All Your Base Are Belong to Us*

All Your Base Are Belong to Us*

Cutie with Long Q-T: A baby girl is born with an irregular heartbeat. Out of synchrony, her heart stops beating several times. By Day 2 doctors perform emergency surgery to implant a cardiac defibrillator. They cut off the sympathetic nerves to prevent further stimulation of this condition.  She is put on a slew of medications but it’s too soon to know if they are the right ones for her condition. Her diagnosis? Long Q-T syndrome.

Choreographing a Ballet: Every heart beat is powered by a wave of electrical activity caused by carefully choreographed opening and closing of ion channels that move sodium, potassium and calcium ions into and out of cardiac cells on a millisecond time scale. This electrical activity is picked up in an ECG which parses out the events as a repeating waveform labeled P, Q, R, S, and T (image). Each waveform triggers the cardiac muscles to contract rhythmically, pushing blood out of the chambers of the heart. In long Q-T syndrome, the lengthening of the Q-T interval reflects a delay in resetting the lower heart chambers (“repolarizing”) so that the arrival of a new heart beat occurs before the conclusion of the last one. This can set off a confusion of waveforms which appear to twist around a point, resembling the ballet movement torsades des pointes (see to trigger fainting, seizures or sudden cardiac death. 

Choosing a Channelopathy: Long Q-T syndrome occurs in 1 of every 2,000 persons. About 2/3 of the cases are due to mutations in two potassium channel genes which cause them to fail to open. Another 10% of mutations are found in sodium channels which make them fail to close. Either way, the Q-T interval is prolonged. But potassium and sodium channels have very different responses to drugs. Before treatment, it’s important to know where the defect lies. With our baby girl, her condition was too serious to play around with different drugs. So the scientists at Stanford University took the unprecedented step of sending her DNA for whole genome sequencing. It took 13 years for the first human genome to be fully sequenced. This baby girl’s DNA was sequenced before she was 10 days old. A mutation was found in the KCNH2 gene encoding a potassium channel known to be defective in long Q-T. She was taken off sodium channel blockers, put on more appropriate medication, and sent home. As one of the scientist’s remarked, “This is the future of genetic testing and we hope, the future of medicine.”

What’s normal anyway?: It is somewhat stunning to note that sequencing revealed 3,711,590 single nucleotide variants and 754,196 insertions and deletions that would cause more than 900 protein variants in our baby girl! Some of these could potentially cause other disorders, possibly in the future. We may all have our genomes fully sequenced in the not too distant future and we must ponder what we would do with this information?

REF: Molecular Diagnosis of Long-QT syndrome at 10 Days of Life by Rapid Whole Genome Sequencing (2014) Priest et al.

News story:

*Know your meme: AYBABTU


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71 Responses to All Your Base Are Belong to Us*

  1. Sunil Bajpai says:

    Amazing. Thank you!

  2. Rajini Rao says:

    Thanks!  A long read, I’m afraid, although I tried to stick to the basics but still keep the science. 

  3. Attn: Sally Hodges.

  4. The more people know how vital to the future of medicine that genetics is (are?), the faster we’ll get around objections based purely on misinformation and ignorance. So thank you for posting this.

  5. Rajini Rao says:

    Thanks, Craig Froehle . The news stories do a good job of spreading excitement, but there tends to be more hype than science. This builds up unrealistic expectations or concerns. We’ve been dealing with some hype relating to virus research recently and it’s surprisingly hard to combat fears and misinformation.

  6. Superb, excellent, thanks for the article with such wealth of knowledge about the future of medicine & how it is going to impact our lives. Genome sequencing, gene testing what is the future going to be like is some thing to ponder about.

  7. The advances in computing power has been astounding…1st genome sequencing 13 years and this cute girl’s DNA sequenced in less than 10 days..simply awe-inspiring….also full credit to the scientist at Stanford…and a big thanks to you Rajini Rao for bringing it to us in a language that we can understand. 

  8. Rajini Rao says:

    Jeff Brown interestingly, the ECG is measured from the skin surface and is not the same as the “action potential” waveform that happens at the cellular level. Not being a physician, I’m more vague about the meaning of all those parts of the ECG spikes because they don’t correspond directly to the opening and closing of ion channels (which I know in gory detail!). Hopefully, a physician will know more.

    Tagging Able Lawrence 

  9. My genomes are not fully sequenced? Oh man, and I thought I’m good at rummy!

    Excellent article, great achievement by medical scientist!

  10. Rajini Rao says:

    Jitendra Mulay wouldn’t you like a royal flush? (My rummy is rusty, maybe I mixed up terms?)

  11. Rajini Rao says:

    I found this nice video that explains the heartbeat: 048 How to Read an Electrocardiogram (ECG/EKG)

    If anyone wants to know what is meant by “depolarization” and “repolarization”, just ask. That’s where the ion channels come in.

    You guys know that there is a voltage difference across every cell, right? 🙂

  12. James Harris says:

    Great share Rajini Rao. Fascinating to me that reading the genome can be used in this way already. Hate to admit kind of behind on the subject! And it is crucially important. Kind of think this should be a mainstream article too. Well at least we have its benefit here on G+. Great job.

  13. Rajini Rao says:

    James Harris what I didn’t mention is that there is a faster/cheaper way which is to sequence only those regions already known to be important in disorders. That’s already commercially available through companies like 23andMe, etc. (not sure what their legal status is now, there was some ruling about them recently). Many mutations can be missed by this shortcut approach, but they are a good start. I suspect this group went in for whole genome sequencing because they are in an academic research hospital where the facility was available. 

    I’m hoping that Ian Bosdet stops by and lends his expert opinion on the genome sequencing aspects!  

  14. Rajini Rao says:

    Jeff Brown glad you caught the meme 😀 My son showed it to me a few years ago and I couldn’t stop laughing. (The inside joke for the non-biologists is that DNA is made up of 4 “bases” which form the letters of the genetic code.) 

  15. Nope, not so much! 😦

    Great video!

  16. Rajini Rao About heart stops I have some experience in myself, because when running and touching the anaerobic umbral calculations are performed by our superintelligent bio-engine to got balance with the new situation of lactic acid produced. And the ultra quickly calculations are made with beats 0. Then the heart beats can go out, reaching a level over 85% of highest heart rate, or if the effort slows,going down. Because of the energy of running hits of legs 0 beats can last, in my case around a minute. I got computarized graphics of myself showing it.

    Thanks for the high level of the contact of yours, Dr. Rajini.

  17. Rajini Rao says:

    The point about exercise is interesting and relevant to long QT syndrome as well. There are people who carry these mutations but don’t show any symptoms. However, if their ECG is taken shortly after exercise, the delay is noticeable. These people may be susceptible to sudden cardiac death brought about by exercise (fortunately, very rare!). In the paper referenced in the post, the father of the baby carried the mutation but in his case ECG irregularities were revealed only after stressing the heart by exercise. 

  18. Thank you for posting this! A great morning read with great info. When I did my short stint at the study of neuroscience, bioelectricity was one of the most fascinating processes to me.

  19. Rajini Rao says:

    Thanks, Tshaka Armstrong . I study proteins that move charges, so “electricity” in biology is fascinating to me too 🙂

  20. Rajini Rao Exercise extreme must be done just for people trained from infance. But when researchers got data of the fisiological changes involved the result is amazing. ECG waves change,testosterons level goes up, burning proteins instead of carbonhidrates, and endorphines take control of the brain mood.

    I used to say that players play in a state of God´s grace.

    And this is known thanks to people like you.

    I just can feel it.

  21. Rajini Rao Excellent precis description. A minor (nuance) suggestion though “_so that the arrival of a new heart beat occurs before the conclusion of the last one_” may be changed as so that the arrival of a new heart beat may occur before the conclusion of the last one since it does not always occur. 

  22. Rajini Rao says:

    Able Lawrence , thanks! It’s a matter of chance, right? Any idea why they did a sympathectomy? I can pull out the exact phrase if you want. Edit: they performed a “left 

    sympathetic ganglionectomy to reduce adrenergic stimulus”. 

  23. Sequencing is getting faster and cheaper. Definitely exciting. Great post :) (And good title choice!)

  24. Rajini Rao says:

    Carissa Braun thanks for noticing AYBABTU 😉 Methinks the challenge before us now is what we do with all that genomic information and how we analyze and use it. 

  25. alev uneri says:

    Very impressive and promising story for the future of medicine, great share, thanks Rajini Rao

  26. Rajini Rao Cardiology is not my area. Sympathetic activity can increase heart rate which can increase the risk of re-entrant phenomena leading to arrhythmia. 

  27. Thank you for sharing.  I hope this is the path Genetic Testing will take.  Glad for the little baby.  Love the meme, a picture of Gene Robbing came to me.

  28. Fascinating!

    I’m noting that they were looking for just one of a handful of specific markers, for the various known channelopathies. Was the whole-genome sequencing then just because there aren’t premade tests ready to match just the sequences in those areas around fixed patterns, or was there a deeper reason that the whole thing needed to be sequenced?

  29. Yonatan Zunger It is not less costly to do targeted sequencing compared to whole exome sequencing these days. 

  30. Able Lawrence Ah, that makes sense. 

  31. Rajini Rao says:

    Yonatan Zunger I was hoping someone would ask me this since I didn’t want to make my post much longer 🙂 There are about a dozen genes contributing to long Q-T in the commercial gene panels and KCNH2 is one of them. So they would have found it using the cheaper more limited screen. I suspect they used whole genome sequencing because they had access to it. That said, they argue that there are at least 4 other gene mutations that likely combined with the main one to give the severe symptoms in the child. The father has the KCNH2 mutation but is mostly asymptomatic (they found irregularities after they stressed his heart by exercise). They suggest that another mutation inherited from the mother had an additive effect with the KCNH2 mutation.

    In the discussion they say that whole genome sequencing is unbiased and has more potential to uncover rare variants: “By moving beyond the confines of today’s clinical testing panels, whole genome sequencing will yield more genetic data on each patient which will be a useful substrate for the discovery of modifier genes and may eventually lead to better risk-stratification for affected family members”. Nice spin, although I would also opt for whole genome sequencing if it were available, why not? 🙂

  32. Liz Krane says:

    I had no idea we were using whole genome sequencing for diagnostics like this. And what an amazing story! Rajini Rao have you or would you sequence your genome through something like 23andMe or a better version of it in the future?

  33. Liz Krane Rajini Rao Now a days, whole exome sequencing is done very commonly for suspected genetic diseases. There are two options, pay a package for the whole exome or pay per each exon and usually whole exome might work out cheaper. I do not think they are doing whole genome sequencing (even when people say whole genome, it is rarely the entire genome since certain regions are difficult to sequence and it is rarely required). Exome means, the complement of exons, the part of the genome that is translated into proteins. the mRNA coding regions minus the introns.  

  34. Rajini Rao says:

    Liz Krane right now, whole genome sequencing (WGS) is mostly done at academic medical centers where it is accessible. For example, a colleague who had melanoma had his treatment tailored to his specific cancer after WGS (sadly, he lost that battle). If I was in a similar situation, I would certainly try and get it done, especially in the future when there will be better analytical tools! I think 23andMe has more limited insight so I might wait a while. How about you? 

  35. Rajini Rao says:

    Able Lawrence I agree. For example, exome sequencing is being done by geneticists to correlate gene variants to complex disorders like hypertension. Coincidentally, I’ve just been bothering emailing a colleague to do the genetic analysis for a human sodium transporter that we study, with blood pressure values in patient databases so that we can do functional analysis on the gene variants of this transporter. 

  36. Liz Krane says:

    Thanks Able Lawrence! Exoms, exons and introns, oh my! So much I don’t know 😀

  37. Liz Krane says:

    Rajini Rao I’d love to know about my DNA just for fun and (morbid?) curiosity when it gets better and cheaper. I wonder when (if?) WGS will become something everyone does..

  38. Liz Krane When eukaryotic RNA is transcribed from the DNA coding strand, it contains both protein coring regions in multiple segments (exons) interspersed with non coding regions called introns. This large piece of RNA (HnRNA) is the spliced to remove the introns to form the mRNA which is then used as the blueprint for protein synthesis. Introns do have regulatory elements and rarely mutations in introns can also cause disease. 

  39. Liz Krane Curiosity killed the cat, they say. It is not always good to know it. It can have unintended (harmful) consequences. There is no point in knowing about things that you cant do anything about. 

  40. Rajini Rao says:

    Well, I’m far too pragmatic to be concerned about my mortality (generally speaking) so I would have only academic curiosity in knowing what lies in my genome. My only caveat is that there is a lot we don’t understand so I suspect that I would only get some limited use from it. A well known recent case of knowing about things that you can do something about is of Angelina Jolie and the BRCA mutation. In her case, it made a lot of sense to have pre-emptive surgery since she inherited a major risk factor for breast cancer. 

  41. Liz Krane says:

    Able Lawrence Ohhhh ok, thanks for the quick explainer!

  42. Jim Carver says:

    Able Lawrence I don’t believe that. In fact a statement like that bothers me to no end.

  43. Mary T says:

    Thank you for another excellent and informative post Rajini Rao ~ I did not realize we were this far along with gene sequencing.

  44. Deen Abiola says:

    This is the second one of these I’ve seen last month! As awesome as this is, I think it’s worth tempering expectations by pointing out that the fact these great results make the news shows them as exceptions. Most pathologies don’t make it past the interpretation state, to speak of actionable pharmacological options which then work!

    Able Lawrence I think it is fair to take the authors at their word since presumably, they know the difference between ‘silent’ and protein coding portions of the genome?

  45. Rajini Rao says:

    Mara Rose , glad you enjoyed it!  

    Deen Abiola , true, but having the information gathered will allow a retrospective analysis when we do know more, right? I missed the comment by Able Lawrence re. WGS vs. exome sequencing. They did indeed do WGS, according to the paper I read. That’s what made the news.

  46. Rajini Rao says:

    OK, here is the excerpt on WGS from the methods section: “The unprocessed whole genome sequence data passing QC totaled 1,239,367,160 reads of 100 base pair length.” They also say that the “read depth” was 8 although I’m not sure what that means (8x coverage?).

  47. Jeff Brown It’s pretty cool how it all works. Different amounts/concentrations of different types of charged ions separated at the cell membrane create an electrical potential difference (i.e., a voltage). And when specific selective ion channels open in response to voltage changes, the ions flow through and offset the balance of charges to such an extent that an action potential (“signal”) is propagated (“fired”).

    The ECG is only detecting the overall external bulk electrical activity differences at the skin’s surface (sort of like how an EEG for the brain is interpreting large-scale activity, not individual action potentials of each neuron).

    A standard 12-lead ECG is often used where each electrode serves as a contact point or sensor to ultimately measure voltage changes. You can think of sensors like cameras recording the same event from 12 different viewpoints — each lead can provide slightly different information of the local electrical activity at that position during each heart beat.

    In a classically normal individual, the axis of the heart and axis of electrical conduction through tissue and fibers tends to be in the direction from the upper right to lower left across the chest, generally speaking. If the overall macroscopic path of conductance is toward a positive lead (such as in the left arm or left leg) or away from a negative lead, the ECG recording will register an upward deflection away from baseline (and a negative deflection for the opposite scenario).

    These deflections are what cause the waveform tracings. Different points in the waveform are identified by letters for reference — Willem Einthoven, the inventor of the ECG, initially called each point A, B, C, and D, but after making corrections to the equipment/amplifiers to refine the signal, he discovered a 5th wave, so he relabeled them P, Q, R, S, and T (why he started with P, I don’t know).

    The general electrical activity shown by the P-wave corresponds to atrial contractions (top chambers of the heart), the QRS complex corresponds to ventricular contractions (bottom chambers), and the T-wave corresponds to ventricular relaxation (electrical “recovery”). Atrial relaxation during repolarization is masked by the more dominant ventricular contraction/depolarization (QRS) and is not seen. (Not to get too complicated, but sometimes a prominent U-wave will show up after the T-wave in some abnormal circumstances, and there is also a J-point as well not labeled above.)

    The size or height of the deflections of the tracing (y-axis) are measured in millimeters (corresponding to millivolts), and the length or duration (x-axis) is measured in milliseconds. The shape, size, duration, and spacing of the waves and intervals between the waves matter (with well-defined statistically normal ranges or limits), and a single ECG literally contains hundreds of pieces of information for diagnostic or screening purposes.

    (For example, if the P-wave was larger or more “tented” in appearance, that may suggest a bulkier (i.e., hypertrophic) right atrium, which normally makes an insignificant electrical contribution compared to a thicker/stronger left atrium but in this case adds more signal. And then you’d have to think about all the causes of a large right atrium — anything causing the heart to pump harder against increased resistance, such as a narrow heart valve, right-sided heart failure, or a lung disease like COPD.)

  48. Rajini Rao To expand on the sympathectomy explanation, the most worrisome aspects of LQTS as you now know are fainting/syncope or seizures (from a lack of cerebral perfusion pressure) and a high incidence of sudden arrhythmic cardiac death, of which a major precipitating factor is adrenergic stimuli responsible for trigger activity of early after-depolarizations (which are membrane potential oscillations during the plateau/phase 2 of cardiac AP or later during phase 3 repolarization that cross the threshold to give rise to an abnormal electrical impulse and premature beat that then feeds into a reentry circuit and perpetuates).

    Adrenergic receptors respond to catecholamines (norepinephrine and epinephrine/adrenaline), so first-line pharmacotherapy is usually beta-adrenergic blockers or “beta blockers”. Stimulation of beta-1 receptors leads to increased heart rate (positive chronotropic effects), increased contractility (positive inotropic effects), and increased conduction velocity (positive dromotropic effects). Blocking these receptors would help suppress arrhythmias by decreasing conduction and prolonging refractory periods to “break” the abnormal electrical conduction cycle.

    However, beta-blockers are only effective three-quarters of the time and are insufficient for resistant or high-risk cases like in neonates (I presume). They probably also can’t receive an implantable pacemaker or cardioverter-defibrillator, so the only remaining course of treatment aside from pharmacotherapy or device therapy is to perform a left cervicothoracic sympathetic ganglionectomy (the procedure is known as “left cardiac sympathetic denervation” or LCSD, which is much easier to say :P).

    The LCSD surgery ablates specific fibers of that sympathetic nerve bundle to (mostly) target the heart and avoid loss of sympathetic output elsewhere (i.e., to avoid causing Horner’s syndrome of ptosis, miosis, and anhidrosis — droopy eyelids, pinpoint pupils, and absence of sweating).

    Although this approach is currently standard of care, it does seem a bit primitive from a futurist perspective. Maybe there will be some way to anticipate and modify this down the road (not to go too Gattaca on anyone just yet :P).

  49. Rajini Rao says:

    Johnathan Chung many thanks for filling a big hole in my understanding of sympathetic input and beta blockers!  I vaguely recall that they alter the leak (depolarizing) current to change the pacemaker frequency. The story of the ECG invention and labeling was fascinating! Not only did they do the LCSD as you’ve described, the surgeons also implanted a defibrillator in the neonate..apparently one of the earliest cases to date (she was 2 days old). And yes, they sent her home on beta blockers 🙂

  50. Rajini Rao says:

    Greg Greene so glad that you enjoy these much as I enjoy writing them! 

  51. Rajini Rao I see. I wasn’t sure if newborns were eligible for ICDs (implantable defibrillators) which is why I said “probably”, but I should have known they were on the cutting edge of medicine 😀

    I don’t remember exactly how the ion channel functions are altered. I’m in “rest and digest mode” right now, so I’ll have to look it up later 😛

  52. Rajini Rao says:

    Johnathan Chung if there’s one thing I know about surgeons is that they are not lacking in guts! One is never too young or old or small or large to escape the scalpel 🙂 Actually, I did look up how the sympathetic input works at the cellular level. After repolarization of the pacemaker potential, the “funny current” is activated by hyperpolarizing potential. This is a mixed sodium/potassium conductance, so it causes a slow depolarization that brings the membrane to threshold, spontaneously firing another action potential. The funny current is also activated by cAMP which is elevated by sympathetic (beta adrenergic) stimulation and decreased by muscarinic M2 receptor stimulation. This brings the cardiac membrane potential to threshold faster and increases heart rate in the former case and slows heart beat in the latter case, respectively. Hope I got that right (it used to be a question on our medical school cell physiology exam!).

  53. Gretchen S. says:

    I love the style and clarity of your explanation! Thank you! I also love how genetic sequencing is now fast enough to use in cases like this.

  54. Rajini Rao says:

    Thanks, Gretchen S.  🙂

  55. Tom Lee says:

    Very informative here. Very good to know. Thanks !

  56. Brilliant conversation between Rajini and Johnathan Chung

  57. Roses are Red, Violets are Blue, and,

    All you’re Base are Belong to Us..

    I only remember it’s Pong! 

  58. Marta Rauch says:

    Thank you Rajini Rao 

  59. Rajini Rao another well written post and some even better comments.

    I have a question- I, similar to many men, suffer from fear of blood and injection needles.

    I am told that my blood pressure drops. Looks like fear messes up this choreography?

  60. Rajini Rao says:

    mandar khadilkar  pssst… I’m squeamish too 🙂 From a physiological sense, a drop in blood pressure could be a good thing if you are would bleed less and clot faster. But if you faint, that’s not so good! 

    Typically, when one is frightened, the sympathetic nervous system kicks in to increase heart rate (as Johnathan and I were discussing in gruesome technical detail above). But in the case of phobias, something called the vasovagal response occurs, which does the opposite (the vagal nerve is part of the parasympathetic response). There’s a nice explanation here:

  61. Thanks Rajini Rao for sharing this! You are a great teacher!

    Since heart repolarization and cochlear hair cell repolarization both depend on the same type of transmembrane potassium channels, failure of universal newborn hearing screening (isolated bilateral sensorineural hearing loss) might be the only clue to the presence of delayed myocardial repolarization (QTc > 440 msec) sufficient to increase the risk of sudden death.  

    Prompt neonatal diagnostic confirmation of isolated sensorineural hearing loss, folowed by careful electrocardiographic evlauation for abnormal ventricular repolaization might prevent KCNQ1 or KCNE1 mutation-related sudden infant death syndrome (SIDS).

  62. Rajini Rao says:

    Iain Macadair many thanks for the extra information on the link between hearing and potassium channels. It makes sense that one of the causes of SIDS could be sudden cardiac death. 

    It’s also worth noting that mutations in many ion transporters and channels cause deafness. Some other examples are proton pumps and calcium pumps (PMCA).

  63. Hi beautiful, how are you doing? please i will like us to chart much better on email so we can share some pics am so interested in you right now my email is

  64. Alphonsa Roy says:

    That was really great news. 😊😊😊

  65. Noor Haleem says:

    Very nice picture

  66. Noor Haleem says:

    Thanks for sharing

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