Genome analysis-Opinion

Write a blog post to share your perspective on diagnostic full genome sequence analysis. This posting will be more “opinion” based than others.

The genome analysis-Opinion.

There are more than 2.0 billion Muslims that comprise 23% of population living in almost 50 Muslim and many non-Muslim countries in the world.
Muslims follow the religion of monotheistic belief called Islam, which permits its followers to marry with their first cousins. In some cases the inter-family marriages for generations result in congenital disorders. Nowadays in developed countries if a Muslim man or women plan to marry their immediate relatives the transmission of congenital disorder can be prevented with the use of genome analysis.
The chromosomal micro-array analysis has been suggested as the first-tier diagnostic test for the patients with developmental delay and intellectual delay as well as the people with history of chromosomal anomalies and three consecutive miscarriages (Miller et al., 2010). The Muslim couple interested in marriage in the immediate family need to have their genome analysis done especially if similar marriages have taken place in the past and there is a family history of congenital anomalies. The matter of affording the genome analysis is interesting as the people in my culture spend a lump sum of money on the weddings etc. The couple that is planning to marry in the family should proceed in a safe way and get the whole genome sequence analysis (WGS) done to exclude any major contraindication to the wedding plans and avoid the complications in their future progeny. It the children have developmental delays or some mysterious conditions, which are not diagnosed by the regular tests genome sequencing is recommended.
Exome analysis was used to diagnose the cause of rare Mendelian disorder Miller syndromethat is caused by the alteration of a gene DHODH extending onto the 09 exons in the total exome and was involved in the synthesis of pyrimidine (Bamshad. et. al., 2011). It is cheaper to do the total exome analysis but in complicated conditions the whole genome sequencing (WGS) is advised. WGS was used to diagnose a rare recessive form of Charcot-Marie-Tooth-disease. The underlying genetic mutation was identified to be compound heterozygous allele with two mutations (Lupski et al., 2010). WGS is not only used to diagnose a complicated disease but is also done to help and guide the treatment of a complex genetic variant with complex inheritance. L-dopa responsive dystonia (DRD) is inherited in a diverse fashion (autosomal recessive {TH gene}, autosomal dominant {GCH1 gene}, {SPR gene} autosomal recessive or dominant). In a case study of fraternal twins diagnosed with DRD did not respond to the current treatment (dopamine), a WGS done for the twins identified a DRD variant involving genes with disruption of multiple enzymes. The treatment with L-dopa and a serotonin precursor showed marked improvement in the clinical conditions of these twins with DRD (Bainbridge et al., 2011).
Thorough genome analysis is also advised in some cryptic (mysterious) mutation of 20-100 bp genes resulting in the altered genes by-products mostly proteins. These proteins are special biomarkers as they are the present in tumor cells and are also causative factors of some cancers. KRAS and TP53 are the genes studied extensively in the causation of different kinds of cancer such as colorectal cancer and lung cancer. (Vogelstein et.al, 2012 & Wang et al., 2011). As in the study of treatment of the congenital diseases WGS is also recommended in the patients with the cancer non-responsive to the standardized treatment. These patients many of the times have the altered mutation resulting in an alternative reason of causing the cancer of the similar nature as seen before in other patients. The WGS will discern the cryptic mutation and help the physician decide an alternative treatment. Acute Myeloid Leukemia (AML) is caused by the translocation between the chromosome 15 and 17. In some variants cases the translocation can occur on 3 or 4 different sites and such mutation is only diagnosed by the WGS. The AML resulting of t (15; 17) is responsive to the general treatment but the AML resulting from different mutation are not responsive to the treatment thus making the WGS a diagnostic test (Welch et al., 2011)

References:

• Bainbridge, M. N., Wiszniewski, W., Murdock, D. R., Friedman, J., Gonzaga-Jauregui, C., Newsham, I., … others. (2011). Whole-genome sequencing for optimized patient management. Science Translational Medicine, 3(87), 87re3–87re3.
• Bamshad, M. J., Ng, S. B., Bigham, A. W., Tabor, H. K., Emond, M. J., Nickerson, D. A.,& Shendure, J. (2011). Exome sequencing as a tool for Mendelian disease gene discovery. Nature Reviews Genetics, 12(11), 745–755.
• Lupski, J. R., Reid, J. G., Gonzaga-Jauregui, C., Rio Deiros, D., Chen, D. C., Nazareth, L., … others. (2010). Whole-genome sequencing in a patient with Charcot–Marie–Tooth neuropathy. New England Journal of Medicine, 362(13), 1181–1191.
• Miller, D. T., Adam, M. P., Aradhya, S., Biesecker, L. G., Brothman, A. R., Carter, N. P.,… Ledbetter, D. H. (2010). Consensus Statement: Chromosomal Microarray Is a First-Tier Clinical Diagnostic Test for Individuals with Developmental Disabilities or Congenital Anomalies. The American Journal of Human Genetics,86(5), 749–764. doi:10.1016/j.ajhg.2010.04.006
• Vogelstein, B., Wang, Q., Pandey, A., Kinzler, K. W., & Papadopoulos, N. (2012). Mutant Proteins as Cancer-Specific Biomarkers. Google Patents. Retrieved from http://www-google-com.proxy.library.umkc.edu/patents/US20140051105
• Wang, Q., Chaerkady, R., Wu, J., Hwang, H. J., Papadopoulos, N., Kopelovich, L., …others. (2011). Mutant proteins as cancer-specific biomarkers. Proceedings of the National Academy of Sciences, 108(6), 2444–2449.
• Welch, J. S., Westervelt, P., Ding, L., Larson, D. E., Klco, J. M., Kulkarni, S., … others. (2011). Use of whole-genome sequencing to diagnose a cryptic fusion oncogene. Jama,305(15), 1577–1584.