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10.1007/s00467-016-3513-3 http://scihub22266oqcxt.onion/10.1007/s00467-016-3513-3 C5483602!5483602 !27766458     free     free     free Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 265.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 265.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Warning: imagejpeg(C:\Inetpub\vhosts\kidney.de\httpdocs\phplern\27766458 .jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117       Pediatr+Nephrol 2017 ; 32 (3 ): 467-476 Nephropedia Template TP {{tp|p=27766458 |t=2017. Evaluating Mendelian nephrotic syndrome genes for evidence for risk alleles or oligogenicity that explain heritability |pdf=|usr=}}{{27766458 }} gab.com Text Evaluating Mendelian nephrotic syndrome genes for evidence for risk alleles or oligogenicity that explain heritability JO: Pediatr Nephrol http://www.kidney.de/pget.php?&tw=1&pmid=27766458 #FOAvip BACKGROUND: More than 30 genes can harbor rare exonic variants sufficient to cause nephrotic syndrome (NS), and the number of genes implicated in monogenic NS continues to grow. However, outside the first year of life, the majority of affected patients, particularly in ancestrally mixed populations, do not have a known monogenic form of NS. Even in those children classified with a monogenic form of NS, there is phenotypic heterogeneity. Thus, we have only discovered a fraction of the heritability of NS-the underlying genetic factors contributing to phenotypic variation. Part of the "missing heritability" for NS has been posited to be explained by patients harboring coding variants across one or more previously implicated NS genes, insufficient to cause NS in a classical Mendelian manner, but that nonetheless have a sufficient impact on protein function to cause disease. However, systematic evaluation in patients with NS for rare or low-frequency risk alleles within single genes, or in combination across genes ("oligogenicity"), has not been reported. To determine whether, compared with a reference population, patients with NS have either a significantly increased burden of protein-altering variants ("risk-alleles"), or a unique combination of them ("oligogenicity"), in a set of 21 genes implicated in Mendelian forms of NS. METHODS: In 303 patients with NS enrolled in the Nephrotic Syndrome Study Network (NEPTUNE), we performed targeted amplification paired with next-generation sequencing of 21 genes implicated in monogenic NS. We created a high-quality variant call set and compared it with a variant call set of the same genes in a reference population composed of 2,535 individuals from phase 3 of the 1000 Genomes Project. We created both a "stringent" and a "relaxed" pathogenicity-filtering pipeline, applied them to both cohorts, and computed the burden of variants in the entire gene set per cohort, the burden of variants in the entire gene set per individual, the burden of variants within a single gene per cohort, and unique combinations of variants across two or more genes per cohort. RESULTS: With few exceptions when using the relaxed filter, and which are likely the result of confounding by population stratification, NS patients did not have a significantly increased burden of variants in Mendelian NS genes in comparison to a reference cohort, nor was there any evidence for oligogenicity. This was true when using both the relaxed and the stringent variant pathogenicity filter. CONCLUSION: In our study, there were no significant differences in the burden or particular combinations of low-frequency or rare protein-altering variants in a previously implicated Mendelian NS genes cohort between North American patients with NS and a reference population. Studies in larger independent cohorts or meta-analyses are needed to assess the generalizability of our discoveries and also address whether there is in fact small but significant enrichment of risk alleles or oligogenicity in NS cases that was undetectable with this current sample size. It is still possible that rare protein-altering variants in these genes, insufficient to cause Mendelian disease, still contribute to NS as risk alleles and/or via oligogenicity. However, we suggest that more accurate bioinformatic analyses and the incorporation of functional assays would be necessary to identify bona fide instances of this form of genetic architecture as a contributor to the heritability of NS. Twit Text FOAVip Evaluating Mendelian nephrotic syndrome genes for evidence for risk alleles or oligogenicity that explain heritability ????Pediatr Nephrol http://www.kidney.de/pget.php?&tw=1&pmid=27766458 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=27766458 #FOAvip English Wikipedia <ref>{{Cite pmid|27766458 }}</ref> Evaluating Mendelian nephrotic syndrome genes for evidence for risk alleles or oligogenicity that explain heritability #MMPMID27766458 Crawford BD ; Gillies CE ; Robertson CC ; Kretzler M ; Otto EA ; Vega-Warner V ; Sampson MG Pediatr Nephrol 2017[Mar]; 32 (3 ): 467-476 PMID27766458 show ga BACKGROUND: More than 30 genes can harbor rare exonic variants sufficient to cause nephrotic syndrome (NS), and the number of genes implicated in monogenic NS continues to grow. However, outside the first year of life, the majority of affected patients, particularly in ancestrally mixed populations, do not have a known monogenic form of NS. Even in those children classified with a monogenic form of NS, there is phenotypic heterogeneity. Thus, we have only discovered a fraction of the heritability of NS-the underlying genetic factors contributing to phenotypic variation. Part of the "missing heritability" for NS has been posited to be explained by patients harboring coding variants across one or more previously implicated NS genes, insufficient to cause NS in a classical Mendelian manner, but that nonetheless have a sufficient impact on protein function to cause disease. However, systematic evaluation in patients with NS for rare or low-frequency risk alleles within single genes, or in combination across genes ("oligogenicity"), has not been reported. To determine whether, compared with a reference population, patients with NS have either a significantly increased burden of protein-altering variants ("risk-alleles"), or a unique combination of them ("oligogenicity"), in a set of 21 genes implicated in Mendelian forms of NS. METHODS: In 303 patients with NS enrolled in the Nephrotic Syndrome Study Network (NEPTUNE), we performed targeted amplification paired with next-generation sequencing of 21 genes implicated in monogenic NS. We created a high-quality variant call set and compared it with a variant call set of the same genes in a reference population composed of 2,535 individuals from phase 3 of the 1000 Genomes Project. We created both a "stringent" and a "relaxed" pathogenicity-filtering pipeline, applied them to both cohorts, and computed the burden of variants in the entire gene set per cohort, the burden of variants in the entire gene set per individual, the burden of variants within a single gene per cohort, and unique combinations of variants across two or more genes per cohort. RESULTS: With few exceptions when using the relaxed filter, and which are likely the result of confounding by population stratification, NS patients did not have a significantly increased burden of variants in Mendelian NS genes in comparison to a reference cohort, nor was there any evidence for oligogenicity. This was true when using both the relaxed and the stringent variant pathogenicity filter. CONCLUSION: In our study, there were no significant differences in the burden or particular combinations of low-frequency or rare protein-altering variants in a previously implicated Mendelian NS genes cohort between North American patients with NS and a reference population. Studies in larger independent cohorts or meta-analyses are needed to assess the generalizability of our discoveries and also address whether there is in fact small but significant enrichment of risk alleles or oligogenicity in NS cases that was undetectable with this current sample size. It is still possible that rare protein-altering variants in these genes, insufficient to cause Mendelian disease, still contribute to NS as risk alleles and/or via oligogenicity. However, we suggest that more accurate bioinformatic analyses and the incorporation of functional assays would be necessary to identify bona fide instances of this form of genetic architecture as a contributor to the heritability of NS. |*Alleles [MESH] |Adolescent [MESH] |Adult [MESH] |Age of Onset [MESH] |Child [MESH] |Child, Preschool [MESH] |Cohort Studies [MESH] |Female [MESH] |Gene Frequency [MESH] |Genetic Variation [MESH] |High-Throughput Nucleotide Sequencing [MESH] |Humans [MESH] |Male [MESH] |Middle Aged [MESH] |Mutation, Missense [MESH] |Nephrotic Syndrome/*genetics [MESH] |Phenotype [MESH] |Reference Values [MESH] |Risk [MESH]Evaluating Mendelian nephrotic syndrome genes for evidence for risk al(epmc).pdf DeepDyve Pubget Overpricing