A Novel Deletion Mutation in Keratin 5 Causing the Removal of 5 Amino Acids and Elevated Mutant mRNA Levels in Dowling–Meara Epidermolysis Bullosa Simplex (original) (raw)
Related papers
2008
In genetic association studies, deviation from Hardy-Weinberg equilibrium (HWD) can be due to recent admixture or selection at a locus, but is most commonly due to genotyping errors. In addition to its utility for identifying potential genotyping errors in individual studies, here we report that HWD can be useful in detecting the presence, magnitude and direction of genotyping error across multiple studies. If there is a consistent genotyping error at a given locus, larger studies, in general, will show more evidence for HWD than small studies. As a result, for loci prone to genotyping errors, there will be a correlation between HWD and the study sample size. By contrast, in the absence of consistent genotyping errors, there will be a chance distribution of p-values among studies without correlation with sample size. We calculated the evidence for HWD at 17 separate polymorphic loci investigated in 325 published genetic association studies. In the full set of studies, there was a significant correlation between HWD and locus-standardised sample size (p ¼ 0.001). For 14/17 of the individual loci, there was a positive correlation between extent of HWD and sample size, with the evidence for two loci (5-HTTLPR and CTSD) rising to the level of statistical significance. Among single nucleotide polymorphisms (SNPs), 15/23 studies that deviated significantly from Hardy-Weinberg equilibrium (HWE) did so because of a deficit of heterozygotes. The inbreeding coefficient (F(is)) is a measure of the degree and direction of deviation from HWE. Among studies investigating SNPs, there was a significant correlation between F(is) and HWD (R ¼ 0.191; p ¼ 0.002), indicating that the greater the deviation from HWE, the greater the deficit of heterozygotes. By contrast, for repeat variants, only one in five studies that deviated significantly from HWE showed a deficit of heterozygotes and there was no significant correlation between F(is) and HWD. These results indicate the presence of HWD across multiple loci, with the magnitude of the deviation varying substantially from locus to locus. For SNPs, HWD tends to be due to a deficit of heterozygotes, indicating that allelic dropout may be the most prevalent genotyping error.
Evaluating the impact of genotype errors on rare variant tests of association
Frontiers in Genetics, 2014
The new class of rare variant tests has usually been evaluated assuming perfect genotype information. In reality, rare variant genotypes may be incorrect, and so rare variant tests should be robust to imperfect data. Errors and uncertainty in SNP genotyping are already known to dramatically impact statistical power for single marker tests on common variants and, in some cases, inflate the type I error rate. Recent results show that uncertainty in genotype calls derived from sequencing reads are dependent on several factors, including read depth, calling algorithm, number of alleles present in the sample, and the frequency at which an allele segregates in the population. We have recently proposed a general framework for the evaluation and investigation of rare variant tests of association, classifying most rare variant tests into one of two broad categories (length or joint tests). We use this framework to relate factors affecting genotype uncertainty to the power and type I error rate of rare variant tests. We find that non-differential genotype errors (an error process that occurs independent of phenotype) decrease power, with larger decreases for extremely rare variants, and for the common homozygote to heterozygote error. Differential genotype errors (an error process that is associated with phenotype status), lead to inflated type I error rates which are more likely to occur at sites with more common homozygote to heterozygote errors than vice versa. Finally, our work suggests that certain rare variant tests and study designs may be more robust to the inclusion of genotype errors. Further work is needed to directly integrate genotype calling algorithm decisions, study costs and test statistic choices to provide comprehensive design and analysis advice which appropriately accounts for the impact of genotype errors.
The American Journal of Human Genetics, 2019
More than 100,000 genetic variants are classified as disease causing in public databases. However, the true penetrance of many of these rare alleles is uncertain and might be overestimated by clinical ascertainment. Here, we use data from 379,768 UK Biobank (UKB) participants of European ancestry to assess the pathogenicity and penetrance of putatively clinically important rare variants. Although rare variants are harder to genotype accurately than common variants, we were able to classify as high quality 1,244 of 4,585 (27%) putatively clinically relevant rare (MAF < 1%) variants genotyped on the UKB microarray. We defined as ''clinically relevant'' variants that were classified as either pathogenic or likely pathogenic in ClinVar or are in genes known to cause two specific monogenic diseases: maturity-onset diabetes of the young (MODY) and severe developmental disorders (DDs). We assessed the penetrance and pathogenicity of these high-quality variants by testing their association with 401 clinically relevant traits. 27 of the variants were associated with a UKB trait, and we were able to refine the penetrance estimate for some of the variants. For example, the HNF4A c.340C>T (p.Arg114Trp) (GenBank: NM_175914.4) variant associated with diabetes is <10% penetrant by the time an individual is 40 years old. We also observed associations with relevant traits for heterozygous carriers of some rare recessive conditions, e.g., heterozygous carriers of the ERCC4 c.2395C>T (p.Arg799Trp) variant that causes Xeroderma pigmentosum were more susceptible to sunburn. Finally, we refute the previous disease association of RNF135 in developmental disorders. In conclusion, this study shows that very large population-based studies will help refine our understanding of the pathogenicity of rare genetic variants.
American journal of epidemiology, 2010
The authors survey uncommon variants (minor allele frequency, 5%) that have reached genome-wide significance (P 10 À7 ) in genome-wide association study(ies) (GWAS). They examine the typical effect sizes of these associations; whether they have arisen in multiple GWAS on the same phenotype; and whether they pertain to genetic loci that have other variants discovered through GWAS, perceived biologic plausibility from the candidate gene era, or known mutations associated with related phenotypes. Forty-three associations with minor allele frequency of 5% or less and P 10 À7 were studied, 12 of which involved nonsynonymous variants. Per-allele odds ratios ranged from 1.03 to 22.11. Thirty-two associations had P 10 À8 . Eight uncommon variants were identified in multiple GWAS. For 14 associations, also other common polymorphisms with genome-wide significance were identified in the same loci. Thirteen associations pertained to genetic loci considered to have biologic plausibility for association in the candidate gene era, and mutations with related phenotypic effects were identified for 11 associations. Twenty-five uncommon variants are common in at least 1 of the 4 different ancestry samples of the International HapMap Project. Although the number of uncommon variants with genome-wide significance is still limited, these data suggest a possible confluence of rare/uncommon and common genetic variation on the same genetic loci.
Journal of Dermatological Science, 1998
DNA polymorphic markers are useful for the prenatal diagnosis of generalized recessive dystrophic epidermolysis bullosa (GRDEB) in families with at least one child affected with the disease. It is our policy to investigate families at risk using DNA polymorphic markers before a new pregnancy is intended, to inform about the real chances of offering an accurate prenatal diagnosis based on such DNA markers. We have analysed 10 Spanish families with at least one child affected with GRDEB with three different markers linked to the type VII collagen gene: the intragenic P6uII RFLP, and two markers mapped close to the COL7A1 gene, an MspI polymorphism belonging to the anonymous marker D3S2, and the microsatellite D3S1100. The P6uII marker was partially informative in two of 10 families, and was not informative in the other eight families. The MspI marker was partially informative in two of 10 families, and was fully informative in three additional families; it was not informative in five families. The D3S1100 microsatellite was partially informative in two out of 10 families, and fully informative in the other eight families. Combination of all three markers was shown to be partially informative in one family and fully informative in the remaining nine families. Using this combination of markers, we have inferred an accurate linkage-based prenatal diagnosis of GRDEB in four pregnancies. Surprisingly, the intragenic marker P6uII had a very limited usefulness, despite the results of previous studies; the microsatellite D3S1100 offered the best results for an eventual prenatal diagnosis of GRDEB. However, families at risk should be informed that extragenic markers may fail due to the possibility of recombination, estimated as 5% for D3S1100.
Journal of Medical Genetics, 2005
Background: The haplotype based association method offers a powerful approach to complex disease gene mapping. In this method, a few common haplotypes that account for the vast majority of chromosomes in the populations are usually examined for association with disease phenotypes. This brings us to a critical question of whether rare haplotypes play an important role in influencing disease susceptibility and thus should not be ignored in the design and execution of association studies. Methods: To address this question we surveyed, in a large sample of 1873 white subjects, six candidate genes for osteoporosis (a common late onset bone disorder), which had 29 SNPs, an average marker density of 13 kb, and covered a total of 377 kb of the DNA sequence. Results: Our empirical data demonstrated that two rare haplotypes of the parathyroid hormone (PTH)/PTH related peptide receptor type 1 and vitamin D receptor genes (PTHR1 and VDR) with frequencies of 1.1% and 2.9%, respectively, had significant effects on osteoporosis phenotypes (p = 4.2 6 10 26 and p = 1.6 6 10 24 , respectively). Large phenotypic differences (4.0,5.0%) were observed between carriers of these rare haplotypes and non-carriers. Carriers of the two rare haplotypes showed quantitatively continuous variation in the population and were derived from a wide spectrum rather than from one extreme tail of the population phenotype distribution. Conclusions: These findings indicate that rare haplotypes/variants are important for disease susceptibility and cannot be ignored in genetics studies of complex diseases. The study has profound implications for association studies and applications of the HapMap project.
Genetic tests and their evaluation: Can we answer the key questions
Genetics in Medicine, 2004
The rapid pace of research in the field of genetics has already yielded many benefits. The development of new genetic tests is one such example. Before there can be widespread uptake of these tests they need to be evaluated to confirm the benefits of their use. The authors review some of the key features of the evaluation of diagnostic tests focusing on analytical and clinical validity. Test properties such as sensitivity, specificity, likelihood ratios, positive and negative predictive values, and how they relate to molecular genetic testing are discussed.