Exome sequencing in undiagnosed inherited and sporadic ataxias.

Inherited ataxias are clinically and genetically heterogeneous, and a molecular diagnosis is not possible in most patients. Having excluded common sporadic, inherited and metabolic causes, we used an unbiased whole exome sequencing approach in 35 affected individuals, from 22 randomly selected families of white European descent. We defined the likely molecular diagnosis in 14 of 22 families (64%). This revealed de novo dominant mutations, validated disease genes previously described in isolated families, and broadened the clinical phenotype of known disease genes. The diagnostic yield was the same in both young and older-onset patients, including sporadic cases. We have demonstrated the impact of exome sequencing in a group of patients notoriously difficult to diagnose genetically. This has important implications for genetic counselling and diagnostic service provision

Mutations in the SPG7 gene cause chronic progressive external ophthalmoplegia through disordered mitochondrial DNA maintenance.

Despite being a canonical presenting feature of mitochondrial disease, the genetic basis of progressive external ophthalmoplegia remains unknown in a large proportion of patients. Here we show that mutations in SPG7 are a novel cause of progressive external ophthalmoplegia associated with multiple mitochondrial DNA deletions. After excluding known causes, whole exome sequencing, targeted Sanger sequencing and multiplex ligation-dependent probe amplification analysis were used to study 68 adult patients with progressive external ophthalmoplegia either with or without multiple mitochondrial DNA deletions in skeletal muscle. Nine patients (eight probands) were found to carry compound heterozygous SPG7 mutations, including three novel mutations: two missense mutations c.2221G>A; p.(Glu741Lys), c.2224G>A; p.(Asp742Asn), a truncating mutation c.861dupT; p.Asn288*, and seven previously reported mutations. We identified a further six patients with single heterozygous mutations in SPG7, including two further novel mutations: c.184-3C>T (predicted to remove a splice site before exon 2) and c.1067C>T; p.(Thr356Met). The clinical phenotype typically developed in mid-adult life with either progressive external ophthalmoplegia/ptosis and spastic ataxia, or a progressive ataxic disorder. Dysphagia and proximal myopathy were common, but urinary symptoms were rare, despite the spasticity. Functional studies included transcript analysis, proteomics, mitochondrial network analysis, single fibre mitochondrial DNA analysis and deep re-sequencing of mitochondrial DNA. SPG7 mutations caused increased mitochondrial biogenesis in patient muscle, and mitochondrial fusion in patient fibroblasts associated with the clonal expansion of mitochondrial DNA mutations. In conclusion, the SPG7 gene should be screened in patients in whom a disorder of mitochondrial DNA maintenance is suspected when spastic ataxia is prominent. The complex neurological phenotype is likely a result of the clonal expansion of secondary mitochondrial DNA mutations modulating the phenotype, driven by compensatory mitochondrial biogenesis

US Cosmic Visions: New Ideas in Dark Matter 2017: Community Report

This white paper summarizes the workshop "U.S. Cosmic Visions: New Ideas in Dark Matter" held at University of Maryland on March 23-25, 2017.Comment: 102 pages + reference

The evolution of the plastid chromosome in land plants: gene content, gene order, gene function

This review bridges functional and evolutionary aspects of plastid chromosome architecture in land plants and their putative ancestors. We provide an overview on the structure and composition of the plastid genome of land plants as well as the functions of its genes in an explicit phylogenetic and evolutionary context. We will discuss the architecture of land plant plastid chromosomes, including gene content and synteny across land plants. Moreover, we will explore the functions and roles of plastid encoded genes in metabolism and their evolutionary importance regarding gene retention and conservation. We suggest that the slow mode at which the plastome typically evolves is likely to be influenced by a combination of different molecular mechanisms. These include the organization of plastid genes in operons, the usually uniparental mode of plastid inheritance, the activity of highly effective repair mechanisms as well as the rarity of plastid fusion. Nevertheless, structurally rearranged plastomes can be found in several unrelated lineages (e.g. ferns, Pinaceae, multiple angiosperm families). Rearrangements and gene losses seem to correlate with an unusual mode of plastid transmission, abundance of repeats, or a heterotrophic lifestyle (parasites or myco-heterotrophs). While only a few functional gene gains and more frequent gene losses have been inferred for land plants, the plastid Ndh complex is one example of multiple independent gene losses and will be discussed in detail. Patterns of ndh-gene loss and functional analyses indicate that these losses are usually found in plant groups with a certain degree of heterotrophy, might rendering plastid encoded Ndh1 subunits dispensable

GWAS meta-analysis of intrahepatic cholestasis of pregnancy implicates multiple hepatic genes and regulatory elements

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder affecting 0.5–2% of pregnancies. The majority of cases present in the third trimester with pruritus, elevated serum bile acids and abnormal serum liver tests. ICP is associated with an increased risk of adverse outcomes, including spontaneous preterm birth and stillbirth. Whilst rare mutations affecting hepatobiliary transporters contribute to the aetiology of ICP, the role of common genetic variation in ICP has not been systematically characterised to date. Here, we perform genome-wide association studies (GWAS) and meta-analyses for ICP across three studies including 1138 cases and 153,642 controls. Eleven loci achieve genome-wide significance and have been further investigated and fine-mapped using functional genomics approaches. Our results pinpoint common sequence variation in liver-enriched genes and liver-specific cis-regulatory elements as contributing mechanisms to ICP susceptibility

Regional inequalities in infant mortality within North Carolina, Usa

Many European countries have traditional- ly had lower infant mortality rates than the United States, and while such rates are generally decreasing in most developed countries, U.S. rates remain higher. Some researchers have separated black and white population groups to demonstrate how U.S. white infant mortality rates are comparable to European rates. North Carolina has had infant mortality rates above the national average for both whites and blacks during most of the 1980s. Regionalization of infant mortality (Infants less than one year of age) within North Carolina utilizing county-based data over two averaged time periods, 1976 to 1980 and 1983 to 1987, reveals four distinct patterns . > In general, a * ' U-shaped ' ' curve with high innercity infant mortality, lower rates in decentralized small towns and suburbs followed by higher rates once again in areas that are simultaneously poor, black and rural explains regional aspects of this social problem in North Carolina.eu des taux de mortalité infantile moins élevés que les Etats-Unis. Alors que ces taux tendent généralement à baisser dans la plupart des pays développés, ceux des Etats- Unis restent élevés. Certains chercheurs ont séparé deux groupes au sein de la population : les Noirs et les Blancs, afin de démontrer le degré de ressemblance entre les taux de mortalité infantile chez les Blancs et les taux européens. La Caroline du Nord présente des taux de mortalité infantile au-dessus de la moyenne, aussi bien chez les populations blanches que noires, pour une grande partie des années 80. La régionalisation de la mortalité infantile (enfants âgés de moins d'un an) en Caroline du Nord révèle quatre répartitions distinctes quand on utilise les données des comtés sur deux périodes moyennes, de 1976 à 1980 et de 1983 à 1987. Généralement, une courbe en forme de « U » avec une mortalité infantile élevée dans les villes, des taux plus bas dans les petites villes décentralisées et les banlieues, suivis par des taux plus élevés encore une fois dans des régions à la fois pauvres, noires et rurales, explique le mieux les aspects régionaux de ce problème social en Caroline du Nord.Pyle Gerald F. Regional inequalities in infant mortality within North Carolina, Usa . In: Espace, populations, sociétés, 1990-3. Les inégalités géographiques de la mortalité (I) - The Geographical Inequalities of Mortality (I) pp. 439-445

From African health and influenza pandemics to disease in Russia: the medical history of K. David Patterson

This paper is a personal commentary on the contributions of noted medical historian K. David Patterson. The eightieth anniversary of the onset of the Great Influenza Pandemic of 1918-19 serves as a reminder of his contributions. His works on slavery and disease in Africa, influenza diffusion and the history of cholera and other diseases periodically appeared in Social Science and Medicine. With a publishing career that lasted from 1971 to 1996, his enduring contributions include revised estimates of mortality in Africa during the influenza pandemic of 1918-1919.Africa Influenza Cholera Medical history