There are over 400 rare diseases of the skeleton and for many of them there are no treatments and little understanding of why they happen. The aim of this GeCIP domain is to use the extensive expertise within the UK to make the most of the information from the 100,000 Genomes Project, so that we can develop better tests and treatments for people with these conditions. We will achieve this by supporting patients with rare bone diseases to get into the project and then, when their results are known, work with them and their doctors to understand the results better.
We will study the information from patients (including their symptoms, healthcare usage and X-ray changes both cross-sectionally and longitudinally) to determine sub-phenotypes and link this to their genomic data. This improved scientific understanding will be vital for developing better tests and treatments to improve the care and quality of life of patients. We will study how these new tests and treatments can work for patients in the NHS.
Finally, this GeCIP is committed to providing the best training for the next generation of doctors and researchers in rare diseases of the skeleton.
|SUBDOMAIN||SUBDOMAIN LEAD/S||RESEARCH DESCIPTION|
|Adult Metabolic||R Keen|
|Bone fragility / Paediatric Metabolic||M Balasubramanian||Osteogenesis Imperfecta (OI) is the commonest form of inherited bone fragility disorders affecting 1 in 20,000 live births. It is a heterogeneous disease resulting in variable presentations. Dominantly inherited forms of OI are considered to be type 1 collagenopathies, with 90% of patients having mutations in COL1A1/COL1A2. In the remainder 10% of patients, a small proportion is due to rare, recessive genes whilst the rest are unknown. It is this group of patients that we are targeting through recruitment to the 100,000 Genomes project and Genomics England sequencing efforts will be focused on this patient cohort (10 patients/ year).|
|Craniofacial||A Wilkie||Craniosynostosis is heterogeneous in its causes, with monogenic, polygenic, and environmental (mostly prenatal) factors all playing a role. The importance of monogenic causes is illustrated by the fact that a specific mutation or causative chromosomal rearrangement can currently be identified in ~25% of all craniosynostosis. Such monogenic forms are enriched in patients exhibiting a positive family history, additional syndromic features, and fusion of the coronal or multiple cranial sutures. Overall there are 10-15% of patients who match these characteristics, but in whom a genetic cause cannot currently be identified: Genomics England sequencing efforts will be focused on this patient cohort (theoretical maximum ~50 patients/year).|
|Health Economics||R Pinedo-Villanueva|
|Imaging/ dREAMS||AC Offiah||The International Nosology and Classification of Genetic Skeletal Dysplasias recognizes 42 groups, encompassing 436 conditions (1). Despite these groupings, definitive diagnosis of the skeletal dysplasias is complicated by the rarity of individual conditions, the large phenotypic and genotypic heterogeneity (different disorders may look similar, subtypes of the same disorder may look different, conditions caused by the same gene may look different), and by a lack of standardization in the medical vocabulary used to describe the clinical and radiological phenotypes. An accurate diagnosis leads to tailored genetic confirmation, appropriate family counselling, understanding of disease pathways and development of novel therapies. It also supports research through precise assessment of radiological response to therapy and genotype/phenotype correlations.|
|Multiple Epiphyseal Dysplasia||M Briggs||Multiple ephiphyseal dysplasia (MED) is one of the more common bone dysplasias affecting ~1 in 20,000 children. Both autosomal dominant and recessive forms are recognised. AD-MED is genetically heterogeneous and results from mutations in the genes encoding matrilin-3, type IX collagen and COMP. However, extensive genetic analysis has consistently demonstrated that mutations in other, as yet unidentified genes, can also result in AD-MED. The proportion of AD-MED that does not have a genetic basis ascribed varies between 30-70% depending on diagnostic rigour. This sub-group of MED patients have been targeted for recruitment to tHE 100,000 Genomes Project.
Previous studies have also identified cohorts of patients that are phenotypic outliers of the MED ‘disease spectrum’, but which shared distinct clinical and/or radiographic features. Consensus diagnoses for these patients focuses around specific forms of familial hip dysplasia (FHD) and it is clear that these diseases are genetically distinct from ‘classical’ forms of MED result from mutation in matrilin-3, type IX collagen and COMP.
|Patient representative||E Aslin|
|Skeletal Dysplasia||M Irving||While over 50% of skeletal dysplasias have been resolved, a number of recognized diseases remain unresolved or have sub-groups of patients without recognized pathogenic mutations. Further, ultra-rare patients with constellations of skeletal and extra-skeletal features that do not map to existing classification systems also reach clinical attention.|
1) Bonafe L, Cormier-Daire V, Hall C et al Nosology and classification of genetic skeletal disorders: 2015 revision Am J Med Genet A 2015;167:2869-2892 (dREAMS)