This story is about a family and how their lives were touched by recent evolutions in human genome sequencing technology and analysis. This family had two sick children affected by a rare genetic disease called Craniosynostosis that is characterized by abnormal fusion of the cranial plates and other associated problems. After running the full battery of available diagnostic tests, scientists were unable to identify the genetic cause of the disease in this family. The clinicians offered the family the option of having their full genomes sequenced and analyzed using Ingenuity Variant Analysis.

After receiving the whole genome sequence data, they were looking for a needle in a haystack (potentially a single nucleotide change that could be the culprit for the disease) or a single letter amid three billion in the patients’ DNA. The data for the affected patients and their mother and father were loaded into Variant Analysis. A little bit of information was provided to the system, such as the rare genetic disease of interest (Craniosynostosis), that the inheritance pattern is recessive, that the mother and father are unaffected and that the two kids are affected, and then the data was analyzed.

In Variant Analysis, there is a filter cascade or a series of lenses that help us focus on those variants that are most interesting in this particular study. The first filter removes common variants observed in healthy individuals at a high allele frequency on the grounds that these are unlikely to cause a rare disease. Next, the system identifies variants that are predicted to be deleterious and are expected to perturb a biological process or pathway. The system identifies variants that are consistent with the genetics in this study: recessive inheritance pattern. The system also identifies variants that have a relevant causal network— variants that are expected to exert pressure on genes or pathways/sub-networks known to be associated with Craniosynostosis.

This results in one likely causal variant in a gene— interleukin 11 receptor, alpha (IL11RA)— that is heterozygous in the mother and father and homozygous in the two affected children, and it has a direct causal network context that links it through multiple layers of biology down to the phenotype of interest, Craniosynostosis. The family came away with actionable information for reproductive planning, and mankind’s knowledge in the disease area has been fundamentally expanded to support future therapeutic and diagnostic tool development that will directly benefit other patients. This use case illustrates that patients with rare diseases will benefit from medical sequencing coupled with Ingenuity Variant Analysis. As part of the Rare Disease Science Challenge, Ingenuity has donated 100 Variant Analysis samples.

Dione  Bailey, has over 10 years of experience in the life sciences market. She holds a Ph.D. in biochemistry from the University of Delaware and a B.S. in chemistry from the College of New Jersey. Dione has co-authored articles that appeared in Science, Cell, Cancer Research, The American Journal of Human Genetics and Genome Research.

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