Secondary (additional) findings from the 100,000 Genomes Project: Disease manifestation, health care outcomes, and costs of disclosure.

PURPOSE: The UK 100,000 Genomes Project offered participants screening for additional findings (AFs) in genes associated with familial hypercholesterolemia (FH) or hereditary cancer syndromes including breast/ovarian cancer (HBOC), Lynch, familial adenomatous polyposis, MYH-associated polyposis, multiple endocrine neoplasia (MEN), and von Hippel-Lindau. Here, we report disclosure processes, manifestation of AF-related disease, outcomes, and costs. METHODS: An observational study in an area representing one-fifth of England. RESULTS: Data were collected from 89 adult AF recipients. At disclosure, among 57 recipients of a cancer-predisposition-associated AF and 32 recipients of an FH-associated AF, 35% and 88%, respectively, had personal and/or family history evidence of AF-related disease. During post-disclosure investigations, 4 cancer-AF recipients had evidence of disease, including 1 medullary thyroid cancer. Six women with an HBOC AF, 3 women with a Lynch syndrome AF, and 2 individuals with a MEN AF elected for risk-reducing surgery. New hyperlipidemia diagnoses were made in 6 FH-AF recipients and treatment (re-)initiated for 7 with prior hyperlipidemia. Generating and disclosing AFs in this region cost £1.4m; £8680 per clinically significant AF. CONCLUSION: Generation and disclosure of AFs identifies individuals with and without personal or familial evidence of disease and prompts appropriate clinical interventions. Results can inform policy toward secondary findings.

Germline variant testing in serrated polyposis syndrome.

BACKGROUND AND AIM: Serrated polyposis syndrome (SPS) is now known to be the commonest polyposis syndrome. Previous analyses for germline variants have shown no consistent positive findings. To exclude other polyposis syndromes, 2019 British Society of Gastroenterology (BSG) guidelines advise gene panel testing if the patient is under 50 years, there are multiple affected individuals within a family, or there is dysplasia within any of the polyps. METHODS: A database of SPS patients was established at the Oxford University Hospitals NHS Foundation Trust. Patients were referred for genetic assessment based on personal and family history and patient preference. The majority were tested for a hereditary colorectal cancer panel including MUTYH, APC, PTEN, SMAD4, BMPR1A, STK11, NTLH1, POLD1, POLE, GREM1 (40-kb duplication), PMS2, and Lynch syndrome mismatch repair genes. RESULTS: One hundred and seventy-three patients were diagnosed with SPS based on World Health Organization 2019 criteria between February 2010 and December 2020. The mean age of diagnosis was 54.2 ± 16.8 years. Seventy-three patients underwent genetic testing and 15/73 (20.5%) were found to have germline variants, of which 7/73 (9.6%) had a pathogenic variant (MUTYH n = 2, SMAD4 n = 1, CHEK2 n = 2, POLD1 n = 1, and RNF43 n = 1). Only 60% (9/15) of these patients would have been recommended for gene panel testing according to current BSG guidelines. CONCLUSIONS: A total of 20.5% of SPS patients tested were affected by heterozygous germline variants, including previously unreported associations with CHEK2 and POLD1. This led to a change in management in seven patients (9.6%). Current recommendations may miss SPS associated with germline variants, which is more common than previously anticipated.

Using the Dynamic Appraisal of Situational Aggression (DASA) to assess the impact of unit atmosphere on violence risk assessment.

WHAT IS KNOWN ON THE SUBJECT: Research suggests that the Dynamic Appraisal of Situational Aggression (DASA) is a useful risk assessment instrument to identify individuals who might be at risk of aggression in mental health inpatient units. Although, risk assessment research has typically focused on an individual's risk of aggression, recent research has begun exploring whether the DASA could be used to assess the likelihood that a group of patients would be aggressive. WHAT THE PAPER ADDS TO EXISTING KNOWLEDGE: While the DASA was useful for assessing whether an individual was likely to be aggressive, the group average score was not a useful indicator for the likelihood of aggression once the individual DASA score was taken into consideration. Unexpectedly, patients who were assessed as high risk on the DASA were more likely to be aggressive on settled units compared to unsettled units, which included other individuals whose risk was elevated. WHAT ARE THE IMPLICATIONS FOR PRACTICE: There is not enough evidence to suggest that the group DASA average improves the identification of aggression above the individual DASA score. ABSTRACT: INTRODUCTION: The Dynamic Appraisal of Situational Aggression (DASA) is an inpatient aggression risk assessment instrument. Recently, research explored whether the unit atmosphere, as indicated by a unit's average DASA score, was related to inpatient aggression risk, but failed to control for individual risk. AIM: Investigate whether the DASA unit average score or an interaction between the unit average and an individual patient's DASA score was related to the likelihood that an individual would act aggressively. METHOD: Cox regression with repeated assessments and recurrent events was used to analyse 11,243 DASA risk assessments of 113 inpatients collected via retrospective file review. RESULTS: The unit DASA average score was not related to aggression towards staff. There was a negative interaction between the individual and the unit DASA average scores when identifying patient-to-patient aggression; high-risk patients engaged in less aggression when the unit average was heightened relative to units with lower DASA average scores. DISCUSSION: It is possible that there were more nursing interventions and/or patients engaged in greater self-regulation on unsettled units, thus reducing aggression. IMPLICATIONS FOR PRACTICE: Currently, there is insufficient evidence to suggest that the unit average score should be used to supplement individual DASA scores to identify aggression risk.

Clonal expansion of secondary mitochondrial DNA deletions associated with spinocerebellar ataxia type 28.

IMPORTANCE: Progressive external ophthalmoplegia (PEO) is a common feature in adults with mitochondrial (mt) DNA maintenance disorders associated with somatic mtDNA deletions in muscle, yet the causal genetic defect in many patients remains undetermined. OBSERVATIONS: Whole-exome sequencing identified a novel, heterozygous p.(Gly671Trp) mutation in the AFG3L2 gene encoding an mt protease--previously associated with dominant spinocerebellar ataxia type 28 disease--in a patient with indolent ataxia and PEO. Targeted analysis of a larger, genetically undetermined cohort of patients with PEO with suspected mtDNA maintenance abnormalities identified a second unrelated patient with a similar phenotype and a novel, heterozygous p.(Tyr689His) AFG3L2 mutation. Analysis of patient fibroblasts revealed mt fragmentation and decreased AFG3L2 transcript expression. Western blotting of patient fibroblast and muscle showed decreased AFG3L2 protein levels. CONCLUSIONS AND RELEVANCE: Our observations suggest that AFG3L2 mutations are another important cause, albeit rare, of a late-onset ataxic PEO phenotype due to a disturbance of mtDNA maintenance.