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 http://goo.gl/ctSg2d) 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. http://www.ncbi.nlm.nih.gov/pubmed/24973560
News story: http://goo.gl/PZDPc6
*Know your meme: AYBABTU