Neuromuscular disease genetics in under-represented populations: increasing data diversity.

Neuromuscular diseases (NMDs) affect ∼15 million people globally. In high income settings DNA-based diagnosis has transformed care pathways and led to gene-specific therapies. However, most affected families are in low-to-middle income countries (LMICs) with limited access to DNA-based diagnosis. Most (86%) published genetic data is derived from European ancestry. This marked genetic data inequality hampers understanding of genetic diversity and hinders accurate genetic diagnosis in all income settings. We developed a cloud-based transcontinental partnership to build diverse, deeply-phenotyped and genetically characterized cohorts to improve genetic architecture knowledge, and potentially advance diagnosis and clinical management. We connected 18 centres in Brazil, India, South Africa, Turkey, Zambia, Netherlands and the UK. We co-developed a cloud-based data solution and trained 17 international neurology fellows in clinical genomic data interpretation. Single gene and whole exome data were analysed via a bespoke bioinformatics pipeline and reviewed alongside clinical and phenotypic data in global webinars to inform genetic outcome decisions. We recruited 6001 participants in the first 43 months. Initial genetic analyses 'solved' or 'possibly solved' ∼56% probands overall. In-depth genetic data review of the four commonest clinical categories (limb girdle muscular dystrophy, inherited peripheral neuropathies, congenital myopathy/muscular dystrophies and Duchenne/Becker muscular dystrophy) delivered a ∼59% 'solved' and ∼13% 'possibly solved' outcome. Almost 29% of disease causing variants were novel, increasing diverse pathogenic variant knowledge. Unsolved participants represent a new discovery cohort. The dataset provides a large resource from under-represented populations for genetic and translational research. In conclusion, we established a remote transcontinental partnership to assess genetic architecture of NMDs across diverse populations. It supported DNA-based diagnosis, potentially enabling genetic counselling, care pathways and eligibility for gene-specific trials. Similar virtual partnerships could be adopted by other areas of global genomic neurological practice to reduce genetic data inequality and benefit patients globally.

Mitochondrial DNA Analysis from Exome Sequencing Data Improves Diagnostic Yield in Neurological Diseases.

A rapidly expanding catalog of neurogenetic disorders has encouraged a diagnostic shift towards early clinical whole exome sequencing (WES). Adult primary mitochondrial diseases (PMDs) frequently exhibit neurological manifestations that overlap with other nervous system disorders. However, mitochondrial DNA (mtDNA) is not routinely analyzed in standard clinical WES bioinformatic pipelines. We reanalyzed 11,424 exomes, enriched with neurological diseases, for pathogenic mtDNA variants. Twenty-four different mtDNA mutations were detected in 64 exomes, 11 of which were considered disease causing based on the associated clinical phenotypes. These findings highlight the diagnostic uplifts gained by analyzing mtDNA from WES data in neurological diseases. ANN NEUROL 2021;89:1240-1247.

Analysis of DNM3 and VAMP4 as genetic modifiers of LRRK2 Parkinson's disease.

The LRRK2 gene has rare (p.G2019S) and common risk variants for Parkinson's disease (PD). DNM3 has previously been reported as a genetic modifier of the age at onset in PD patients carrying the LRRK2 p.G2019S mutation. We analyzed this effect in a new cohort of LRRK2 p.G2019S heterozygotes (n = 724) and meta-analyzed our data with previously published data (n = 754). VAMP4 is in close proximity to DNM3, and was associated with PD in a recent study, so it is possible that variants in this gene may be important. We also analyzed the effect of VAMP4 rs11578699 on LRRK2 penetrance. Our analysis of DNM3 in previously unpublished data does not show an effect on age at onset in LRRK2 p.G2019S carriers; however, the inter-study heterogeneity may indicate ethnic or population-specific effects of DNM3. There was no evidence for linkage disequilibrium between DNM3 and VAMP4. Analysis of sporadic patients stratified by the risk variant LRRK2 rs10878226 indicates a possible interaction between common variation in LRRK2 and VAMP4 in disease risk.

Leucine rich repeat kinase 2 (LRRK2) GLY2019SER mutation is absent in a second cohort of Nigerian Africans with Parkinson disease.

To date the LRRK2 p.G2019S mutation remains the most common genetic cause of Parkinson disease (PD) worldwide. It accounts for up to 6% of familial and approximately 1.5% of sporadic cases. LRRK2 has a kinase enzymatic domain which provides an attractive potential target for drug therapies and LRRK2 kinase inhibitors are in development. Prevalence of the p.G2019S has a variable ethnic and geographic distribution, the highest reported among Ashkenazi Jews (30% in patients with familial PD, 14% in sporadic PD, 2.0% in controls) and North African Berbers (37% in patients with familial PD, 41% in sporadic PD, and 1% in controls). Little is known about the frequency of the LRRK2 p.G2019S among populations in sub-Saharan Africa. Our group and others previously reported that the p.G2019S is absent in a small cohort of Nigerian PD patients and controls. Here we used Kompetitive Allele Specific PCR (KASP) assay to screen for the p.G2019S in a larger cohort of Black African PD patients (n = 126) and healthy controls (n = 54) from Nigeria. Our analysis confirmed that all patients and controls are negative for the p.G2019S mutation. This report provides further evidence that the LRRK2 p.G2019S is not implicated in PD in black populations from Nigeria and support the notion that p.G2019S mutation originated after the early human dispersal from sub-Saharan Africa. Further studies using larger cohorts and advance sequencing technology are required to underpin the genetic causes of PD in this region.

Truncating mutations in SPAST patients are associated with a high rate of psychiatric comorbidities in hereditary spastic paraplegia.

BACKGROUND: The hereditary spastic paraplegias (HSPs) are a rare and heterogeneous group of neurodegenerative disorders that are clinically characterised by progressive lower limb spasticity. They are classified as either 'pure' or 'complex' where spastic paraplegia is complicated with additional neurological features. Mutations in the spastin gene (SPAST) are the most common cause of HSP and typically present with a pure form. METHODS: We assessed in detail the phenotypic and genetic spectrum of SPAST-related HSP focused on 118 patients carrying SPAST mutations. RESULTS: This study, one of the largest cohorts of genetically confirmed spastin patients to date, contributes with the discovery of a significant number of novel SPAST mutations. Our data reveal a high rate of complex cases (25%), with psychiatric disorders among the most common comorbidity (10% of all SPASTpatients). Further, we identify a genotype-phenotype correlation between patients carrying loss-of-function mutations in SPAST and the presence of psychiatric disorders.

Vocation and avocation: leisure activities correlate with professional engagement, but not burnout, in a cross-sectional survey of UK doctors.

BACKGROUND: Sir William Osler suggested in 1899 that avocations (leisure activities) in doctors are related to an increased sense of vocation (professional engagement) and a decreased level of burnout. This study evaluated those claims in a large group of doctors practicing in the UK while taking into account a wide range of background variables. METHODS: A follow-up questionnaire was sent to 4,457 UK-qualified doctors who had been included in four previous studies of medical school selection and training, beginning in 1980, 1985, 1990 and 1989/1991. A total of 2,845 (63.8%) doctors returned the questionnaire. Questions particularly asked about work engagement, satisfaction with medicine as a career, and personal achievement (Vocation/engagement), stress, emotional exhaustion, and depersonalization (BurnedOut), and 29 different leisure activities (Avocation/Leisure), as well as questions on personality, empathy, work experience, and demography. RESULTS: Doctors reporting more Avocation/Leisure activities tended to be women, to have older children, to be less surface-rational, more extravert, more open to experience, less agreeable, and to fantasize more. Doctors who were more BurnedOut tended to be men, to be more sleep-deprived, to report a greater workload and less choice and independence in their work, to have higher neuroticism, lower extraversion and lower agreeableness scores, and to have lower self-esteem. In contrast, doctors with a greater sense of Vocation/engagement, tended to see more patients, to have greater choice and independence at work, to have a deep approach to work, to have a more supportive-receptive work environment, to be more extravert and more conscientious, and to report greater self-esteem.Avocation/Leisure activities correlated significantly with Vocation/engagement, even after taking into account 25 background variables describing demography, work, and personality, whereas BurnedOut showed no significant correlation with Avocation/Leisure activities. Popular Culture and High Culture did not differ in their influence on Vocation/engagement, although there was a suggestion that Depersonalization was correlated with more interest in Popular Culture and less interest in High Culture. CONCLUSION: In this cross-sectional study there is evidence, even after taking into account a wide range of individual difference measures, that doctors with greater Avocation/Leisure activities also have a greater sense of Vocation/Engagement. In contrast, being BurnedOut did not relate to Avocation/Leisure activities (but did relate to many other measures). Osler was probably correct in recommending to doctors that, 'While medicine is to be your vocation, or calling, see to it that you also have an avocation'.