scholarly journals Genomic analyses in a large clinical cohort reveal high prevalence of MECP2 variants associated with neuropsychiatric phenotypes in adulthood

2021 ◽  
Author(s):  
Claudia Gonzaga-Jauregui ◽  
Alina Kurolap ◽  
Lauren Walsh ◽  
Jeffrey Staples ◽  
Cristopher Van Hout ◽  
...  
Keyword(s):  
Major Depression ◽  
Rett Syndrome ◽  
Clinical Care ◽  
Clinical Information ◽  
Neuropsychiatric Disorders ◽  
Mecp2 Gene ◽  
Sequencing Data ◽  
Clinical Cohort ◽  
Pathogenic Variants ◽  
Increased Risk

Abstract Purpose: To evaluate the phenotypes of individuals with pathogenic and likely pathogenic variants in the MECP2 gene. Methods: We surveyed exome sequencing data from a large clinical care cohort for deleterious variation in the MECP2 gene. We reviewed de-identified clinical information for these individuals to interrogate for neurodevelopmental and neuropsychiatric phenotypes. Results: We identified pathogenic and likely pathogenic variants in MECP2 in individuals with typical and atypical Rett syndrome, and neuropsychiatric phenotypes, and estimate a prevalence of MECP2-associated disorders of 1 in 2,645 individuals. We observed a 7.45x increased relative risk of neuropsychiatric phenotypes, especially major depression, in adult individuals with deleterious variants in MECP2 without a diagnosis of Rett syndrome. Male individuals with missense pathogenic variants in MECP2 appear to have more severe neuropsychiatric phenotypes. Conclusions: We identified and report individuals with heterozygous pathogenic variants in MECP2 and their phenotypes in a large clinical cohort. The observed prevalence of MECP2-associated disorders in our cohort is higher than estimated in the literature. Individuals with pathogenic variants in MECP2 can survive into adulthood but are at increased risk of developing neuropsychiatric disorders, mainly major depression. Pathogenic variation in MECP2 is a likely important contributor to neuropsychiatric disorders in the general population.

scholarly journals Diagnostic exome-based preconception carrier testing in consanguineous couples: results from the first 100 couples in clinical practice

2021 ◽  
Author(s):  
Suzanne C. E. H. Sallevelt ◽  
Alexander P. A. Stegmann ◽  
Bart de Koning ◽  
Crool Velter ◽  
Anja Steyls ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Rare Variants ◽  
Clinical Care ◽  
Carrier Testing ◽  
Carrier Status ◽  
Routine Diagnostics ◽  
Affected Offspring ◽  
Pathogenic Variants ◽  
Increased Risk ◽  
Genetics And Genomics

Abstract Purpose Consanguineous couples are at increased risk of being heterozygous for the same autosomal recessive (AR) disorder(s), with a 25% risk of affected offspring as a consequence. Until recently, comprehensive preconception carrier testing (PCT) for AR disorders was unavailable in routine diagnostics. Here we developed and implemented such a test in routine clinical care. Methods We performed exome sequencing (ES) for 100 consanguineous couples. For each couple, rare variants that could give rise to biallelic variants in offspring were selected. These variants were subsequently filtered against a gene panel consisting of ~2,000 genes associated with known AR disorders (OMIM-based). Remaining variants were classified according to American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines, after which only likely pathogenic and pathogenic (class IV/V) variants, present in both partners, were reported. Results In 28 of 100 tested consanguineous couples (28%), likely pathogenic and pathogenic variants not previously known in the couple or their family were reported conferring 25% risk of affected offspring. Conclusion ES-based PCT provides a powerful diagnostic tool to identify AR disease carrier status in consanguineous couples. Outcomes provided significant reproductive choices for a higher proportion of these couples than previous tests.

scholarly journals Interruptions to Attending Physician Rounds and Their Effect on Resident Education

2021 ◽  
Vol 13 (2) ◽  
pp. 266-275
Author(s):  
Julia Armendariz ◽  
Carla Tamayo ◽  
Justin Slade ◽  
Ilana Belitskaya-Lévy ◽  
Caroline Gray ◽  
...  
Keyword(s):  
Clinical Care ◽  
Text Message ◽  
Clinical Information ◽  
Emotional Reactions ◽  
Common Source ◽  
Structured Interviews ◽  
Negative Effects ◽  
Positive Effects ◽  
Increased Risk ◽  
Attending Rounds

ABSTRACT Background Daily attending rounds (AR) are a cornerstone of teaching and patient care in academic health centers. Interruptions in health care are common and can cause increased risk of errors, incomplete work, and decreased decision-making accuracy. Interruptions to AR may diminish a trainee's capacity to learn and retain information. Objective We characterized and quantified interruptions that occur during AR. Methods We used a mixed-methods design combining a prospective observational study with a qualitative study. AR were observed January to March 2020 to characterize interruptions, followed by semi-structured interviews with the observed physicians to elucidate the effect of interruptions on workflow and the educational value of rounds. Results There were 378 observed interruptions over the course of 30 AR sessions, averaging 12.6 (range 1–22, median 13) interruptions per rounding session. Bedside nursing staff was the most common source of interruptions (25%) and consultant recommendations was the most common topic of interruption (21%). Most interruptions occurred during patient presentations (76%), and the most common method of interaction was text message (24%). Most team members described negative effects of interruptions, including loss of focus and missing critical clinical information; some also reported that certain interruptions had positive effects on education and clinical care. Interns were more likely to report negative emotional reactions to interruptions. Conclusions AR are frequently interrupted for non-urgent topics by a variety of methods and sources. Negative effects included loss of focus, missed information, and increased stress. Proactive communication, particularly between physicians and nurses, was suggested to reduce interruptions.

scholarly journals Intellectual disability and other neuropsychiatric outcomes in high-risk children of mothers with schizophrenia, bipolar disorder and unipolar major depression

2012 ◽  
Vol 200 (4) ◽  
pp. 282-289 ◽  
Author(s):  
Vera A. Morgan ◽  
Maxine L. Croft ◽  
Giulietta M. Valuri ◽  
Stephen R. Zubrick ◽  
Carol Bower ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Intellectual Disability ◽  
Major Depression ◽  
Pervasive Developmental Disorders ◽  
Developmental Disorders ◽  
Unipolar Depression ◽  
Neuropsychiatric Disorders ◽  
Increased Risk ◽  
Obstetric Factors ◽  
Unipolar Major Depression

BackgroundRecent evidence points to partially shared genetics of neuropsychiatric disorders.AimsWe examined risk of intellectual disability and other neuropsychiatric outcomes in 3174 children of mothers with schizophrenia, bipolar disorder or unipolar major depression compared with 3129 children of unaffected mothers.MethodWe used record linkage across Western Australian population-based registers. The contribution of obstetric factors to risk of intellectual disability was assessed.ResultsChildren were at significantly increased risk of intellectual disability with odds ratios (ORs) of 3.2 (95% CI 1.8–5.7), 3.1 (95% CI 1.9–4.9) and 2.9 (95% CI 1.8–4.7) in the maternal schizophrenia, bipolar disorder and unipolar depression groups respectively. Multivariate analysis suggests familial and obstetric factors may contribute independently to the risk. Although summated labour/delivery complications (OR = 1.4, 95% CI 1.0–2.0) just failed to reach significance, neonatal encephalopathy (OR = 7.7, 95% CI 3.0–20.2) and fetal distress (OR = 1.8, 95% CI 1.1–2.7) were independent significant predictors. Rates of rare syndromes in children of mothers with mental disorder were well above population rates. Risk of pervasive developmental disorders, including autism, was significantly elevated for children of mothers with bipolar disorder. Risk of epilepsy was doubled for children of mothers with unipolar depression.ConclusionsOur findings provide epidemiological support for clustering of neuropsychiatric disorders. Further larger epidemiological studies are warranted.

scholarly journals UTILIZATION OF WHOLE EXOME SEQUENCING DATA TO IDENTIFY CLINICALLY RELEVANT PHARMACOGENOMIC VARIANTS IN INFLAMMATORY BOWEL DISEASE

2021 ◽  
Vol 27 (Supplement_1) ◽  
pp. S32-S32
Author(s):  
Daniel Mulder ◽  
Sam Khalouei ◽  
Neil Warner ◽  
Claudia Gonzaga-Jauregui ◽  
Peter Church ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Clinical Care ◽  
Family Members ◽  
Standard Of Care ◽  
Sequencing Data ◽  
Whole Exome ◽  
Variant Filtering ◽  
Increased Risk ◽  
Whole Exome Sequencing Data

Abstract Objectives We hypothesized that variants within clinically relevant pharmacogenes could be identified using a whole exome sequencing (WES) dataset derived from a cohort of over 1000 IBD patients. Methods Pediatric patients diagnosed with IBD underwent WES. We selected 18 genes with supporting literature where specific exonic variants would influence clinical care. Results We identified actionable pharmacogenes variants in 63% of patients. Importantly, 5% of IBD patients were at risk for serious adverse effects from anaesthesia and 3% were at increased risk for thrombosis. Conclusions We identified exonic variants in the majority of our IBD patients that directly impact clinical care. Flowchart of our pharmacogenomic analysis pipeline. After enrolment (n=2309), each patient underwent whole exome sequencing and sequence alignment. Available family members were also sequenced. Analyzed samples were limited to patients and family members with IBD (n=1097). Pharmacogenes relevant to patients with IBD were identified by literature review and evaluation of pharmGKB (total of 18 genes). Variant filtering was performed using Stargazer and GEMINI frameworks. In our cohort, there were 8 relevant pharmacogenes with variants that would alter clinical care based on current guidelines and standard of care. 63% of the patients had at least one variant that could impact care.

scholarly journals International initiative for a curated SDHB variant database improving the diagnosis of hereditary paraganglioma and pheochromocytoma

2021 ◽  
pp. jmedgenet-2020-107652
Author(s):  
Laurene Ben Aim ◽  
Eamonn R Maher ◽  
Alberto Cascon ◽  
Anne Barlier ◽  
Sophie Giraud ◽  
...  
Keyword(s):  
Clinical Care ◽  
Laboratory Diagnosis ◽  
Variants Of Unknown Significance ◽  
Pathogenic Variants ◽  
Increased Risk ◽  
Multistep Process ◽  
Variation Database ◽  
Consensus Classification ◽  
Variant Database ◽  
International Initiative

BackgroundSDHB is one of the major genes predisposing to paraganglioma/pheochromocytoma (PPGL). Identifying pathogenic SDHB variants in patients with PPGL is essential to the management of patients and relatives due to the increased risk of recurrences, metastases and the emergence of non-PPGL tumours. In this context, the ‘NGS and PPGL (NGSnPPGL) Study Group’ initiated an international effort to collect, annotate and classify SDHB variants and to provide an accurate, expert-curated and freely available SDHB variant database.MethodsA total of 223 distinct SDHB variants from 737 patients were collected worldwide. Using multiple criteria, each variant was first classified according to a 5-tier grouping based on American College of Medical Genetics and NGSnPPGL standardised recommendations and was then manually reviewed by a panel of experts in the field.ResultsThis multistep process resulted in 23 benign/likely benign, 149 pathogenic/likely pathogenic variants and 51 variants of unknown significance (VUS). Expert curation reduced by half the number of variants initially classified as VUS. Variant classifications are publicly accessible via the Leiden Open Variation Database system (https://databases.lovd.nl/shared/genes/SDHB).ConclusionThis international initiative by a panel of experts allowed us to establish a consensus classification for 223 SDHB variants that should be used as a routine tool by geneticists in charge of PPGL laboratory diagnosis. This accurate classification of SDHB genetic variants will help to clarify the diagnosis of hereditary PPGL and to improve the clinical care of patients and relatives with PPGL.

scholarly journals Use of SNP chips to detect rare pathogenic variants: retrospective, population based diagnostic evaluation

BMJ ◽  
2021 ◽  
pp. n214
Author(s):  
Weedon MN ◽  
Jackson L ◽  
Harrison JW ◽  
Ruth KS ◽  
Tyrrell J ◽  
...  
Keyword(s):  
Positive Predictive Value ◽  
Predictive Value ◽  
Population Based ◽  
Genome Project ◽  
Personal Genome ◽  
Uk Biobank ◽  
Sequencing Data ◽  
Snp Chip ◽  
Pathogenic Variants ◽  
The Uk

Abstract Objective To determine whether the sensitivity and specificity of SNP chips are adequate for detecting rare pathogenic variants in a clinically unselected population. Design Retrospective, population based diagnostic evaluation. Participants 49 908 people recruited to the UK Biobank with SNP chip and next generation sequencing data, and an additional 21 people who purchased consumer genetic tests and shared their data online via the Personal Genome Project. Main outcome measures Genotyping (that is, identification of the correct DNA base at a specific genomic location) using SNP chips versus sequencing, with results split by frequency of that genotype in the population. Rare pathogenic variants in the BRCA1 and BRCA2 genes were selected as an exemplar for detailed analysis of clinically actionable variants in the UK Biobank, and BRCA related cancers (breast, ovarian, prostate, and pancreatic) were assessed in participants through use of cancer registry data. Results Overall, genotyping using SNP chips performed well compared with sequencing; sensitivity, specificity, positive predictive value, and negative predictive value were all above 99% for 108 574 common variants directly genotyped on the SNP chips and sequenced in the UK Biobank. However, the likelihood of a true positive result decreased dramatically with decreasing variant frequency; for variants that are very rare in the population, with a frequency below 0.001% in UK Biobank, the positive predictive value was very low and only 16% of 4757 heterozygous genotypes from the SNP chips were confirmed with sequencing data. Results were similar for SNP chip data from the Personal Genome Project, and 20/21 individuals analysed had at least one false positive rare pathogenic variant that had been incorrectly genotyped. For pathogenic variants in the BRCA1 and BRCA2 genes, which are individually very rare, the overall performance metrics for the SNP chips versus sequencing in the UK Biobank were: sensitivity 34.6%, specificity 98.3%, positive predictive value 4.2%, and negative predictive value 99.9%. Rates of BRCA related cancers in UK Biobank participants with a positive SNP chip result were similar to those for age matched controls (odds ratio 1.31, 95% confidence interval 0.99 to 1.71) because the vast majority of variants were false positives, whereas sequence positive participants had a significantly increased risk (odds ratio 4.05, 2.72 to 6.03). Conclusions SNP chips are extremely unreliable for genotyping very rare pathogenic variants and should not be used to guide health decisions without validation.

scholarly journals Rare Germline Pathogenic Variants Identified by Multigene Panel Testing and the Risk of Aggressive Prostate Cancer

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1495
Author(s):  
Tú Nguyen-Dumont ◽  
James G. Dowty ◽  
Robert J. MacInnis ◽  
Jason A. Steen ◽  
Moeen Riaz ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Risk Prediction ◽  
Prediction Models ◽  
Risk Prediction Models ◽  
Aggressive Prostate Cancer ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Increased Risk ◽  
Predisposition Genes ◽  
Rare Genetic Variants

While gene panel sequencing is becoming widely used for cancer risk prediction, its clinical utility with respect to predicting aggressive prostate cancer (PrCa) is limited by our current understanding of the genetic risk factors associated with predisposition to this potentially lethal disease phenotype. This study included 837 men diagnosed with aggressive PrCa and 7261 controls (unaffected men and men who did not meet criteria for aggressive PrCa). Rare germline pathogenic variants (including likely pathogenic variants) were identified by targeted sequencing of 26 known or putative cancer predisposition genes. We found that 85 (10%) men with aggressive PrCa and 265 (4%) controls carried a pathogenic variant (p < 0.0001). Aggressive PrCa odds ratios (ORs) were estimated using unconditional logistic regression. Increased risk of aggressive PrCa (OR (95% confidence interval)) was identified for pathogenic variants in BRCA2 (5.8 (2.7–12.4)), BRCA1 (5.5 (1.8–16.6)), and ATM (3.8 (1.6–9.1)). Our study provides further evidence that rare germline pathogenic variants in these genes are associated with increased risk of this aggressive, clinically relevant subset of PrCa. These rare genetic variants could be incorporated into risk prediction models to improve their precision to identify men at highest risk of aggressive prostate cancer and be used to identify men with newly diagnosed prostate cancer who require urgent treatment.

scholarly journals Extended gene panel testing in lobular breast cancer

2021 ◽  
Author(s):  
Elke M. van Veen ◽  
D. Gareth Evans ◽  
Elaine F. Harkness ◽  
Helen J. Byers ◽  
Jamie M. Ellingford ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Genetic Testing ◽  
Detection Rate ◽  
Gene Panel ◽  
Lobular Breast Cancer ◽  
Germline Variants ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Gene Panel Testing ◽  
Increased Risk

AbstractPurpose: Lobular breast cancer (LBC) accounts for ~ 15% of breast cancer. Here, we studied the frequency of pathogenic germline variants (PGVs) in an extended panel of genes in women affected with LBC. Methods: 302 women with LBC and 1567 without breast cancer were tested for BRCA1/2 PGVs. A subset of 134 LBC affected women who tested negative for BRCA1/2 PGVs underwent extended screening, including: ATM, CDH1, CHEK2, NBN, PALB2, PTEN, RAD50, RAD51D, and TP53.Results: 35 PGVs were identified in the group with LBC, of which 22 were in BRCA1/2. Ten actionable PGVs were identified in additional genes (ATM(4), CDH1(1), CHEK2(1), PALB2(2) and TP53(2)). Overall, PGVs in three genes conferred a significant increased risk for LBC. Odds ratios (ORs) were: BRCA1: OR = 13.17 (95%CI 2.83–66.38; P = 0.0017), BRCA2: OR = 10.33 (95%CI 4.58–23.95; P < 0.0001); and ATM: OR = 8.01 (95%CI 2.52–29.92; P = 0.0053). We did not detect an increased risk of LBC for PALB2, CDH1 or CHEK2. Conclusion: The overall PGV detection rate was 11.59%, with similar rates of BRCA1/2 (7.28%) PGVs as for other actionable PGVs (7.46%), indicating a benefit for extended panel genetic testing in LBC. We also report a previously unrecognised association of pathogenic variants in ATM with LBC.

scholarly journals Diabetes and COVID19: a bidirectional relationship

2021 ◽  
Author(s):  
Ranjit Unnikrishnan ◽  
Anoop Misra
Keyword(s):  
Clinical Care ◽  
Severe Disease ◽  
Respiratory Involvement ◽  
Pancreatic Damage ◽  
Increased Risk ◽  
Bidirectional Relationship ◽  
Rapid Spread ◽  
Relationship Of ◽  
The Relationship ◽  
New Onset

AbstractThe advent and rapid spread of the coronavirus disease-2019 (COVID19) pandemic across the world has focused attention on the relationship of commonly occurring comorbidities such as diabetes on the course and outcomes of this infection. While diabetes does not seem to be associated with an increased risk of COVID19 infection per se, it has been clearly demonstrated that the presence of hyperglycemia of any degree predisposes to worse outcomes, such as more severe respiratory involvement, ICU admissions, need for mechanical ventilation and mortality. Further, COVID19 infection has been associated with the development of new-onset hyperglycemia and diabetes, and worsening of glycemic control in pre-existing diabetes, due to direct pancreatic damage by the virus, body’s stress response to infection (including cytokine storm) and use of diabetogenic drugs such as corticosteroids in the treatment of severe COVID19. In addition, public health measures taken to flatten the pandemic curve (such as lockdowns) can also adversely impact persons with diabetes by limiting their access to clinical care, healthy diet, and opportunities to exercise. Most antidiabetic medications can continue to be used in patients with mild COVID19 but switching over to insulin is preferred in severe disease.

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