Planar Cell Polarity Acts Through Septins to Control Collective Cell Movement and Ciliogenesis

The planar cell polarity (PCP) signaling pathway governs collective cell movements during vertebrate embryogenesis, and certain PCP proteins are also implicated in the assembly of cilia. The septins are cytoskeletal proteins controlling behaviors such as cell division and migration. Here, we identified control of septin localization by the PCP protein Fritz as a crucial control point for both collective cell movement and ciliogenesis in Xenopus embryos. We also linked mutations in human Fritz to Bardet-Biedl and Meckel-Gruber syndromes, a notable link given that other genes mutated in these syndromes also influence collective cell movement and ciliogenesis. These findings shed light on the mechanisms by which fundamental cellular machinery, such as the cytoskeleton, is regulated during embryonic development and human disease

Replication of TCF4 through Association and Linkage Studies in Late-Onset Fuchs Endothelial Corneal Dystrophy

Fuchs endothelial corneal dystrophy (FECD) is a common, late-onset disorder of the corneal endothelium. Although progress has been made in understanding the genetic basis of FECD by studying large families in which the phenotype is transmitted in an autosomal dominant fashion, a recently reported genome-wide association study identified common alleles at a locus on chromosome 18 near TCF4 which confer susceptibility to FECD. Here, we report the findings of our independent validation study for TCF4 using the largest FECD dataset to date (450 FECD cases and 340 normal controls). Logistic regression with sex as a covariate was performed for three genetic models: dominant (DOM), additive (ADD), and recessive (REC). We found significant association with rs613872, the target marker reported by Baratz et al.(2010), for all three genetic models (DOM: P = 9.33×10−35; ADD: P = 7.48×10−30; REC: P = 5.27×10−6). To strengthen the association study, we also conducted a genome-wide linkage scan on 64 multiplex families, composed primarily of affected sibling pairs (ASPs), using both parametric and non-parametric two-point and multipoint analyses. The most significant linkage region localizes to chromosome 18 from 69.94cM to 85.29cM, with a peak multipoint HLOD = 2.5 at rs1145315 (75.58cM) under the DOM model, mapping 1.5 Mb proximal to rs613872. In summary, our study presents evidence to support the role of the intronic TCF4 single nucleotide polymorphism rs613872 in late-onset FECD through both association and linkage studies

Genetic Drivers of Kidney Defects in the DiGeorge Syndrome

Background The DiGeorge syndrome, the most common of the microdeletion syndromes, affects multiple organs, including the heart, the nervous system, and the kidney. It is caused by deletions on chromosome 22q11.2; the genetic driver of the kidney defects is unknown. Methods We conducted a genomewide search for structural variants in two cohorts: 2080 patients with congenital kidney and urinary tract anomalies and 22,094 controls. We performed exome and targeted resequencing in samples obtained from 586 additional patients with congenital kidney anomalies. We also carried out functional studies using zebrafish and mice. Results We identified heterozygous deletions of 22q11.2 in 1.1% of the patients with congenital kidney anomalies and in 0.01% of population controls (odds ratio, 81.5; P=4.5×10(-14)). We localized the main drivers of renal disease in the DiGeorge syndrome to a 370-kb region containing nine genes. In zebrafish embryos, an induced loss of function in snap29, aifm3, and crkl resulted in renal defects; the loss of crkl alone was sufficient to induce defects. Five of 586 patients with congenital urinary anomalies had newly identified, heterozygous protein-altering variants, including a premature termination codon, in CRKL. The inactivation of Crkl in the mouse model induced developmental defects similar to those observed in patients with congenital urinary anomalies. Conclusions We identified a recurrent 370-kb deletion at the 22q11.2 locus as a driver of kidney defects in the DiGeorge syndrome and in sporadic congenital kidney and urinary tract anomalies. Of the nine genes at this locus, SNAP29, AIFM3, and CRKL appear to be critical to the phenotype, with haploinsufficiency of CRKL emerging as the main genetic driver. (Funded by the National Institutes of Health and others.)

A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.

This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ng.3448Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.We thank all participants of all the studies included for enabling this research by their participation in these studies. Computer resources for this project have been provided by the high-performance computing centers of the University of Michigan and the University of Regensburg. Group-specific acknowledgments can be found in the Supplementary Note. The Center for Inherited Diseases Research (CIDR) Program contract number is HHSN268201200008I. This and the main consortium work were predominantly funded by 1X01HG006934-01 to G.R.A. and R01 EY022310 to J.L.H

Disorders of sex development: effect of molecular diagnostics

Disorders of sex development (DSDs) are a diverse group of conditions that can be challenging to diagnose accurately using standard phenotypic and biochemical approaches. Obtaining a specific diagnosis can be important for identifying potentially life-threatening associated disorders, as well as providing information to guide parents in deciding on the most appropriate management for their child. Within the past 5 years, advances in molecular methodologies have helped to identify several novel causes of DSDs; molecular tests to aid diagnosis and genetic counselling have now been adopted into clinical practice. Occasionally, genetic profiling of embryos prior to implantation as an adjunct to assisted reproduction, prenatal diagnosis of at-risk pregnancies and confirmatory testing of positive results found during newborn biochemical screening are performed. Of the available genetic tests, the candidate gene approach is the most popular. New high-throughput DNA analysis could enable a genetic diagnosis to be made when the aetiology is unknown or many differential diagnoses are possible. Nonetheless, concerns exist about the use of genetic tests. For instance, a diagnosis is not always possible even using new molecular approaches (which can be worrying for the parents) and incidental information obtained during the test might cause anxiety. Careful selection of the genetic test indicated for each condition remains important for good clinical practice. The purpose of this Review is to describe advances in molecular biological techniques for diagnosing DSDs

Replication of the TCF4 intronic variant in late-onset Fuchs corneal dystrophy and evidence of independence from the FCD2

PURPOSE. Fuchs corneal dystrophy (FCD) is an autosomal dominant disease of the corneal endothelium with variable penetrance and expressivity. Recently, rs613872, an intronic variation of TCF4 associated with late-onset FCD, was reported. The present study was undertaken to examine this association in our cohort of FCD patients, to assess the significance of this finding, and to investigate the candidacy of TCF4 in the context of the mapped FCD2 locus. METHODS. The authors recruited 170 patients with late-onset FCD and 180 age-matched controls. Blood samples were collected, and genomic DNA was extracted. A panel of nine SNPs spanning the entire TCF4 locus was genotyped both on this cohort and on three previously reported FCD2-linked families. The association of an individual SNP with late-onset FCD was evaluated with the Fisher exact test, and the coding exons and exon-intron boundaries of TCF4 were sequenced in 96 affected persons. RESULTS. The risk allele G of rs613872 is associated significantly with late-onset FCD (odds ratio, 4.2; P ϭ 4.28 ϫ 10 Ϫ15 ) and was present in male and female affected persons without any sex bias, replicating recent findings, though the authors found no apparent correlation with the severity of the disease phenotype. Moreover, the risk allele did not cosegregate with the disease phenotype in any of the three FCD2-linked families. The authors did not identify any pathogenic variants in the coding region of TCF4. CONCLUSIONS. The authors report the first independent replication of rs613872 conferring risk of late-onset FCD. Their data suggest that this risk factor is likely independent of the FCD2 locus, whose causality remains unknown. (Invest Ophthalmol Vis Sci

Linkage of a mild late-onset phenotype of Fuchs corneal dystrophy to a novel locus at 5q33.1q35.2

PURPOSE. To identify the disease locus associated with autosomal dominant Fuchs corneal dystrophy (FCD) in a large family and to compare the progression of severity in families mapped to the FCD1 and FCD2 loci. METHODS. Seventeen individuals in a large family were examined by slit lamp biomicroscopy. Blood samples were collected, DNA was extracted, and a genome-wide scan was performed with a microarray SNP chip. After initial generation of a genome-wide, two-point LOD score, linkage was confirmed and the critical interval was established by genotyping of short tandem repeat (STR) microsatellite markers. RESULTS. A genome-wide linkage scan localized the disease interval to the long arm of chromosome 5, with a maximum two-point parametric LOD score of 3.41. Haplotype analyses refined the critical interval to 5q33.1-q35.2, spanning a 27-Mb (29-cM) region. Clinical examination of affected individuals in this family revealed an early onset of FCD at approximately age 40, after which progression of the disease was significantly attenuated compared to the FCD1-and FCD2-linked families. CONCLUSIONS. Late-onset FCD is linked to a novel locus on 5q33.1-q35.2 and is associated with a milder severity in age at onset and rate of progression than the FCD1 and FCD2 loci. Correlation of individual genotypes with unique rates of disease progression will provide important tools for disease management, as well as for identifying the underlying genetic lesion, offer insight into the pathomechanism of FCD. (Invest Ophthalmol Vis Sci. 2009;50:5667-5671

Design of Container Ship Main Engine Waste Heat Recovery Supercritical CO2 Cycles, Optimum Cycle Selection through Thermo-Economic Optimization with Genetic Algorithm and Its Exergo-Economic and Exergo-Environmental Analysis

In the present study, energy and exergy analyses of a simple supercritical, a split supercritical and a cascade supercritical CO2 cycle are conducted. The bottoming cycles are coupled with the main two-stroke diesel engine of a 6800 TEU container ship. An economic analysis is carried out to calculate the total capital cost of these installations. The functional parameters of these cycles are optimized to minimize the electricity production cost (EPC) using a genetic algorithm. Exergo-economic and exergo-environmental analyses are conducted to calculate the cost of the exergetic streams and various exergo-environmental parameters. A parametric analysis is performed for the optimum bottoming cycle to investigate the impact of ambient conditions on the energetic, exergetic, exergo-economic and exergo-environmental key performance indicators. The theoretical results of the integrated analysis showed that the installation and operation of a waste heat recovery optimized split supercritical CO2 cycle in a 6800 TEU container ship can generate almost 2 MW of additional electric power with a thermal efficiency of 14%, leading to high fuel and CO2 emission savings from auxiliary diesel generators and contributing to economically viable shipping decarbonization

Design of Container Ship Main Engine Waste Heat Recovery Supercritical CO₂ Cycles, Optimum Cycle Selection through Thermo-Economic Optimization with Genetic Algorithm and Its Exergo-Economic and Exergo-Environmental Analysis

In the present study, energy and exergy analyses of a simple supercritical, a split supercritical and a cascade supercritical CO2 cycle are conducted. The bottoming cycles are coupled with the main two-stroke diesel engine of a 6800 TEU container ship. An economic analysis is carried out to calculate the total capital cost of these installations. The functional parameters of these cycles are optimized to minimize the electricity production cost (EPC) using a genetic algorithm. Exergo-economic and exergo-environmental analyses are conducted to calculate the cost of the exergetic streams and various exergo-environmental parameters. A parametric analysis is performed for the optimum bottoming cycle to investigate the impact of ambient conditions on the energetic, exergetic, exergo-economic and exergo-environmental key performance indicators. The theoretical results of the integrated analysis showed that the installation and operation of a waste heat recovery optimized split supercritical CO2 cycle in a 6800 TEU container ship can generate almost 2 MW of additional electric power with a thermal efficiency of 14%, leading to high fuel and CO2 emission savings from auxiliary diesel generators and contributing to economically viable shipping decarbonization

Age-Severity Relationships in Families Linked to FCD2 with Retroillumination Photography

Fuchs corneal dystrophy (FCD) is a common ocular disorder that affects approximately 4% of the United States population over the age of 40. This study examines the age-severity relationship in families with late-onset FCD through the use of retroillumination photography