9 weeks postpartum is optimal to avoid delays in detection and intervention.

Unexpected changes in birth experiences during the COVID-19 pandemic: Implications for maternal mental health.

PURPOSE: This study examined the rates of unexpected birth experiences due to the COVID-19 pandemic and its association with women's postpartum mental health symptoms (depression, generalized anxiety, and PTSD). METHODS: Our cross-sectional analysis included postpartum women (N = 506) who reported on birth plan changes attributed to the COVID-19 pandemic through the PEACE (Perinatal Experiences and COVID-19 Effects) Study, an online survey that took place between May 2020 and May 2021. Covariates included sociodemographic variables, number of days since the pandemic, pre-pregnancy mental health history, and protective factors such as social support, distress tolerance, and resilience. RESULTS: Prevalent COVID-19 pandemic changes in the birth experience included not having support people (e.g., partners and friends) permitted to participate in the baby's delivery (33.5%), reduced access to preferred medications before or after delivery (9.7%), unavailable health care providers for the baby's birth as planned (9.6%), and other changes (13.8%). The reduced access to medications was associated with those reporting higher levels of depressive (ß = .10, p < .01) and PTSD symptoms (ß = .07, p < .05). Separation from their baby for a long period after delivery (ß = .10, p < .05) and other changes (ß = .10, p < .01) were associated with higher levels of PTSD symptoms. CONCLUSION: Unexpected changes to the birth experience due to the COVID-19 pandemic may have small but persistent effects on depressive and PTSD symptoms. Given increased vigilance and its association with subsequent PTSD, acknowledging any fear of viral contagion within the hospital setting but informing women the plans for ensuring safety may be preventive for later mental health symptomatology.

Incidental Findings from Deep Phenotyping Research in Psychiatry: Legal and Ethical Considerations.

Substantial advancement in the diagnosis and treatment of psychiatric disorders may come from assembling diverse data streams from clinical notes, neuroimaging, genetics, and real-time digital footprints from smartphones and wearable devices. This is called "deep phenotyping" and often involves machine learning. We argue that incidental findings arising in deep phenotyping research have certain special, morally and legally salient features: They are specific, actionable, numerous, and probabilistic. We consider ethical and legal implications of these features and propose a practical ethics strategy for managing them.

Maternal-fetal bonding during the COVID-19 pandemic.

BACKGROUND: The pregnant population experienced unique COVID-19 physical and psychosocial stressors such as direct health concerns related to the virus and loss of access to resources since the COVID-19 emerged as a global pandemic in early 2020. Despite these COVID-19-related stress and concerns, the maternal experience of bonding with their unborn children has not been well studied. This work aimed to study the association between mental health history, current mental health symptoms, psychological factors, COVID-19-related worries, and self-reported maternal-fetal bonding of pregnant women. METHODS: This online, survey-based cross-sectional study focused on women pregnant during the pandemic and assessed 686 women using data collected from May 19, 2020 to October 3, 2020. Enrolled respondents completed assessments in which they self-reported maternal-fetal bonding, mental health symptomatology, psychological factors, and COVID-19-related worries regarding health, pregnancy, and resources. RESULTS: Depressive symptoms in pregnant women were associated with lower quality maternal-fetal bonding, while a higher level of anxiety was positively associated with bonding; however, past history of depression or generalized anxiety diagnosis did not appear to be as relevant as active symptomatology. Maternal resilience, but not distress tolerance, appeared to be a protective factor resulting in improved bonding. Higher levels of worry regarding impact of COVID-19 on health were significantly associated with improved bonding, while worries regarding the impact of COVID-19 on the pregnancy or resources were not significantly associated with bonding. The study also found associations between different sociodemographic variables and bonding, including a strong positive association between first time motherhood and bonding and a negative association between higher education and income and bonding. CONCLUSIONS: This study was the first to report potential protective and risk factors to the maternal-fetal bonding process in women pregnant during the COVID-19 pandemic. Unique COVID-19 concerns exist; however, anxiety and COVID-19 concerns do not appear to undermine maternal-fetal bonding while active depressive symptomatology may negatively influence bonding; interventions increasing maternal resilience may be particularly valuable.

Harnessing the paradoxical phenotypes of APOE ɛ2 and APOE ɛ4 to identify genetic modifiers in Alzheimer's disease.

The strongest genetic risk factor for idiopathic late-onset Alzheimer's disease (LOAD) is apolipoprotein E (APOE) ɛ4, while the APOE ɛ2 allele is protective. However, there are paradoxical APOE ɛ4 carriers who remain disease-free and APOE ɛ2 carriers with LOAD. We compared exomes of healthy APOE ɛ4 carriers and APOE ɛ2 Alzheimer's disease (AD) patients, prioritizing coding variants based on their predicted functional impact, and identified 216 genes with differential mutational load between these two populations. These candidate genes were significantly dysregulated in LOAD brains, and many modulated tau- or ß42-induced neurodegeneration in Drosophila. Variants in these genes were associated with AD risk, even in APOE ɛ3 homozygotes, showing robust predictive power for risk stratification. Network analyses revealed involvement of candidate genes in brain cell type-specific pathways including synaptic biology, dendritic spine pruning and inflammation. These potential modifiers of LOAD may constitute novel biomarkers, provide potential therapeutic intervention avenues, and support applying this approach as larger whole exome sequencing cohorts become available.

Predicting phenotype from genotype: Improving accuracy through more robust experimental and computational modeling.

Computational prediction yields efficient and scalable initial assessments of how variants of unknown significance may affect human health. However, when discrepancies between these predictions and direct experimental measurements of functional impact arise, inaccurate computational predictions are frequently assumed as the source. Here, we present a methodological analysis indicating that shortcomings in both computational and biological data can contribute to these disagreements. We demonstrate that incomplete assaying of multifunctional proteins can affect the strength of correlations between prediction and experiments; a variant's full impact on function is better quantified by considering multiple assays that probe an ensemble of protein functions. Additionally, many variants predictions are sensitive to protein alignment construction and can be customized to maximize relevance of predictions to a specific experimental question. We conclude that inconsistencies between computation and experiment can often be attributed to the fact that they do not test identical hypotheses. Aligning the design of the computational input with the design of the experimental output will require cooperation between computational and biological scientists, but will also lead to improved estimations of computational prediction accuracy and a better understanding of the genotype-phenotype relationship.