Childhood-onset Leber hereditary optic neuropathy

BACKGROUND: The onset of Leber hereditary optic neuropathy (LHON) is relatively rare in childhood. This study describes the clinical and molecular genetic features observed in this specific LHON subgroup. METHODS: Our retrospective study consisted of a UK paediatric LHON cohort of 27 patients and 69 additional cases identified from a systematic review of the literature. Patients were included if visual loss occurred at the age of 12 years or younger with a confirmed pathogenic mitochondrial DNA mutation: m.3460G>A, m.11778G>A or m.14484T>C. RESULTS: In the UK paediatric LHON cohort, three patterns of visual loss and progression were observed: (1) classical acute (17/27, 63%); (2) slowly progressive (4/27, 15%); and (3) insidious or subclinical (6/27, 22%). Diagnostic delays of 3-15 years occurred in children with an insidious mode of onset. Spontaneous visual recovery was more common in patients carrying the m.3460G>A and m.14484T>C mutations compared with the m.11778G>A mutation. Based a meta-analysis of 67 patients with available visual acuity data, 26 (39%) patients achieved a final best-corrected visual acuity (BCVA) ≥0.5 Snellen decimal in at least one eye, whereas 13 (19%) patients had a final BCVA <0.05 in their better seeing eye. CONCLUSIONS: Although childhood-onset LHON carries a relatively better visual prognosis, approximately 1 in 5 patients will remain within the visual acuity criteria for legal blindness in the UK. The clinical presentation can be insidious and LHON should be considered in the differential diagnosis when faced with a child with unexplained subnormal vision and optic disc pallor

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.)

The phenotypic spectrum of proximal 6q deletions based on a large cohort derived from social media and literature reports

Proximal 6q (6q11-q15) deletions are extremely rare and little is known about their phenotypic consequences. Since parents and caregivers now use social media to seek information on rare disorders, the Chromosome 6 Project has successfully collaborated with a Facebook group to collect data on individuals worldwide. Here we describe a cohort of 20 newly identified individuals and 25 literature cases with a proximal 6q deletion. Microarray results and phenotype data were reported directly by parents via a multilingual online questionnaire. This led to phenotype descriptions for five subregions of proximal 6q deletions; comparing the subgroups revealed that 6q11q14.1 deletions presented less severe clinical characteristics than 6q14.2q15 deletions. Gastroesophageal reflux, tracheo/laryngo/bronchomalacia, congenital heart defects, cerebral defects, seizures, and vision and respiratory problems were predominant in those with 6q14.2q15 deletions. Problems related to connective tissue (hypermobility, hernias and foot deformities) were predominantly seen in deletions including the COL12A1 gene (6q13). Congenital heart defects could be linked to deletions of MAP3K7 (6q15) or TBX18 (6q14.3). We further discuss the role of ten genes known or assumed to be related to developmental delay and/or autism (BAI3, RIMS1, KCNQ5, HTR1B, PHIP, SYNCRIP, HTR1E, ZNF292, AKIRIN2 and EPHA7). The most influential gene on the neurodevelopmental phenotype seems to be SYNCRIP (6q14.3), while deletions that include more than two of these genes led to more severe developmental delay. We demonstrate that approaching individuals via social media and collecting data directly from parents is a successful strategy, resulting in better information to counsel families

Possible explosion crater origin of small lake basins with raised rims on Titan

The Cassini mission discovered lakes and seas comprising mostly methane in the polar regions of Titan. Lakes of liquid nitrogen may have existed during the epochs of Titan’s past in which methane was photochemically depleted, leaving a nearly pure molecular nitrogen atmosphere and, thus, far colder temperatures. The modern-day small lake basins with sharp edges have been suggested to originate from dissolution processes, due to their morphological similarity to terrestrial karstic lakes. Here we analyse the morphology of the small lake basins that feature raised rims to elucidate their origin, using delay-Doppler processed altimetric and bathymetric data acquired during the last close flyby of Titan by the Cassini spacecraft. We find that the morphology of the raised-rim basins is analogous to that of explosion craters from magma–water interaction on Earth and therefore propose that these basins are from near-surface vapour explosions, rather than karstic. We calculate that the phase transition of liquid nitrogen in the near subsurface during a warming event can generate explosions sufficient to form the basins. Hence, we suggest that raised-rim basins are evidence for one or more warming events terminating a nitrogen-dominated cold episode on Titan

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