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BackgroundPrimary ciliopathies represent a group of inherited disorders due to defects in the primary cilium, the ‘cell’s antenna’. The 100,000 Genomes Project was launched in 2012 by Genomics England (GEL), recruiting National Health Service (NHS) patients with eligible rare diseases and cancer. Sequence data were linked to Human Phenotype Ontology (HPO) terms entered by recruiting clinicians.MethodsEighty-three prescreened probands were recruited to the 100,000 Genomes Project suspected to have congenital malformations caused by ciliopathies in the following disease categories: Bardet-Biedl syndrome (n=45), Joubert syndrome (n=14) and ‘Rare Multisystem Ciliopathy Disorders’ (n=24). We implemented a bespoke variant filtering and analysis strategy to improve molecular diagnostic rates for these participants.ResultsWe determined a research molecular diagnosis for n=43/83 (51.8%) probands. This is 19.3% higher than previously reported by GEL (n=27/83 (32.5%)). A high proportion of diagnoses are due to variants in non-ciliopathy disease genes (n=19/43, 44.2%) which may reflect difficulties in clinical recognition of ciliopathies. n=11/83 probands (13.3%) had at least one causative variant outside the tiers 1 and 2 variant prioritisation categories (GEL’s automated triaging procedure), which would not be reviewed in standard 100,000 Genomes Project diagnostic strategies. These include four structural variants and three predicted to cause non-canonical splicing defects. Two unrelated participants have biallelic likely pathogenic variants in LRRC45, a putative novel ciliopathy disease gene.ConclusionThese data illustrate the power of linking large-scale genome sequence to phenotype information. They demonstrate the value of research collaborations in order to maximise interpretation of genomic data.

The phrase anterior segment dysgenesis (ASD), also sometimes known as anterior segment ocular or mesenchymal dysgenesis (ASOD or ASMD, OMIM #107250), was first used in 1981 by Hittner and colleagues to describe a range of developmental defects in structures at the front of the eye.1 These defects are thought to result from abnormal migration or differentiation of the neural crest derived mesenchymal cells that give rise to the cornea, iris, and other components of the anterior chamber during eye development.2,3 Conditions falling within the ASD spectrum include aniridia, posterior embryotoxon, Axenfeld’s anomaly, Reiger’s anomaly/syndrome, Peters’ anomaly, and iridogoniodysgenesis. Aniridia (OMIM #106210) ranges from almost complete absence of the iris, through enlargement and irregularity of the pupil mimicking a coloboma, to small slit-like defects in the anterior layer visible only with a slit lamp. In Axenfeld’s anomaly (OMIM #109120), the Schwalbe’s line is prominent and centrally displaced (posterior embryotoxon) with peripheral iris strands fused to it. Eye signs in Rieger’s anomaly (OMIM #109120) patients may include malformations of the anterior chamber angle and aqueous drainage structures (iridogoniodysgenesis), microcornea, iris hypoplasia, eccentric pupil (corectopia), iris tears (polycoria), and iridocorneal tissue adhesions traversing the anterior chamber angle.4,5 In Reiger’s syndrome (OMIM #180500), patients have ASD in association with underdeveloped or misshapen teeth (hypodontia) and may also have hearing loss, heart defects and skeletal abnormalities. Peters’ anomaly (OMIM #604229) consists of a central corneal leucoma, absence of the posterior corneal stroma and Descemet membrane, and varying degrees of iris and lenticular attachment to the posterior cornea. All of these conditions carry with them an increased risk of glaucoma owing to abnormalities in the Schlemm’s canal and trabecular meshwork. Human ASD phenotypes are genetically heterogeneous,6 resulting from mutations in seven different transcription factor genes ( PAX6, PITX2, PITX3, FOXC1, FOXE3, …

5 páginas, 1 figura, 3 tablas.-- et al., Autosomal dominant retinitis pigmentosa (ADRP) is caused by mutations in two known genes, rhodopsin and peripherin/Rds, and seven loci identified only by linkage analysis. Rhodopsin and peripherin/Rds have been estimated to account for 20-31% and less than 5% of ADRP, respectively. No estimate of frequency has previously been possible for the remaining loci, since these can only be implicated when families are large enough for linkage analysis. We have carried out such analyses on 20 unrelated pedigrees with 11 or more meioses. Frequency estimates based on such a small sample provide only broad approximations, while the above estimations are based on mutation detection in much larger clinic based patient series. However, when markers are informative, linkage analysis cannot fail to detect disease causation at a locus, whereas mutation detection techniques might miss some mutations. Also diagnosing dominant RP from a family history taken in a genetic clinic may not be reliable. It is therefore interesting that 10 (50%) of the families tested have rhodopsin-RP, suggesting that, in large clearly dominant RP pedigrees, rhodopsin may account for a higher proportion of disease than had previously been suspected. Four (20%) map to chromosome 19q, implying that this is the second most common ADRP locus. One maps to chromosome 7p, one to 17p, and one to 17q, while none maps to 1cen, peripherin/Rds, 8q, or 7q. Three give exclusion of all of these loci, showing that while the majority of dominant RP maps to the known loci, a small proportion derives from loci yet to be identified., We gratefully acknowledge the Wellcome Trust (grant numbers 035535/Z/92, 043006/Z/94, and 042375/Zl94), the Foundation Fighting Blindness USA, and the British Retinitis Pigmentosa Society for funding this research.

The involvement of genes with expanded tracts of (CAG)n in some neurodegenerative diseases is well established. Whether genes containing these motifs could also have a role in degenerative diseases affecting the retina, which is also neural in origin, is unknown. We investigated (CAG)n expansions as a cause of disease in a panel of eight autosomal dominant retinitis pigmentosa (ADRP) pedigrees, including families known to map to the RP9, RP11, and RP13 loci, using the technique known as "repeat expansion detection" (RED). An expansion was detected in one of the unlinked families, but it did not segregate with the disease and was thus nonpathogenic. Expansions were not detected in any other families. In conclusion, expanded (CAG)n repeats are not the cause of disease in the families we have studied, but given the high level of heterogeneity in RP and in retinal degenerations in general they remain strong candidates for involvement in other forms of retinal dystrophy.

3 páginas, 2 figuras, 2 tablas.-- et al., A form of autosomal dominant retinitis pigmentosa (ADRP) mapping to chromosome 17p has been reported in a single large South African family. We now report a new family with severe early onset ADRP which maps to 17p. Linkage and haplotype analysis in this family places the ADRP locus in the 5 cM interval between markers AFMc024za5 and D17S1845, confirming the data obtained in the South African family. The discovery of a second 17p linked family may imply that this is one of the more common loci for dominant RP. In addition, the confirmation of an RP diagnosis at this locus is of interest since loci for a dominant cone dystrophy and Leber's congenital amaurosis (LCA1) have recently been linked to the same markers. While the cone dystrophy locus may be allelic with RP, our data and that of Goliath et al show that distinct genes are responsible for dominant RP and Leber's congenital amaurosis on chromosome 17p., We thank the Wellcome Trust (grant numbers 035535/2/92/Z and 042375/Z/941Z) for funding this research.