Assessing the Interocular Symmetry of Foveal Outer Nuclear Layer Thickness in Achromatopsia

Purpose: We examine the interocular symmetry of foveal outer nuclear layer (ONL) thickness measurements in subjects with achromatopsia (ACHM). Methods: Images from 76 subjects with CNGA3- or CNGB3-associated ACHM and 42 control subjects were included in the study. Line or volume scans through the fovea of each eye were acquired using optical coherence tomography (OCT). Image quality was assessed for each image included in the analysis using a previously-described maximum tissue contrast index (mTCI) metric. Three foveal ONL thickness measurements were made by a single observer and interocular symmetry was assessed using the average of the three measurements for each eye. Results: Mean (± standard deviation) foveal ONL thickness for subjects with ACHM was 79.7 ± 18.3 μm (right eye) and 79.2 ± 18.7 μm (left eye) compared to 112.9 ± 15.2 (right eye) and 112.1 ± 13.9 μm (left eye) for controls. Foveal ONL thickness did not differ between eyes for ACHM (P = 0.636) or control subjects (P = 0.434). No significant relationship between mTCI and observer repeatability was observed for either control (P = 0.140) or ACHM (P = 0.351) images. Conclusions: While foveal ONL thickness is reduced in ACHM compared to controls, the high interocular symmetry indicates that contralateral ONL measurements could be used as a negative control in early-phase monocular treatment trials. Translational Relevance: Foveal ONL thickness can be measured using OCT images over a wide range of image quality. The interocular symmetry of foveal ONL thickness in ACHM and control populations supports the use of the non-study eye as a control for clinical trial purposes

Optical coherence tomography: an assessment of current training across all levels of seniority in 8 ophthalmic units in the united kingdom

BACKGROUND: Optical Coherence Tomography (OCT) is becoming an increasingly integral part of ophthalmological clinical practice. The accurate interpretation of OCT images is important both in terms of diagnosis and in directing subsequent management. The aim of this study was to determine the clinical competence in OCT image interpretation of ophthalmologists in different subspecialties and grades. METHODS: Eight OCT images demonstrating a single macular pathology and two normal scans were selected by case notes review. These ten images were shown to thirty doctors and 10 non-medical staff from eight units. They were asked to identify each lesion, the average thickness of the lesion, and the axis at which the OCT was taken. One point was awarded for each correct answer. RESULTS: The mean scores for the correct qualitative identification of the OCT lesion (with a maximum score of 10) for different grades of doctors and non-medical staff were as follows: medical retinal consultants (MRC), 9 (range, 8–10); vitreoretinal consultants (VRC), 7 (range, 6–9); non-retinal consultants (NRC), 4 (range, 2–6); vitreoretinal fellows (VRF), 4 (range, 3–7); specialist registrars (SpR), 3 (range, 2–5); senior house officers (SHO), 4 (range, 3–6); orthoptists, 1 (range, 0–1); ancillary staff, 2 (range, 0–3). CONCLUSION: A wide range in the ability to accurately interpret OCT images has been demonstrated. All doctors would thereby benefit from further training in the interpretation of OCT scans

Genetics of photoreceptor degeneration and regeneration in zebrafish

Zebrafish are unique in that they provide a useful model system for studying two critically important problems in retinal neurobiology, the mechanisms responsible for triggering photoreceptor cell death and the innate stem cell–mediated regenerative response elicited by this death. In this review we highlight recent seminal findings in these two fields. We first focus on zebrafish as a model for studying photoreceptor degeneration. We summarize the genes currently known to cause photoreceptor degeneration, and we describe the phenotype of a few zebrafish mutants in detail, highlighting the usefulness of this model for studying this process. In the second section, we discuss the several different experimental paradigms that are available to study regeneration in the teleost retina. A model outlining the sequence of gene expression starting from the dedifferentiation of Müller glia to the formation of rod and cone precursors is presented

100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care — Preliminary Report

BACKGROUND: The U.K. 100,000 Genomes Project is in the process of investigating the role of genome sequencing in patients with undiagnosed rare diseases after usual care and the alignment of this research with health care implementation in the U.K. National Health Service. Other parts of this project focus on patients with cancer and infection. METHODS: We conducted a pilot study involving 4660 participants from 2183 families, among whom 161 disorders covering a broad spectrum of rare diseases were present. We collected data on clinical features with the use of Human Phenotype Ontology terms, undertook genome sequencing, applied automated variant prioritization on the basis of applied virtual gene panels and phenotypes, and identified novel pathogenic variants through research analysis. RESULTS: Diagnostic yields varied among family structures and were highest in family trios (both parents and a proband) and families with larger pedigrees. Diagnostic yields were much higher for disorders likely to have a monogenic cause (35%) than for disorders likely to have a complex cause (11%). Diagnostic yields for intellectual disability, hearing disorders, and vision disorders ranged from 40 to 55%. We made genetic diagnoses in 25% of the probands. A total of 14% of the diagnoses were made by means of the combination of research and automated approaches, which was critical for cases in which we found etiologic noncoding, structural, and mitochondrial genome variants and coding variants poorly covered by exome sequencing. Cohortwide burden testing across 57,000 genomes enabled the discovery of three new disease genes and 19 new associations. Of the genetic diagnoses that we made, 25% had immediate ramifications for clinical decision making for the patients or their relatives. CONCLUSIONS: Our pilot study of genome sequencing in a national health care system showed an increase in diagnostic yield across a range of rare diseases. (Funded by the National Institute for Health Research and others.)

Germline selection shapes human mitochondrial DNA diversity.

Approximately 2.4% of the human mitochondrial DNA (mtDNA) genome exhibits common homoplasmic genetic variation. We analyzed 12,975 whole-genome sequences to show that 45.1% of individuals from 1526 mother-offspring pairs harbor a mixed population of mtDNA (heteroplasmy), but the propensity for maternal transmission differs across the mitochondrial genome. Over one generation, we observed selection both for and against variants in specific genomic regions; known variants were more likely to be transmitted than previously unknown variants. However, new heteroplasmies were more likely to match the nuclear genetic ancestry as opposed to the ancestry of the mitochondrial genome on which the mutations occurred, validating our findings in 40,325 individuals. Thus, human mtDNA at the population level is shaped by selective forces within the female germ line under nuclear genetic control, which ensures consistency between the two independent genetic lineages.NIHR, Wellcome Trust, MRC, Genomics Englan

Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis

Background Rare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes. Methods We did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11744 individuals with European ancestry (including 2085 patients). One GWAS used genotypes from 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration of survival. All-cause mortality was the primary endpoint in survival analyses. Findings A locus near SOX17 (rs10103692, odds ratio 1·80 [95% CI 1·55–2·08], p=5·13×10– ¹⁵) and a second locus in HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1·56 [1·42–1·71], p=7·65×10– ²⁰) within the class II MHC region were associated with pulmonary arterial hypertension. The SOX17 locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25–1·48], p=1·69×10– ¹²; and rs10103692). Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reduced SOX17 expression. The HLA-DPA1/DPB1 rs2856830 genotype was strongly associated with survival. Median survival from diagnosis in patients with pulmonary arterial hypertension with the C/C homozygous genotype was double (13·50 years [95% CI 12·07 to >13·50]) that of those with the T/T genotype (6·97 years [6·02–8·05]), despite similar baseline disease severity. Interpretation This is the first study to report that common genetic variation at loci in an enhancer near SOX17 and in HLA-DPA1/DPB1 is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more common in pulmonary arterial hypertension than suggested by rare mutations in SOX17. Further studies are needed to confirm the association between HLA typing or rs2856830 genotyping and survival, and to determine whether HLA typing or rs2856830 genotyping improves risk stratification in clinical practice or trials. Funding UK NIHR, BHF, UK MRC, Dinosaur Trust, NIH/NHLBI, ERS, EMBO, Wellcome Trust, EU, AHA, ACClinPharm, Netherlands CVRI, Dutch Heart Foundation, Dutch Federation of UMC, Netherlands OHRD and RNAS, German DFG, German BMBF, APH Paris, INSERM, Université Paris-Sud, and French ANR

Quantifying Surface‐Height Change Over a Periglacial Environment With ICESat‐2 Laser Altimetry

We use Ice, Cloud, and land Elevation Satellite 2 (ICESat-2) laser altimetry crossovers and repeat tracks collected over the North Slope of Alaska to estimate ground surface-height change due to the seasonal freezing and thawing of the active layer. We compare these measurements to a time series of surface deformation from Sentinel-1 interferometric synthetic aperture radar (InSAR) and demonstrate agreement between these independent observations of surface deformation at broad spatial scales. We observe a relationship between ICESat-2-derived surface subsidence/uplift and changes in normalized accumulated degree days, which is consistent with the thermodynamically driven seasonal freezing and thawing of the active layer. Integrating ICESat-2 crossover estimates of surface-height change yields an annual time series of surface-height change that is sensitive to changes in snow cover during spring and thawing of the active layer throughout spring and summer. Furthermore, this time series exhibits temporal correlation with independent reanalysis datasets of temperature and snow cover, as well as an InSAR-derived time series. ICESat-2-derived surface-height change estimates can be significantly affected by short length-scale topographic gradients and changes in snow cover and snow depth. We discuss optimal strategies of post-processing ICESat-2 data for permafrost applications, as well as the future potential of joint ICESat-2 and InSAR investigations of permafrost surface-dynamics

Haemophilia A diagnosis by simultaneous analysis of two variable dinucleotide tandem repeats within the factor VIII gene.

Haemophilia A is a bleeding disorder caused by defects in the gene coding for the co-factor, factor VIII (FVIII). The few available intragenic restriction fragment length polymorphisms (RFLPs) currently used in carrier detection and prenatal diagnosis of haemophilia A are informative in only about 65% of cases. We earlier reported a multi-allelic dinucleotide tandem repeat, (CA)n, specific to intron 13, which remains the single most informative marker within the FVIII gene. We here report a second informative dinucleotide repeat of the form (GT)n (AG)n, located to intron 22 of the FVIII gene. The polymerase chain reaction (PCR) method was used to examine the variability of the repeat in 60 individuals (75 X-chromosomes) and revealed four alleles. The calculated heterozygosity rate is 45%, and family studies showed X-linked mendelian inheritance. The intron 22 dinucleotide repeat is tightly linked with established RFLPs and tracks with haemophilia A in family studies. We now show that by simultaneous amplification of the intron 13 and 22 repeats using PCR all alleles for both markers are detectable on a single polyacrylamide gel. The information thus obtained from a single multiplexed analysis is greater than from multiple RFLP analyses. Hence, rapid haplotype determination by simultaneous amplification and detection of two intragenic dinucleotide repeats should supersede less informative RFLP analysis