Search

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.

Background/aims: Familial exudative vitreoretinopathy (FEVR) is an inherited blinding condition characterised by abnormal development of the retinal vasculature. FEVR has multiple modes of inheritance, and homozygous mutations in LRP5 have recently been reported as underlying the recessive form of this disease. The aim of this study was to examine LRP5 in a consanguineous recessive FEVR family and to clarify the eye and bone phenotype associated with recessive FEVR. Methods: All family members were examined by slit lamp biomicroscopy and indirect ophthalmoscopy. Linkage to LRP5 was determined by genotyping microsatellite markers, constructing haplotypes and calculating lod scores. Mutation screening of LRP5 was performed by polymerase chain reaction amplification of genomic DNA followed by direct sequencing. Bone mineral density (BMD) was evaluated in all family members using dual energy x ray absorptiometry (DEXA). Results: The clinical features observed in this family were consistent with a diagnosis of recessive FEVR. A homozygous LRP5 missense mutation, G550R, was identified in all affected individuals and all unaffected family members screened were heterozygous carriers of this mutation. Reduced BMD, hyaloid vasculature remnants, and nystagmus were features of the phenotype. Conclusion: Recessive mutations in LRP5 can cause FEVR with reduced BMD and hyaloid vasculature remnants. Assessment of a patient with a provisional diagnosis of FEVR should therefore include investigation of BMD, with reduced levels suggestive of an underlying LRP5 mutation.

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, …

BACKGROUND/AIMS—Familial exudative vitreoretinopathy (FEVR) is associated with mutations in the Norrie disease gene in X linked pedigrees and with linkage to the EVR1 locus at 11q13 in autosomal dominant cases. A large autosomal dominant FEVR family was studied, both clinically and by linkage analysis, to determine whether it differed from the known forms of FEVR. METHODS—Affected members and obligate gene carriers from this family were examined by slit lamp biomicroscopy, indirect ophthalmoscopy, and in some cases fluorescein angiography. Patient DNAs were genotyped for markers at the EVR1 locus on chromosome 11q13. RESULTS—The clinical evaluation in this family is consistent with previous descriptions of FEVR pedigrees, but linkage analysis proves that it has a form of FEVR genetically distinct from the EVR1 locus on 11q. CONCLUSION—This proves that there are at least three different loci associated with comparable FEVR phenotypes, a situation similar to that existing for many forms of retinal degeneration.

Autosomal dominant retinitis pigmentosa results from mutations in 14 known proteins, and at least two further loci have been highlighted by genetic linkage in families (reviewed by the RetNet website; http://www.sph.uth.tmc.edu/Retnet/). The known genes include those encoding components of the phototransduction cascade, retinal transcription factors and retinal structural proteins.1 The list also includes four ubiquitously expressed splicing factors: pre-mRNA processing factor 8 (PRPF8),2 PRPF31,3 PRPF34 and PAP-1, also known as RP9.5 6 Splicing is a complex process that involves the precise excision of introns from pre-mRNA by a macromolecular structure called the spliceosome. Three of the splicing factors implicated in autosomal dominant retinitis pigmentosa (ADRP) are components of the U4/U6-U5 tri-snRNP particle, an essential component of the spliceosome.7 8 Mutations in one of these, PRPF31, have been reported to cause between 5 and 20% of ADRP.9 10 In this report, a new mutation in the PRPF31 gene is described, together with the clinical phenotype. The proband was a 33-year-old female with a corrected visual acuity of 58 and 51 ETDRS letters in the right and left eye, respectively (approximate Snellen equivalents of 6/18 and 6/36). She had a myopic refraction with a spherical equivalence of −2 dioptres in each eye. Nyctalopia had been present since the middle of the second decade, and she had noticed a decrease in her central vision since the beginning of the third decade. At the most recent examination, she had early …

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.

Background: Leber’s congenital amaurosis (LCA) accounts for 5% of inherited retinal disease and is usually inherited as an autosomal recessive trait. Genetic and clinical heterogeneity exist. Mutations have been described in the RPE65, CRB1, RPGRIP1, AIPL1, GUCY2D, and CRX genes and other pedigrees show linkage to the LCA3 and LCA5 loci. The latter is a new locus which maps to 6q11-q16. The ocular findings and the evolution of the macula staphyloma are described in five members of a Pakistani family with consanguinity and a mutation in the LCA5 gene. Methods: 13 family members including five affected individuals consented to DNA analysis and ocular examination including fundal photography. Results: Ocular abnormalities are described. The most striking feature was the progression of macula abnormalities in three brothers resulting in a colobomatous appearance in the eldest compared to only mild atrophy in the youngest. The phenotypic pattern of this mutation in this Pakistani family contrasts with the “Old Order River Brethren” who were of Swiss descent, in whom the mutation was first described. Conclusion: The evolution of a new phenotypic picture is presented to a mutation in LCA5.

Juvenile onset dominant optic atrophy (DOA) is the most common inherited optic atrophy with a variable prevalence of between 1 in 10 000 (Denmark) and 1 in 50 000.1,2 The majority of cases have been shown to have mutations in the OPA1 gene on chromosome 3.3–5 Reduced visual acuity of insidious onset, temporal pallor of the optic disc, centrocaecal scotoma, and generalised dyschromatopsia are the key clinical features.6 Recent studies, however, have shown that penetrance within families is much lower than first realised and the assignment of status using clinical criteria alone can result …

We read with interest the article by Durnian and Clark who presented a retrospective cohort of infants that fell outside evidence level B guidelines for screening retinopathy of prematurity (ROP) and we wish to discuss some further points.1 The data presented in table 1 highlight that all 11 babies would be missed if screening was according to level B evidence and 2 of these would still be missed using the good practice points evidence. An alternative conclusion would be that if the guidelines had been amended to screen infants under 32 weeks or 1251 g then one extra baby would have been missed (who fortunately did not require treatment). It is also debatable based on the information presented, if any of the babies absolutely required treatment as others …

We read with interest the recent article of Papanikolaou et al 1 describing a possible inherited form of Salzmann's nodular …

Editor,—Congenital hereditary endothelial dystrophy (CHED) and posterior polymorphous corneal dystrophy (PPCD) are phenotypically distinct diseases of the corneal endothelium. Linkage analysis has mapped a locus for autosomal dominant PPCD to chromosome 20p11.1 Subsequently, other researchers placed a locus for autosomal dominant CHED (designated CHED1 by the human genome mapping workshop) in an overlapping genetic interval,2 suggesting that these two disorders may be allelic variants of the same defective gene. However, CHED is more commonly inherited as an autosomal recessive (AR) disease,3 and linkage analysis in a large consanguineous recessive Saudi Arabian pedigree excluded CHED1 as the causative locus.4 Genetic heterogeneity in this condition was further confirmed by linkage analysis in a large consanguineous Irish pedigree5 in which a second CHED genetic locus (CHED2) was subsequently localised more distally at 20p13.6 We now present a Pakistani pedigree with …