Search of over 500,000 genomes yields thirteen individuals apparently resistant to severe genetic diseases

Thirteen individuals with genetic mutations that cause severe diseases but whose medical records indicate they are healthy have been identified in a sample of over half a million genomes. Publishing in Nature Biotechnology, the study authors say such ‘resilient’ individuals could hold the key to identifying protective mutations against genetic diseases, although the patients were not followed up with due to the absence of appropriate consent forms.

 

Dr. Ada Hamosh, Professor and Clinical Director McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (webpage):

Expertise: Cystic Fibrosis, Genetics and Inherited Diseases, Clinical implications of human genome project

“Chen and colleagues report the identification of 13 “resilient” individuals carrying severe deleterious mutations for diseases that manifest in early childhood. Among 589,306 individuals, only 13 individuals with mutations in 8 different genes were identified. The vast majority of samples were screened by genotyping, which covers only a small portion of the genome. Unfortunately, none of the 13 patients could be recontacted to ensure the correct samples were used and to validate the sequence using an independent method. The lack of clinical manifestation (phenotype) could also not be verified in more detail. Only 5 of the 13 original specimens could be resequenced.

“The 3 individuals carrying homozygous mutations (in both copies of the gene) for cystic fibrosis are most likely a technical error as this mutation is well and thoroughly described as pathogenic. Homozygous individuals for this relatively rare mutation are rare even among cystic fibrosis sample groups. The individual carrying the FGFR1 mutation for Pfeiffer syndrome may be a mosaic (i.e. the mutation is present only in certain cell types) or may simply have a mild form of the condition that was not recognized. This is not uncommon for Pfeiffer syndrome.

“This paper asks an intriguing question. We already know that resilience to severe Mendelian disease is possible (e.g, high fetal hemoglobin can blunt or hide the presence of sickle cell disease in patients who are homozygous for the sickle variant). Because of the inability to confirm the source or validity of the variants and the inability to recontact the individuals, this paper does not constitute a proof of principle.”

 

Dr. Scott Hebbring, Associate Research Scientist, Marshfield Clinic Research Foundation, Clinical Adjunct Professor, University of Wisconsin – Madison (webpage):

Expertise: human genetics, identifying genetic variants associated with clinical outcomes

“This is a fascinating study and represents one of the first to systematically identify healthy individuals who are resilient to their genetic background that is likely to cause devastating Mendelian disease. Chen et al leveraged extensive genetic/genomic data from multiple sources, albeit dominated by 23andMe. The methods applied were suitable but as appropriately stated by the authors, inherent limitations with the study design, DNA availability, and clinical data availability adds caveats.

“First, there was insufficient DNA material to independently validate the expected genetic variants for eight of the 13 individuals believed to be resilient to the Mendelian diseases. This may be relevant given the moderately high error rate during the authors’ previous attempts to validate specific specimens where DNA was available.

“Second, many of the 13 candidate Mendelian disease resilient individuals could not be re-contacted. Reconnecting with these individuals would be important to verify that none had symptoms that could be linked to their genetic background. As such, some of the patients may have had the disease that went unreported. In reality, most diseases can be expressed very differently between individuals, even in those who have the same genetic variant. Different environmental exposures and other genetic factors may influence how a genetic variant affects a spectrum of disease outcomes. This study is unique in attempting to assess one extreme in that spectrum. It may not be surprising that some individuals may actually have symptoms but they are either not reported or initially attributed to the genetic variant(s).

“This study emphasizes, like many preceding disease specific studies, that genetic data is often very important but not always absolute when predicting outcomes. This will be vitally important as genetic/genomic data is rapidly incorporated in healthcare as part of “precision medicine.”

 

Patricia Page, Co Director, JScreen, Department of Human Genetics, Emory University (webpage):

Expertise: newborn and preconception genetic screening and public health genomics

“Many genetic studies focus on identifying the genetic variants underpinning a particular condition or syndrome.  The current study turns this approach on its head by instead identifying healthy “resilient” individuals whose genetic test results suggest that they should be affected by severe, fully penetrant, childhood onset conditions.  By combining the data from over 500,000 individuals genotyped or sequenced across 12 studies, thirteen adults that seem to have escaped their genetic destiny were identified. The importance of these “resilient individuals” lies in the hope that their genomes contain clues to protective mechanisms that could lead to new therapies.

“While an important step forward, this study highlights challenges in identifying “resilient” individuals.  Notably, due to restrictive initial consent processes, none of the individuals identified in the study could be re-contacted to complete the follow up evaluations needed to rule out alternative explanations for their health.  Therefore, the resilience of these individuals cannot be conclusively confirmed.  The small number of individuals identified highlights the importance of large, prospective initiatives such as the Precision Medicine Initiative that will hopefully result in extensive genomic data sets combined with robust clinical information.  Despite its limitations, this study demonstrates the potential for identification of new targets for therapeutic interventions when researchers are willing to share data for the common good.

“Even in the absence of new therapies though, improving our understanding of the penetrance and variable expressivity of specific mutations and conditions is critically important for clinical care, especially in the realms of preconception and prenatal screening where potentially life-altering decisions are reliant on accurate predictions.”

 

Declared interests (see GENeS register of interests policy):

Dr. Ada Hamosh: I am Scientific Director of OMIM (Online Mendelian Inheritance in Man) and am funded by NHGRI for that. I am a co-investigator of the Baylor-Hopkins Center for Mendelian Genomics, committed to identifying novel disease genes.  Other than these, grants I have not financial disclosures related to this topic.  In the interest of full disclosure, but really irrelevant to this, is that my husband serves on the Scientific Advisory Board of GlaxoSmithKline and is a founder of a new company called Blade Therapeutics.

 

Reference:

Analysis of 589,306 genomes identifies individuals resilient to severe Mendelian childhood diseases” by Rong Chen et al., published in Nature Biotechnology on Monday, 11 April 2016

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