Epidemiologic analysis of families with isolated anorectal malformations suggests high prevalence of autosomal dominant inheritance

Background: Anorectal malformations (ARM) are rare abnormalities that occur in approximately 1 in 3000 live births with around 40% of patients presenting with isolated forms. Multiple familial cases reported, suggest underlying genetic factors that remain largely unknown. The recurrence in relatives is considered rare, however transmission rates of ARM by affected parents have never been determined before. The inheritance pattern of ARM was investigated in our database of patients with isolated ARM. Results: Within our cohort of 327 patients with isolated ARM we identified eight adult patients from eight families who had in total 16 children with their healthy spouse. Of these ten had ARM, resulting in a recurrence risk of approximately one in two live births (10 of 16; 62%). From 226 families with 459 siblings we found two affected siblings in five families. Hence, the recurrence risk of ARM among siblings is approximately one in 92 live births (5 of 459; 1.0%). Conclusions: Comparing the observed recurrence risk in our cohort with the prevalence in the general population, we see a 1500-fold increase in recurrence risk for offspring and a 32-fold increase if a sibling is affected. The recurrence risk of approximately 62% indicates an autosomal dominant mode of inheritance. Reliable figures on recurrence of ARM are becoming increasingly important since improved surgical techniques are able to maintain sexual function resulting in more offspring of patients with ARM. These data allow more precise counseling of families with ARM and support the need for genetic studies

Genome-wide association study in patients with posterior urethral valves

Congenital lower urinary tract obstructions (LUTO) are most often caused by posterior urethral valves (PUV), a male limited anatomical obstruction of the urethra affecting 1 in 4,000 male live births. Little is known about the genetic background of PUV. Here, we report the largest genome-wide association study (GWAS) for PUV in 4 cohorts of patients and controls. The final meta-analysis included 756 patients and 4,823 ethnicity matched controls and comprised 5,754,208 variants that were genotyped or imputed and passed quality control in all 4 cohorts. No genome-wide significant locus was identified, but 33 variants showed suggestive significance (P < 1 × 10−5). When considering only loci with multiple variants residing within < 10 kB of each other showing suggestive significance and with the same effect direction in all 4 cohorts, 3 loci comprising a total of 9 variants remained. These loci resided on chromosomes 13, 16, and 20. The present GWAS and meta-analysis is the largest genetic study on PUV performed to date. The fact that no genome-wide significant locus was identified, can be explained by lack of power or may indicate that common variants do not play a major role in the etiology of PUV. Nevertheless, future studies are warranted to replicate and validate the 3 loci that yielded suggestive associations

Research perspectives in the etiology of congenital anorectal malformations using data of the International Consortium on Anorectal Malformations: evidence for risk factors across different populations

Contains fulltext : 89406.pdf (publisher's version ) (Closed access)PURPOSE: The recently established International Consortium on Anorectal Malformations aims to identify genetic and environmental risk factors in the etiology of syndromic and nonsyndromic anorectal malformations (ARM) by promoting collaboration through data sharing and combined research activities. METHODS: The consortium attempts to recruit at least 1,000 ARM cases. DNA samples are collected from case-parent triads to identify genetic factors involved in ARM. Several genetic techniques will be applied, including SNP arrays, gene and whole exome sequencing, and a genome-wide association study. Questionnaires inquiring about circumstances before and during pregnancy will be used to obtain environmental risk factor data. RESULTS: Currently, 701 ARM cases have been recruited throughout Europe. Clinical data are available from all cases, and DNA samples and questionnaire data mainly from the Dutch and German cases. Preliminary analyses on environmental risk factors in the Dutch and German cohort found associations between ARM and family history of ARM, fever during first trimester of pregnancy and maternal job exposure to cleaning agents and solvents. CONCLUSION: First results show that both genetic and environmental factors may contribute to the multifactorial etiology of ARM. The International Consortium on Anorectal Malformations will provide possibilities to study and detect important genes and environmental risk factors for ARM, ultimately resulting in better genetic counseling, improved therapies, and primary prevention.1 november 201

Identification of de novo variants in nonsyndromic cleft lip with/without cleft palate patients with low polygenic risk scores

[Background]: Nonsyndromic cleft lip with/without cleft palate (nsCL/P) is a congenital malformation of multifactorial etiology. Research has identified >40 genome-wide significant risk loci, which explain less than 40% of nsCL/P heritability. Studies show that some of the hidden heritability is explained by rare penetrant variants. [Methods]: To identify new candidate genes, we searched for highly penetrant de novo variants (DNVs) in 50 nsCL/P patient/parent-trios with a low polygenic risk for the phenotype (discovery). We prioritized DNV-carrying candidate genes from the discovery for resequencing in independent cohorts of 1010 nsCL/P patients of diverse ethnicities and 1574 population-matched controls (replication). Segregation analyses and rare variant association in the replication cohort, in combination with additional data (genome-wide association data, expression, protein–protein-interactions), were used for final prioritization. [Conclusion]: In the discovery step, 60 DNVs were identified in 60 genes, including a variant in the established nsCL/P risk gene CDH1. Re-sequencing of 32 prioritized genes led to the identification of 373 rare, likely pathogenic variants. Finally, MDN1 and PAXIP1 were prioritized as top candidates. Our findings demonstrate that DNV detection, including polygenic risk score analysis, is a powerful tool for identifying nsCL/P candidate genes, which can also be applied to other multifactorial congenital malformations.The present study was supported by the German Research Foundation (DFG)-Grants BE 3828/8-1, LU 1944/2-1, MA 2546/5-1, and LU1944/3-1

Whole exome resequencing reveals recessive mutations in TRAP1 in individuals with CAKUT and VACTERL association

Congenital abnormalities of the kidney and urinary tract (CAKUT) account for approximately half of children with chronic kidney disease and they are the most frequent cause of end-stage renal disease in children in the US. However, its genetic etiology remains mostly elusive. VACTERL association is a rare disorder that involves congenital abnormalities in multiple organs including the kidney and urinary tract in up to 60% of the cases. By homozygosity mapping and whole exome resequencing combined with high-throughput mutation analysis by array-based multiplex PCR and next-generation sequencing, we identified recessive mutations in the gene TNF receptor-associated protein 1 (TRAP1) in two families with isolated CAKUT and three families with VACTERL association. TRAP1 is a heat shock protein 90-related mitochondrial chaperone possibly involved in antiapoptotic and endoplasmic reticulum-stress signaling. Trap1 is expressed in renal epithelia of developing mouse kidney E13.5 and in the kidney of adult rats, most prominently in proximal tubules and in thick medullary ascending limbs of Henle’s loop. Thus, we identified mutations in TRAP1 as highly likely causing CAKUT or CAKUT in VACTERL association

ISL1 is a major susceptibility gene for classic bladder exstrophy and a regulator of urinary tract development.

Previously genome-wide association methods in patients with classic bladder exstrophy (CBE) found association with ISL1, a master control gene expressed in pericloacal mesenchyme. This study sought to further explore the genetics in a larger set of patients following-up on the most promising genomic regions previously reported. Genotypes of 12 markers obtained from 268 CBE patients of Australian, British, German Italian, Spanish and Swedish origin and 1,354 ethnically matched controls and from 92 CBE case-parent trios from North America were analysed. Only marker rs6874700 at the ISL1 locus showed association (p = 2.22 × 10-08). A meta-analysis of rs6874700 of our previous and present study showed a p value of 9.2 × 10-19. Developmental biology models were used to clarify the location of ISL1 activity in the forming urinary tract. Genetic lineage analysis of Isl1-expressing cells by the lineage tracer mouse model showed Isl1-expressing cells in the urinary tract of mouse embryos at E10.5 and distributed in the bladder at E15.5. Expression of isl1 in zebrafish larvae staged 48 hpf was detected in a small region of the developing pronephros. Our study supports ISL1 as a major susceptibility gene for CBE and as a regulator of urinary tract development

Characterization of Heat and Momentum Transfer in Sintered Metal Foams

In this study, metal foams made by the Slip Reaction Foam Sintering (SRFS)-process are investigated concerning their thermophysical and permeability properties. Using the acquired experimental data, a proposal is made for the calculation of the inner surface temperature of the combustion chamber as well as the temperature distribution inside the chamber wall, which consists of a structural element, the metal foam and a thermal barrier coating, equipped with laser drilled micro-holes

EXPERIMENTAL INVESTIGATION OF HEAT TRANSFER AND PRESSURE DROP IN POROUS METAL FOAMS

Metal foams made by the SlipReactionFoamSintering (SRFS)-process are investigated. In these foams the pores are produced by a reaction between iron and a weak acid. The generated hydrogen forms pores in a metal powder slurry. These pores remain in the foam after sintering. Also secondary pores are found in these foams because of the sintering of the metal powder slurry. The metal powder base of the foams is Inconel 625 and Hastelloy B. Foam samples with a variety of different porosities of the two metals in the range of about 62 % to 87 % are used as well as samples made out of sintered metal powder which were not foamed with porosities of around 50 %. The motivation for this study is to use these foams as combustion chamber walls in gas fired power plants. By using porous walls effusion cooling can be applied to keep the wall temperatures low. Air is used as a fluid to study the flow characteristics of these samples. Their pressure drop with air at room temperature is measured in the range of velocities of up to around 1 m/s. The parameters characterizing the foams are obtained using the Darcy-Forchheimer equations resulting in the permeability and the inertial coefficients. The dependency on the porosity is discussed. The volumetric heat transfer is measured for the foams by a transient method based on an air flow with a sinusoidal temperature wave, which is attenuated by the sample. The obtained volumetric heat transfer coefficients are discussed and transferred to Nu-Re correlations. Correlations between the heat transfer coefficients and the pressure drop coefficients are made

Effective thermal conductivity of metallic foams determined with the transient plane source technique

This article presents experimental results of thermal conductivity in metal foams. The thermal conductivity of cellular solids differs from those of their corresponding dense material. Therefore, the various pore size level effects contributing to the thermal conductivity are comprised by introducing an effective thermal conductivity. In this work we investigated metallic foams with a porosity ranging from 0.65 to 0.82 manufactured by the Slip Reaction Foam Sintering (SRFS) Process using a nickel-based powder. For the determination of the effective thermal conductivity at room temperature, we employed the Transient Plane Source Technique also known as Hot Disk. We verified the influence of the porosity and the thermal conductivity of the solid phase on the effective conductivity and compared the measured values of the effective conductivity with theoretical ones calculated using the thermal conductivity of the solid phase and the solid volume fraction. We present here a simple model that demonstrates the influence of the geometry of the grid elements qualitatively, discuss the applicability of the method to heterogeneous materials such as metallic foams and give an outlook about further investigations at higher temperatures

Characterisation of Air flow Through Sintered Metal Foams

This study investigates air flow in metallic foams, which are produced by the SlipReactionFoamSintering (SRFS)-process. It was conducted as part of the collaborative research center (SFB) 561 “Thermally Highly Loaded, Porous and Cooled Multi-Layer Systems for Combined Cycle Power Plants”. The flow through a porous medium is analysed by Darcy’s equation with the Dupuit/Forchheimer extension. All measurements can be described very well by this equation and permeability and inertial coefficients are obtained for a large quantity of samples with different base materials and different porosities. A threshold porosity of 70 % is observed, above which the pressure loss starts sinking significantly with porosity. Additionally, it was found, that the permeability was anisotropic. Permeability is lower in the direction of gravity during foaming. Scattering in the data of the permeability and inertial coefficients versus the porosity is observed and discussed