Patients faced with a genetic disease are asking clinicians. In many instances there is a known underlying reason for a disorder afflicting a family. Medical Information UK the knowledge of a specific disease-causative mutation(s) allows not only better disease prognosis but also allows families to ensure that the next generation of kids will be free of disease.
Single-gene disorders are individually rare, but with more than 3500 Mendelian disorders, for half of which disease gene has not yet been uncovered, enthrall an enormous impact on the well-being of over 500,000 children in Canada.
Genetics in conjunction with pre-implantation genetic diagnostics (PDG), can save life long suffering from a genetic disease, but only if there is a clear understanding of disease susceptibility. Knowing individual’s genomic profile allow us to better prepare or to avoid the negative impacts they might have on health and lifespan of the individual an his/her descendants.
Until recently we did not know how to identify rapidly the underlying mutations within our genome. The genetic mapping process required analysis of multiple affected families with similar disease manifestations, but in many cases the final result was inconclusive as resolution of this analysis was too low.
Recently genetic technologies have developed at neck braking speed creating a huge gap in understanding of the benefits and limitations for general population as well as the majority of medical professionals. In the short years since the first Next Generation Sequencing (NGS) became available it has dramatically accelerated multiple areas of genomics research, uncovering genetic defects underlying inherited disorders.
Today, the number of known disease causing mutations exceeds 100,000 in more than 3700 different genes. However, this figure represents only a small fraction of the clinically relevant genetic variants in the human genome – recent studies have estimated that about 40% of disease-causing mutations are so rare that they occur only in one family.
NGS, and specifically exome sequencing, brings new ways of assessing genetic disorders: protein-coding genes constitute only approximately 1% of the human genome but harbor about 85% of the disease-causing mutations. Therefore, exome analysis allows capturing most Mendelian disorders that are caused by “coding mutations” or splice-site mutations.
Our current challenge is the ability to identify a pathogenic variant among the many thousands of new variants detected in each individual. With the development of bioinformatics analysis tools and the availability and rapidly decreasing cost exome sequencing offer new opportunities for identifying new causes of genetic disease.
Several initiatives such as the Canadian Pediatric Genetic Disorders Sequencing (CPGDS) Consortium that evolved in to larger Finding of Rare Disease Genes (FORGE Canada), and Rare Disease Consortium for Autosomal Loci (RaDiCAL) aim to characterize Mendelian disorders through exome sequencing.
This technology already has lead to remarkable life-saving discoveries: Nicholas Volker is the first boy saved by sequencing technology. Since birth he was afflicted with “mysterious” severe inflammatory bowel disease due to a mutation in XIAP – one of immune response genes, so doctors figured our that a bone morrow transplant will cure his disease. Another remarkable example is Shelby’s story who was a severely disabled by an autism-like disorder to ditch a wheelchair after scientists where able to find appropriate medication based on her genetic profile.
Pioneering work is being done at Children’s Mercy Hospitals and Clinics in Kansas City where physicians sequenced genomes of 40 sick babies in the Neonatal Intensive Care Unit within 50 hours. “Up to one third of babies admitted to a NICU in the U.S. have genetic diseases,” said Stephen Kingsmore, M.B. Ch.B., D.Sc., FRCPath, Director of the Center for Pediatric Genomic Medicine at Children’s Mercy. “By obtaining an interpreted genome in about two days, physicians can make practical use of diagnostic results to tailor treatments to individual infants and children.”
Ironically, the power of exome sequencing is not yet harnessed for analysis of fertility and family planning. Understanding of inherited genetic risks helps to avoid many preventable tragedies such as children’s death due to heart failure as majority of these conditions are congenital – i.e. have underlying genetic cause.
Family is the essential unit of health from multiple perspective and members share the same environmental risk factors such as dietary habits, as well as emotional and genetic connections that together impact on happiness and longevity. Therefore, we advocate proactive family planning starting with genetic analysis of prospective parents.