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Rare Disease

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 rare disease research studies are now complete. These included 5 research studies which were seeking new information about the genetic causes of rare conditions:

  • Motor neurone disease (MND; aka amyotrophic lateral sclerosis)

  • Eye malformation

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

  • Disorders of sex development

  • Primary ciliary dyskinesia

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

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

The SGP research study used DNA samples and phenotype data from the Scottish Motor Neurone Disease Register and the Edinburgh Brain Bank. Whole genome sequencing was carried out at Edinburgh Genomics on 366 MND DNA samples.

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.

In order to find new genetic insights the data are now included in an international collaboration with 35+ institutions led by the New York Genome Center and New York's Columbia University Medical Center Institute for Genomic Medicine.

The results from this research are expected 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 made use of a 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 167 cases was carried out through SGP. Primary analysis is complete, with further analysis continuing in 2020 alongside previously generated exome data.

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

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

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

Professor Andrew Jackson

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

The SGP microcephalic dwarfism whole genome sequencing study made 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 SGP study sequenced 167 cases. Two new research findings on the causes of Saul-Wilson syndrome and IMAGe syndrome have already been published from this work and functional studies for an additional novel disease gene are underway.Further work is now being taken forward through an ERC Advanced Grant.

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.

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Professor Ed Tobias

(Professor of Genetic Medicine, University of Glasgow) led 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.

Analysis of research data for this study is continuing, with functional studies being carried out on a de novo mutation identified in the cohort.

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.

Primary Ciliary Dyskinesia

Primary ciliary dyskinesia (PCD) is a genetic disorder of motile cilia. As a result of abnormal motile cilia structure or function, PCD patients present with a chronic respiratory disease, often presenting initially as neonatal respiratory distress syndrome (NRDS) and therefore seen as a missed diagnostic opportunity.

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Dr Pleasantine Mill

(Disease Mechanisms, MRC Human Genetics Unit, University of Edinburgh) led the SGP Primary Ciliary Dyskinesia (PCD) project

The SGP study was a collaboration between the MRC IGMM and the Royal Hospital for Sick Children in Edinburgh. Families were identified as potentially suitable for recruitment to the project, as clinically confirmed PCD but lacking a genetic diagnosis.

A total of 7 families were recruited to the project and diagnoses were made in 6 patients, with a strongly suspected diagnosis in another.

The results prompted a UK multi-centre meeting on the genetics of PCD in 2019, involving clinicians and scientists from Edinburgh, Glasgow, London and Southampton. The meeting discussed current recommendations for genetic testing in suspected cases of PCD and concluded that further work was needed. A joint publication will be submitted in 2020 and further collaborations are planned.

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