Kindred 1-A Kindred 1 (A+B) Filter Dominant Recessive Dominant Recessive Dominan
ID: 175263 • Letter: K
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Kindred 1-A Kindred 1 (A+B) Filter Dominant Recessive Dominant Recessive Dominant Recessive Dominant Recessive Dominant Recessive 4,687 2,654 1,525 NS/SS/I 2,863 2,859 3,940 2,362 3,099 4,670 1,810 Not in dbSNP129 641 102 647 114 369 53 105 25 63 21 Not in HapMap 8 898 123 923 128 506 46 Not in either 456 31 464 Predicted damaging 204 204 12 83 Each cell indicates the number of genes with nonsynonymous (NS) variants, splice acceptor and donor site mutations (SS) and coding indels (l). Filtering either by requiring the presence of NS/SS/I variants in siblings (kindred 1 (A+B)) or of multiple unrelated individuals (columns) or by excluding annotated variants (rows) identifies 26 and 8 candidate genes under a dominant model and only a single candidate gene, DHODH, under a recessive model (light gray cells). Exclusion of mutations predicted to be benign using PolyPhen (row 5) increases sensitivity under a dominant model but excludes DHODH under a recessive model because a variant in kindred 1 is predicted to be benign. A single candidate gene is identified in kindred 1 under a recessive model and excluding benign mutations (dark gray ce but this candidate is excluded in comparisons with unrelated cases of Miller syndrome. Mutations in this candidate, DNAH5, were found to cause a primary ciliary dyskinesia in kindred 1. The asterisk indicates that a second gene, CDC27, was also identified as a candidate gene, but this is due to the presence of multiple copies of a processed pseudogene that recurrently gave rise to a false positive s in excome analysesExplanation / Answer
Miller syndrome is a rare disorder that is inherited in the autosomal recessive pattern. So, generally the causing variants are not visible in the public SNP databases and in control exomes.
Genes responsible for recessive diseases are easier to be identified than those responsible for dominant diseases. This is because very few genes in any individual have two or more rare non-synonymous variants.
Variants are not identified easily in the current sequencing maps due to low coverage. The filtering of these variants is done by using public SNP database, which has an uneven confirmation of variation across the genome. The study depended on catalogs of common variation exome wide (HapMap8) or genome wide (1000 genome project). The estimates of allele frequencies are also available in these databases.
The increase in the control exome number gradually reduces the importance of dbSNP in this analysis. As the deeper details of polymorphism are revealed, determining frequency-based thresholds is necessary for defining common variation that is not likely to cause the disease.
NS- non-synonymous
SS- splice acceptor and donor site mutations
dbSNP129 – new variant that is not present in the datasets used for comparison
HapMap8 – Exome data from previous study
Kindred1 is an individual with Mendelian disorder. Kindred1A and Kindred1B are two siblings with the disorder. Kindred2 and Kindred3, kindred1 (A+B) are other cases of individuals with Mendelian disorder.
The table explains the number of genes in the dominant and recessive categories that possess the given types of variants leading to Mendelian disorder in each of the individuals.
Each individual of kinderd1 (A and B) are found to have at least one single variant of NS/SS/I type in approximately 4600 genes. These are categorized under dominant. If these variants are observed to be present in two or more in number in approximately 2800 genes, then they are categorized under recessive.
In the dominant model, for the identification of Miller syndrome, each individual is needed to be having at least one NS/SS/I variant in the same gene. If these variants are filtered against dbSNP129 and eight HapMap exomes, the candidate gene pool decreased to approximately 40-fold compared to the entire CCDS gene set (NCBI consensus coding sequence data set).
In the recessive model, each individual is required to have at least two of NS/SS/I variants in the same gene and the candidate pool is decreased to greater than 500-fold in comparison to the CCDS gene set.
These two individuals were considered to be the causal factors for Miller syndrome. The decreased pool of candidate genes with variants for Miller syndrome in the dominant model was 228 and in the recessive model it was found to be 9.
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