Neurology

Ataxia, chorea and other hyperkinetic movement disorders are frequently seen in the neurology clinic but fall within the ‘rare-disease’ category with an overall frequency of around 5-10/100,000. Ataxia is genetically defined in around 60% of patients and Huntington’s disease (HD) is diagnosed in around 80% of the choreiform conditions but nearly all are currently untreatable. Teams within GeCIP have contributed to the increase in molecular diagnosis in this group but many still do not have a genetic diagnosis. There are excellent UK and European collaborations for gene identification, and validation of potential pathogenic variants as well as novel assays for investigating the pathogenicity, understanding disease mechanisms and carrying out novel drug screening.

One in six people aged 80 and over have dementia, while early onset dementias (<65 years old) affect around 40,000 people in the UK. Alzheimer’s disease (AD) and frontotemporal dementia (FTD) are the commonest causes of dementia and thought to explain 50–70% of all cases. After age, a family history of AD/FTD is the most important risk factor and studies of dizygotic and monozygotic twin pairs have revealed heritability estimates of between 60% and 80%. Our greatest understanding of AD, FTD and other causes of dementia has come from the identification of inherited disease genes. In AD, three autosomal dominant genes; APP, PSEN1, and PSEN2 account for around 65% of early onset disease.
Important risk factors for late onset AD also exist, such as ApoE4. In FTD 40% of patients have a family history and the important genes identified include MAPT, GRN and C9ORF72. Overall, mutations in GRN, MAPT and C9ORF72 together account for 17% of FTD cases (mutations in VCP and CHMP2B are rare, each explaining less than 1% of the familial FTD).

Motor neurone disease (MND, also called a myotrophic lateral sclerosis, ALS) is a relentlessly progressive neurodegenerative disorder with just three years average survival. Overlap in the pathology and genetics of MND and FTD is so great that they are now considered phenotypic variants of a common disease spectrum.

An important part of the 100,000 genomes project is the implementation and long-term sustainability of genome sequencing as an NHS diagnostic test for the UK population. Transferring the experience, knowledge and techniques gained from the 100,000 genomes project into the diagnostic laboratory setting will be essential in establishing this important test into routine NHS diagnostic test.

Several of the larger diagnostic genetics laboratories around the UK have already implemented next generation sequencing gene panels into practice but the use of genome sequencing will be the ultimate genetic test. There will be a number of important tasks to perfect in the development of stringent diagnostic genome sequencing that range from data handling and long term storage of results, through to genomic coverage and variant interpretation. In addition, in the first instance genome sequencing will likely be combined with Sanger sequencing but as laboratories become more experienced and confident the use of Sanger sequencing will likely become redundant.

Rare inherited neurological disorders such as hereditary spastic paraplegia (HSP), leukodystrophy, moyamoya disease and idiopathic basal ganglia calcification are separately rare with individual disease incidences of around 1-2 per 100,000 but altogether they account for a significant proportion of neurological disease. The molecular diagnostic rate varies between these disorders, in HSP around 60-70% of the genes have been identified but in disorders such as moyamoya disease the number of disease genes are few. No specific treatments are available in these conditions and identifying disease genes and pathways in these groups will not only allow an accurate diagnosis but also reveal important information on overlapping pathways in commoner neurological disorders.

Mitochondrial disorders have emerged as one of the largest groups of inherited neurometabolic disease. Epidemiological studies indicate that they affect approximately 1:5,000 of the population.(1) A molecular diagnosis is only possible in approximately half of these families. A proportion have mutations of mitochondrial DNA (mtDNA) responsible for their disorder. The remainder have a presumed nuclear genetic defect which can be autosomal dominant, autosomal recessive or X-linked. (2)

Whole exome studies have had a major impact on the molecular diagnosis of mitochondrial disorders (e.g. (3)). This has led to the identification of a wide array of new genetic causes for defects of the mitochondrial respiratory chain, revealing new mechanisms potentially amenable to treatment. However, conventional exome approaches have only identified molecular basis in approximately 60% of families, leaving a large minority without a genetic diagnosis.