Rare Disease Research Studies

Some people suffer from a rare medical condition which is thought to have a genetic cause. Studying the genome of a person with a rare disease can help researchers to discover whether known mutations may be causing their health problem. Genomic analysis may also identify new genes or other genetic causes of the condition.

The Scottish Genomes Partnership is funding 4 research studies which are seeking new information about the genetic causes of rare conditions. These are:

  • Motor Neurone Disease (MND; aka amyotrophic lateral sclerosis)

  • Eye malformation

  • Microcephaly disorders (extreme reduction in brain size) and primordial dwarfism

  • Disorders of sex development

More information about these studies can be found below.

Motor Neurone Disease

Motor Neurone Disease (MND) is a rapidly progressive and fatal neurodegenerative disorder, characterised by loss of motor neurone function. Substantial progress in understanding the genetic basis of MND has occurred in the last 10 years, but the existing data suggest that additional genes remain to be found.

Professor Tim Aitman (Director of CGEM, University of Edinburgh) is leading the SGP Motor Neurone Disease research project

The SGP research study is using DNA samples and phenotype data from the Scottish Motor Neurone Disease Register as well as the Edinburgh Brain Bank. Whole genome sequencing has been carried out at Edinburgh Genomics on 337 MND DNA samples to date and sequencing of further cases is in progress. Initial analysis is underway.

To date, pathogenic or loss of function variants in known genes have been identified in 17% of these Scottish cases. Frequencies of identified variants are being compared to 1372 ethnically matched genomes from the Lothian Birth Cohort (Deary et al 2012, Nature, 482, 212-215) that were also sequenced at Edinburgh Genomics.

International collaborations have been established for federation and data sharing.

The results from this research are anticipated to make a significant contribution to the ongoing international genome sequencing activities in MND.

Eye Malformation

Some individuals are born with severe eye malformations which have a genetic cause. Improving knowledge about how these genes go wrong helps us to understand normal development, can help in ongoing treatment, and may help prevent similar problems in the future.

Professor David FitzPatrick (Joint Section Head: Disease Mechanisms, MRC Human Genetics Unit) is leading the SGP Eye Malformation research project

The SGP whole genome sequencing study is making use of resource of more than 5000 samples from individuals with severe eye malformations and their family members, which have been collected over many years by researchers at the MRC Human Genetics Unit in Edinburgh. This cohort of samples has been instrumental in identifying causative genes in a variety of eye malformations, including the two major loci that cause anophthalmia (missing eyes). Using this resource, whole exome sequencing (which identifies protein coding regions of the genome) has been carried out on cases of severe bilateral eye malformation with some success. However, the causes of many eye malformations are still unknown.

Whole genome sequencing of 142 samples is now in progess through SGP. The data analysed to date are of extremely high quality. Work is underway with bioinformaticians to improve the calling of plausible gene variants and explore structural variation of the genome which may be a cause of the eye malformation.

More information about Professor FitzPatrick's MRC-funded research on Disease Mechanisms can be found here.

Microcephaly and Primordial Dwarfism

Microcephaly disorders are characterised by an extreme reduction in brain size. Individuals with primordial dwarfism are often described as the "smallest people in the world".

Professor Andrew Jackson

(Programme Leader, MRC Human Genetics Unit) is leading the SGP Microcephalic Dwarfism project

The SGP microcephalic dwarfism whole genome sequencing study is making use of an established collection of more than 2000 samples from families with microcephaly disorders.  From this resource, gene mapping and exome sequencing studies have resulted in the identification of 17 disease genes which encode fundamental components of the cell cycle machinery and genome stability pathways. However, the molecular basis of ~50% of patients remains to be established, signifying that a substantial number of additional disease causing genes remain to be identified.

The final whole genome sequencing is now in progress at Edinburgh Genomics with support from SGP. Analyses are seeking to identify coding and regulatory mutations as the molecular basis of these primordial dwarfism cases. Two new research findings on the causes of Saul-Wilson syndrome and IMAGe syndrome have already been published from this work.

More information about Professor Jackson's MRC-funded research programme can be found here.

Disorders of Sex Development

Disorders of sex development (DSD) are a group of rare conditions affecting the reproductive system, in which the reproductive organs and genitals do not develop as expected.

Professor Ed Tobias

(Professor of Genetic Medicine, University of Glasgow) is leading the SGP Disorders of Sex Development (DSD) project

The overall prevalence of DSD has been reported to be around 1 in 300 people. In the majority of cases, using existing methods, no molecular diagnosis is made, increasing the stress for families and the difficulties in management. It is anticipated, however, that next generation sequencing (NGS), will permit the detection of pathogenic mutations in a greater proportion of cases than has been possible to date. In addition, NGS is identifying important new DSD genes. The detection of an underlying causative gene variant can have important benefits for the individual and their family.

Initial analysis of research data for this study is underway, obtained following the high-quality whole genome sequencing carried out at Edinburgh Genomics.

The multi-disciplinary DSD-related team in Glasgow (including staff from clinical and laboratory genetics, paediatric endocrinology and clinical biochemistry), meets monthly, with video-conference links to the other Scottish centres. Prof Tobias’s co-investigators in Glasgow are: Ruth McGowan (NHS Consultant in Clinical Genetics) and Nicola Williams (Head of Laboratory Service) in the West of Scotland Genetic Services and also Faisal Ahmed (Samson Gemmell Professor of Child Health) at the University of Glasgow.

More information about DSD can be obtained here.


© 2020 Scottish Genomes Partnership

Scottish Genomes Partnership gratefully acknowledges the funding received from the Chief Scientist Office of the Scottish Government Health Directorates and the Medical Research Council Whole Genome Sequencing for Health and Wealth Initiative.