##otype-Phenotype Correlation Prediction By In Silico Contributions : A Case Study

Researchers have associated mutations in specific genes with more than 50 hereditary cancer syndromes, which are disorders that may predispose individuals to developing certain cancers. Genetic tests can tell whether a person

CHARGE syndrome is a genetic condition believed to be the result of a sporadic heterozygous mutation in the CHD7 gene. Experiments to determine the precise mutations within the CHD7 gene have concluded that mutations are scattered throughout the gene and include nonsense, frameshift and missense mutations as well as intragenic deletions (Martínez-Quintana et al., 2014). Intragenic deletions were initially reported in 2004 by a team who optimized array comparative genome hybridization (CGH) for high-resolution genome-wide screening of copy-number variations. Array CGH has since become a valuable, genome-wide screening tool for the detection of chromosomal aberrations in the form of copy number imbalances. By utilizing array CGH in two individuals with CHARGE syndrome, the team was able to report a 2.3 Mb de novo overlapping microdeletion on chromosome 8q12 (Vissers et al., 2004).

Some mutations are harmful, however the mutations which are

Complementary DNA sequence analysis – This test detects sequence variants and has a mutation detection frequency of 70 – 93%.

mutation is phenylalanine 508 known as delta F508. Delta F508 is a deletion of 3 nucleotides

relatively rare single-gene or chromosomal disorders. But as result of advances in molecular medicine, genetics is now able to provide information about more common and accordingly more costly diseases such as Alzheimer’s disease, cancer, and coronary artery disease. It is the predictive ability of genetic tests for these diseases that makes them especially intriguing in adopting a preventive medicine approach and reducing overall healthcare expenditures.

Lysosomal storage diseases form due to the modification of lysosomal enzymes. The diseases can be metabolically inherited through gene mutation. In “Lysosomal Storage Disease”, Michael Kruer (2) claims that,

The LOX mutation was discovered by using whole-genome sequencing in a family exhibiting autosomal dominant TAAD. Two individuals from this family affected with TAAD were analyzed, and researchers were able to identify a missense mutation in the lysyl oxidase (LOX) gene,

The researchers were able to show that MGC1203 is involved in BBS in several ways. They noticed that this protein was the only protein to be present in two separate data sets in which they were identifying proteins that interacted with BBS genes in yeast. 3 MGC1203 was also found in similar locations as the BBS genes in tissues that are often affected by the disorder. They saw that of a group of patients with BBS, 6.2 percent had the 430T variation as compared to only 1.4 percent in the control group, showing a strong correlation between BBS and the 430T variant of MGC1203. They then discovered that five patients had two mutations on a locus for BBS, and also found one parent that was homozygous for 430T that was unaffected. This showed that MGC1203 mutations do not cause the BBS disorder, but show that the 430T mutation influences BBS genes. Ultimately, the researchers concluded that slight mutations to this protein can contribute to the BBS disorder epistatically, by modifying BBS genes in patients that already have a genetic background for the disorder. The 430T allele will change the use of a splice junction, resulting in improper use of exons. This that leads to a loss in a message sent by MGC1203, modifying the penetrance and expressivity of BBS genes. These interactions have a strong contribution in the severity of phenotypes between various BBS

Exome sequencing is one example of NGS that is useful when the identity of the specific genes involved in the disease has not yet been identified. The technique, which entails sequencing only the 1% of the genome that is exons and thus codes for proteins, is less costly than whole-genome sequencing and is increasingly being used for the diagnosis of rare inherited disorders. A 2013 study on MHS using exome sequencing was able to identify over 100 RYR1 and CACNA1S variants in an asymptomatic population, reclassify several previously classified pathogenic variants as likely non-pathogenic due to high prevalence, as well as alert several individuals with a high likelihood of MHS based on known pathogenic mutations7. The major use of large scale exome sequencing efforts in MHS is that they will allow researchers to identify the pathogenicity of variants identified in RYR1 and CACNA1S genes. In addition, the technique can be used in combination with functional studies to identify new mutations in families for whom traditional methods have not identified a mutation. A limitation of this technology, however, is that many variants of unknown significance (VUS) are frequently identified, making interpretation and large scale clinical application of the results

genetics, a causative mutation could be mapped to a chromosomal region using linkage analysis of

The affected gene of this disorder is the Shwachman Bodian Diamond Syndrome gene located on chromosome 7 with an interval of 1.9 cM at 7q11 (Boocock et al., 2002). The SBDS gene encodes a protein that is predicted to be 250 amino acids in length; however, this amino acid sequence has no homology to any known domains and there have not been any signal peptides detected (Boocock et al., 2002). The most common mutation that causes the disorder is a conversion mutation; frameshift, missense, and silent mutations have also been described. According to Boocock et al. (2002), the two most common mutations occur in exon two and are a thymine adenine to a cytosine thymine change at position 183 and an eight base pair deletion at the end of the exon. There is a pseudogene copy of SBDS located distally to the original gene that is the cause of the conversion mutations. These mutations can lead to a premature end of the encoded protein. Another unrelated mutation occurs in chromosome 20. In SDS patients, it has been found that there is a deletion of the long arm of chromosome 20 which leads to a loss of the EIF6 gene which functions in ribosome biogenesis (Vali et al., 2013). These mutations only occur in 90% of SDS patients; it has not been determined whether there is a different type of SDS that does not have a mutation or if these symptoms could be the cause of other undefined disorders (Myers et al.,

SNPs&GO (Single Nucleotide Polymorphism Database & Gene Ontology; http://snps.biofold.org/snps-and-go/snps-and-go.html) is an support vector machine (SVM) based method used to predict the disease related mutations from protein sequences with a scoring accuracy of 82% and Matthews correlation coefficient of 0.63. For SNPs&GO, FASTA sequence of whole protein is considered to be an input

Lysosomal storage diseases (LSDs) are a group of genetic disorders, resulting from deficiencies of lysosomal enzyme. Genotype-phenotype correlation is essential for timely and proper treatment allocation. Recently, by integrating prediction outcomes of 7 bioinformatics tools, we developed a SAAMP algorithm to predict amino acid substitutions. To optimize this approach, we evaluated the performance of these bioinformatics tools in a broad array of genes. PolyPhen and PROVEAN had the best performances, while SNP&GOs, PANTHER and I-Mutant had the worst performances. Therefore, SAAMP 2.0 was developed by excluding 3 tools with worst performance, yielding a sensitivity of 94% and a specificity of 90%. To generalize the guideline to

Keywords: Gene Identification, Splicing Site, Principal Component Analysis (PCA); Cased Based Reasoning (CBR); Support Vector Machine(SVM)