Alexandra Murray

A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD

The chromosome 9p21 amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) locus contains one of the last major unidentified autosomal-dominant genes underlying these common neurodegenerative diseases. We have previously shown that a founder haplotype, covering the MOBKL2b, IFNK, and C9ORF72 genes, is present in the majority of cases linked to this region. Here we show that there is a large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72 on the affected haplotype. This repeat expansion segregates perfectly with disease in the Finnish population, underlying 46.0% of familial ALS and 21.1% of sporadic ALS in that population. Taken together with the D90A SOD1 mutation, 87% of familial ALS in Finland is now explained by a simple monogenic cause. The repeat expansion is also present in one-third of familial ALS cases of outbred European descent, making it the most common genetic cause of these fatal neurodegenerative diseases identified to date.

NSD1 Mutations Are the Major Cause of Sotos Syndrome and Occur in Some Cases of Weaver Syndrome but Are Rare in Other Overgrowth Phenotypes

Sotos syndrome is a childhood overgrowth syndrome characterized by a distinctive facial appearance, height and head circumference >97th percentile, advanced bone age, and developmental delay. Weaver syndrome is characterized by the same criteria but has its own distinctive facial gestalt. Recently, a 2.2-Mb chromosome 5q35 microdeletion, encompassing NSD1, was reported as the major cause of Sotos syndrome, with intragenic NSD1 mutations identified in a minority of cases. We evaluated 75 patients with childhood overgrowth, for intragenic mutations and large deletions of NSD1. The series was phenotypically scored into four groups, prior to the molecular analyses: the phenotype in group 1 (n=37) was typical of Sotos syndrome; the phenotype in group 2 (n=13) was Sotos-like but with some atypical features; patients in group 3 (n=7) had Weaver syndrome, and patients in group 4 (n=18) had an overgrowth condition that was neither Sotos nor Weaver syndrome. We detected three deletions and 32 mutations (13 frameshift, 8 nonsense, 2 splice-site, and 9 missense) that are likely to impair NSD1 functions. The truncating mutations were spread throughout NSD1, but there was evidence of clustering of missense mutations in highly conserved functional domains between exons 13 and 23. There was a strong correlation between presence of an NSD1 alteration and clinical phenotype, in that 28 of 37 (76%) patients in group 1 had NSD1 mutations or deletions, whereas none of the patients in group 4 had abnormalities of NSD1. Three patients with Weaver syndrome had NSD1 mutations, all between amino acids 2142 and 2184. We conclude that intragenic mutations of NSD1 are the major cause of Sotos syndrome and account for some Weaver syndrome cases but rarely occur in other childhood overgrowth phenotypes.

The stigmatising implications of presenting schizophrenia as a genetic disease.

This study aimed to investigate the hypothesis that belief in a genetic aetiology of schizophrenia will increase the stigma associated with the disorder. Levels of five potentially stigmatising attitudes were compared in two groups of participants who had read a vignette describing an individual who has schizophrenia. In one group the disorder was explained as being caused by ‘genetic’ factors, and in the other by ‘environmental’ factors. This study found that three of the five potentially stigmatising attitudes measured were increased when participants read a vignette with a genetic causation rather than an environmental causation. Firstly, genetic attributions increased levels of associative stigma towards close relatives (p < 0.001). Secondly, participants viewed recovery as less likely when genetic factors were implicated as causative (p < 0.001). Finally, there was also an increased perception of the character’s “dangerousness” when the condition was explained by genetic factors (p < 0.05). Contrary to previous research was the finding that perceived aetiology had no effect on participant’s desire for social distance from an affected individual. Neither did perceived aetiology influence beliefs about moral accountability. The implications of these findings suggest that genetic counsellors and other health professionals, who are providing genetic information to those affected by schizophrenia should be aware of the possibility that a genetic explanation of schizophrenia could increase potentially stigmatising attitudes towards their clients and their clients’ families. It is also possible that individuals with a diagnosis of schizophrenia may themselves form deterministic interpretations of the genetic information they receive and subsequently be less likely to adopt behavioural advice or adhere to treatment. Counsellors and health professionals should strive to present information in a balanced manner, ensuring recipients understand the multi-factorial causes of the disease.

Uptake of risk-reducing surgery in BRCA gene carriers in Wales, UK

Women who inherit a mutated copy of the BRCA gene have a higher lifetime risk of developing breast cancer. No large epidemiological studies exist looking at BRCA mutation carriers in UK populations. All patients with BRCA1/BRCA2 mutation identified between 1995 and 2015 were included. Individuals were identified from a prospectively gathered data base. Genetics case‐notes were obtained and retrospective analysis performed. 581 female BRCA mutation carriers were identified with a median age of 34 (18‐81) at the time of testing. Of the 301 women who underwent diagnostic testing (symptomatic) 246 had been diagnosed with breast cancer, 89 with ovarian cancer and 37 had both at time of testing. Median age at diagnostic test was 51 (25‐81). 33% of women underwent risk‐reducing mastectomies (RRM); median age at surgery 45. This compares with 37% of women in this diagnostic group who underwent Risk‐reducing bilateral salpingo‐oopherectomies (RRBSO) at a median age of 46. Two hundred and eighty women underwent predictive testing (family history, asymptomatic), median age 36 (18‐81). 34% of women in this predictive group underwent RRM, median age 37. There was a 29% uptake of RRBSO (median age 44 years). Fifteen women (5%) developed breast cancer after being tested; none of these had undergone RRS. This unique study of all BRCA mutation carriers in Wales shows considerable variation in uptake of RRS. The decision to undergo RRS is complex and involves a number of factors, including a womans age and life stage. As BRCA testing becomes more frequent and more gene mutation carriers are identified there will be significant implications for service allocation, screening demands, and provision of risk‐reducing surgery for this high‐risk patient group.

32 Improving patient and public involvement in end of life care research

Introduction Members of the Marie Curie (MC) Expert Voices Group (EVG) have all cared for someone at the end of life. Research EVG (REVG) members use this experience to contribute to research. To improve Patient and Public Involvement (PPI) in end of life research they used motivation theory to review case studies of their contributions Aim(s) To improve the quality of PPI in end of life care (EOLC) research through consideration of motivation, using REVG case studies. Method(s) Review case studies of REVG involvement in EOLC research. Note factors contributing to participant sense of efficacy. Explore alignment with participant professed reasons for contributing to research thus draw together key factors promoting successful PPI. Results Case Studies of REVG involvement at all stages of research cycles included: • Reviewing research submissions e.g. Research Centre QQR • Questionnaire design and wording e.g. Delphi study on advance care planning • Consensus days e.g. Bereavement consensus days • Dissemination e.g. Presentations to government. Brain Tumour information sheet • Impact e.g. Use of case studies for review publications Factors found to contribute to participant sense of efficacy in these examples included: • Targeted informative invitations • Clear jargon free instructions • Good facilitation drawing out participant experiences Ensuring alignment with participant’s reasons for action included: • Opportunities to use all expertise • Understanding the range of participant goals and planning to allow them to be met Conclusion(s) PPI may be more effective if participant motivational needs are understood and planned for. References . Bandura, A. (1993). Perceived self-efficacy in cognitive development and functioning. Educational Psychologist, 28, 117–148. . Csikszentmihalyi, M. (1997b). Finding flow. New York: Basic Books. . de Charms, R. (1976). Enhancing motivation. New York: Irvington. . Deci, E. L. (1980). The psychology of self-determination. Lexington MA: D. C. Heath. . Maslow, A. H. (1968). Towards a psychology of being. New York: Van Nostrand-Rheinhold. . Yin, R. (1994). Case study research: Design and methods (2nd edn.). Thousand Oaks, CA: Sage Publishing.