The 21 genetic conditions that should be reported by patients if found incidentally during whole-genome sequencing

Illustration: DNA associates with histone proteins to form chromatin. Image source: Wikipedia.

There are no established guidelines on which genetic variants should be presented to physicians as incidental findings from whole-genome sequencing. A recent study showed that genetic specialists agreed that pathogenic mutations for 21 common genetic conditions should be disclosed by patients.

For adult patients

APC-associated polyposis
Fabry disease
Familial hypercholesterolemia
Galactosemia
Gaucher disease
Glycogen storage disease type IA
Hereditary breast and ovarian cancer
Homocystinuria
Li-Fraumeni syndrome
Lynch syndrome
Multiple endocrine neoplasia type 1
Multiple endocrine neoplasia type 2
MYH-associated polyposis
Phenylketonuria
Pompe disease
PTEN hamartoma tumor syndrome
Retinoblastoma
Romano-Ward (long QT syndrome)
Tyrosinemia type 1
Von Hippel-Lindau disease
Wilson disease

For pediatric patients (child)

PTEN hamartoma tumor syndrome
Retinoblastoma
Romano-Ward (long QT syndrome)
Von Hippel-Lindau disease

Collecting family history predicts cancer risk better than 23andMe genetic testing, according to a recent study from the Cleveland Clinic:



References

Exploring concordance and discordance for return of incidental findings from clinical sequencing. Green RC, Berg JS, Berry GT, Biesecker LG, Dimmock DP, Evans JP, Grody WW, Hegde MR, Kalia S, Korf BR, Krantz I, McGuire AL, Miller DT, Murray MF, Nussbaum RL, Plon SE, Rehm HL, Jacob HJ. Genet Med. 2012 Apr;14(4):405-10. doi: 10.1038/gim.2012.21. Epub 2012 Mar 15.

Genome sequencing to add new twist to doctor-patient talks. American Medical Association, 2012.

How to talk to patients about genetic testing  http://goo.gl/kkW4m

The Third Component of Genetic Blueprint - Writing in Pen (DNA) vs. Pencil (Epigenetics)

The term epigenetics refers to changes in phenotype (appearance) or gene expression caused by mechanisms other than changes in the underlying DNA sequence, hence the name epi- (Greek: over; above) -genetics. There is no change in the underlying DNA sequence of the organism; the phenotype is expressed by activating some genes while inhibiting others. Epigenetics includes changes in gene function that occur without a change in the sequence of DNA. These changes occur as a result of the interaction of the environment with the genome. Epigenetic determinants activate or silence fetal genes through alterations in DNA, histone methylation and acetylation.


DNA associates with histone proteins to form chromatin. Image source: Wikipedia, GNU Free Documentation License.

From the National Geographic magazine:

"Mother Nature writes some things in pencil and some things in pen. Things written in pen you can't change. That's DNA. But things written in pencil you can. That's epigenetics. Now that we're actually able to look at the DNA and see where the pencil writings are, it's sort of a whole new world."

If you think of our DNA as a piano keyboard and our genes as keys - each key symbolizing a segment of DNA responsible for a particular note, or trait, and all the keys combining to make us who we are - then epigenetic processes determine when and how each key can be struck, changing the tune being played.

Recent studis focuses on a particular epigenetic process called DNA methylation, which is known to make the expression of genes weaker or stronger.

The good news is that some of these processes, unlike our DNA sequences, can be altered. Genes muted by methylation, for example, sometimes can be switched back on again relatively easily. And though it may not happen soon, the hope is that someday epigenetic mistakes will be as simple to repair as a piano that's out of tune.
"


Human chromosomes (grey) capped by telomeres (white). Image source: Wikipedia, public domain.

References:

Twins. National Geographic magazine, 01/2012.

Portrait of twins: series one and series two from National Geographic.

Twins Data Reshaping Nature Versus Nurture Debate. NPR.

Epigenetics, Wikipedia.

Collecting family history predicts cancer risk better than 23andMe genetic testing

Collecting family history predicts cancer risk better than 23andMe genetic testing, according to a recent study from the Cleveland Clinic:

As you're sharing fond family memories, don't forget to bring up family health history -- it's the best gift you can give. Dr. Charis Eng comments on a study she led looking at the important role of family history in predicting future disease risk.

Whole genome sequencing fails to predict risk of most common diseases, according to BMJ.

Related reading

Beware the fortune tellers peddling genetic tests - BMJ http://goo.gl/F0DQt

Family History and Personal Genetic Risk Assessments: A Perspective on the Cleveland Clinic Study. 23andMe.com.

FDA panel: genetic testing should not be available directly to consumers without what amounts to a "prescription". WebMD, 2011.
Genetic testing is available for approximately 2000 clinical conditions - Preparing for Precision Medicine - NEJM, 2012.
How to talk to patients about genetic testing  http://goo.gl/kkW4m

Comments from Twitter

@23andMe: See our perspective of Cleveland Clinic study - http://bit.ly/c373aj - bottom line is 2 aren't the same, so can't compare h2h. Also, we agree that family history is a very important piece, and believe it complements detailed genetic info.

Participation in clean-up of oil spill associated with airway injury and chromosomal damage

In 2002, the oil tanker Prestige spilled more than 67 000 tons of bunker oil, heavily contaminating the coast of northwestern Spain. The study population included local fishermen who were highly exposed (n = 501) or not exposed (n = 177) to oil. They were evaluated 2 years after the spill.

Elevated markers of airway injury

Persons exposed to oil were at increased risk for lower respiratory tract symptoms (risk difference, 8.0). However, lung function did not significantly differ between the groups. Exposed participants also had higher levels of exhaled vascular endothelial growth factor (risk difference, 44.8) and basic fibroblast growth factor (risk difference, 16.0).

Human chromosomes (grey) capped by telomeres (white). Image source: Wikipedia, public domain.

Chromosomal damage

A higher proportion of exposed participants had structural chromosomal alterations (risk difference, 27.4), predominantly unbalanced alterations.

Participation in clean-up of a major oil spill was associated with persistent respiratory symptoms, elevated markers of airway injury in breath condensate, and chromosomal damage.

References:

Health Changes in Fishermen 2 Years After Clean-up of the Prestige Oil Spill. Ann Intern Med, October 19, 2010, vol. 153 no. 8 489-498.

CDC Discourages Patients from Ordering Personal Genomic Tests

Dr. Khoury comments on the personal genomic tests that consumers can buy on the Internet to measure their genetic risk for multiple diseases.

Direct-to-consumer genomewide profiling to assess disease risk provides information about a person's genetic risk of 20 to 40 common polygenic diseases. The tests simultaneously genotype approximately 500,000 variant bases of a person's DNA. Consumers can purchase these tests, currently priced between $400 and $2,000, on the Internet

Proponents argue that providing this type of information directly to consumers may result in improved compliance with health-screening practices and more healthful lifestyle choices.

Skeptics assert that such testing has the potential to cause harm, including anxiety and increased use of unnecessary and expensive screening and medical procedures.

The clinical validity and utility of these tests have not been demonstrated, and given their cost, many observers argue that their sale raises consumer-protection issues.

In a recent study published in the NEJM, subjects who chose to undergo direct-to-consumer genomewide testing, had no short-term changes in psychological health, diet and exercise behavior, or use of screening tests.

References:

Effect of Direct-to-Consumer Genomewide Profiling to Assess Disease Risk. NEJM, 2011.

Beware the fortune tellers peddling genetic tests - BMJ http://goo.gl/F0DQt
"Genetic testing eases pain of hypochondria" - BBC  http://goo.gl/IRCPP

Short telomeres lead to chromosomal instability and increased cancer risk and mortality

Telomeres are essential to preserve the integrity of the genome. Critically short telomeres lead to replicative cell senescence and chromosomal instability and may thereby increase cancer risk.

Leukocyte telomere length was measured by quantitative polymerase chain reaction in 787 participants free of cancer at baseline in 1995 from a prospective, population-based study in Italy. The follow-up period was 10 years.

Human chromosomes (grey) capped by telomeres (white). Image source: Wikipedia, public domain.

11.7% of participants developed cancer (incidence rate, 13.3 per 1000 person-years).

Short telomere length at baseline was associated with incident cancer independently of cancer risk factors (hazard ratio [HR] 1.60).

Compared with participants in the longest telomere length group, the HR for incident cancer was 2.15 in the middle length group and 3.11 in the shortest length group. Furthermore, short telomere length was associated with cancer mortality and individual cancer subtypes with a high fatality rate.

There is an inverse relationship between telomere length and both cancer incidence and mortality.

References:
Telomere Length and Risk of Incident Cancer and Cancer Mortality. Peter Willeit, MD; Johann Willeit, MD; Agnes Mayr, MD; Siegfried Weger, MD; Friedrich Oberhollenzer, MD; Anita Brandstätter, PhD; Florian Kronenberg, MD; Stefan Kiechl, MD. JAMA. 2010;304(1):69-75.

DNA Is a Doctor's Best Friend

The Director of the National Institutes of Health (NIH):

"It did affect me to find out that I was at risk for diabetes, which I had no family history of. But my family has all been extremely lean and I was not so lean, as I discovered when I got this information," Collins says.

The "wake-up call" led Collins to switch up his diet and start an exercise program.

His efforts helped him drop 25 pounds.

Human chromosomes (grey) capped by telomeres (white). Image source: Wikipedia, public domain.

References:

Francis Collins: DNA May Be A Doctor's Best Friend - Shots - NPR Health News.

Video Lecture: Anne Wojcicki from 23andMe Personal Genomics

Direct link here.

23andMe is a personal genomics company based in Mountain View, California that is analyzes saliva samples for genetic information (the average cost for the service is decreasing and is currently $399-$499).

The company name is a play on the 23 pairs of chromosomes that carry every individual’s DNA. 23andMe was co-founded by Anne Wojcicki, wife of Google co-founder Sergey Brin.

"Genes load the gun. Lifestyle pulls the trigger" - Dr. Elliot Joslin.

Whole genome sequencing fails to predict risk of most common diseases, according to BMJ.

Related reading:

Genetic testing is available for approximately 2000 clinical conditions - Preparing for Precision Medicine - NEJM, 2012.

How to talk to patients about genetic testing  http://goo.gl/kkW4m

Faces of America - PBS Series

Faces of America premieres nationally Wednesdays, February 10 - March 3, 2010 on PBS: "What made America? What makes us? These two questions are at the heart of the new PBS series Faces of America with Henry Louis Gates, Jr. who turns to the latest tools of genealogy and genetics to explore the family histories of 12 renowned Americans."

Discovery of telomeres and how they protect chromosomes wins 2009 Nobel Prize for medicine

Three US scientists have won the Nobel Prize for discovering telomeres and how they protect chromosomes from degradation http://bit.ly/2TQ0aF

One of the 3 scientists is Elizabeth Blackburn - see her Google talk embedded below http://bit.ly/3EqJBF



Molecular biologist Elizabeth Blackburn was selected as one of Time magazine's 100 "Most Influential People in the World" in 2007 because of her groundbreaking work on telomeric DNA, which launched the field of telomere research.

On August 18th, 2008, Google welcomed Elizabeth Blackburn to give a one-hour talk at their San Francisco office.

Related:
"Why Immortality Is a Bad Thing" - presence of lots of telomerase is associated with the development of cancer http://bit.ly/ayCtr

Updated: 10/06/2009