Finding answers through whole genome sequencing
Posted: Friday, October 12, 2012 8:01 pm
Little Mathew never outgrew his episodes. They could last for hours or days, disappearing only when he fell asleep. Imagine the horror of watching your child’s little body suddenly become rigid then paralyzed on one side or the other, or both sides, accompanied by painful cries and screaming.
Mathew’s father says, “It is like losing your child on a daily basis.” (See Mathew and his parents in http://bit.ly/SI0Nma)
The cause of sporadic alternating hemiplegia of childhood (AHC) — Mathew’s condition — was a medical mystery for forty years. Only about 700 children in the world have this rare and devastating neurodevelopmental syndrome.
Whole genome sequencing (WGS), unmatched in its power to unravel the underlying genetic causes of rare syndromes, was the key to understanding what causes AHC. In WGS all three billion DNA base pairs are read out—the complete human genome.
Most DNA measurements, within the average consumer’s budget, are based on SNPs (single point DNA variations between people). But SNP chips measure only one-twentieth of one-percentage of the total bases in the whole human genome.
Although SNP-based studies have their place, they are of little use in studying syndromes, like AHC, where one is searching through a haystack for an unknown — it may not even be a “needle”.
With WGS scientists are able to work with a very small numbers of patients to uncover their common genetic “error”. The AHC study, published in September 2012 in Nature Genetics, started with the WGS of ten children and their parents. (http://bit.ly/WMBC2l)
By comparing the whole genomes for the ten children, scientists located a single faulty gene, ATP1A3, in eight out of the ten children. By comparing each child with his/her parent when parental DNA was available, they were able to verify that the mutations in ATP1A3 were spontaneous changes in the DNA of the children that were not inherited from the parents.
The AHC kids each had a critical mutation (or change) in a coding region for the ATP1A3 gene. Many coding regions have to be correctly “spelled” to create a working protein from a given gene. Which coding region in ATP1A3 was mutated varied among the children — but in every case the protein’s function was compromised.
Next the scientists worked with a larger group of 95 AHC individuals. They found mutations in 74 of these 95 patients in the same ATP1A3 gene. These ATP1A3 coding region mutations were comprised of nineteen total different misspellings; only two of those nineteen misspellings accounted for all but a quarter of the mutations.
What does this ATP1A3 gene do? The gene is part of a protein complex that maintains the proper electrochemical balance of sodium and potassium across the plasma membranes of brain cells. One can think of ATP1A3 as part of a sodium/potassium pump. The brain is an electrical organ in the body, and as such, sodium and potassium levels are critically important.
Curiously, the ATP1A3 gene had already been found to cause rapid onset dystonia-parkinsonism disease (RDP). However, the misspellings in the ATP1A3 gene that are associated with RDP are not the same as any of the nineteen misspelling found for the ATP1A3 gene in AHC kids.
The AHC kids have normal levels of the protein complex that makes up the sodium/potassium pump but the pump does not work properly. The RDP individuals have very low levels of a properly working protein complex but not enough to get the job done right. In RDP the problem is transcription; in the AHC cases the problem is with the functionality — leading to two different medical problems.
When I read about WGS finding causes of debilitating syndromes, I reminded of an ex-work associate and her daughter. Her daughter, “Beth”, is now a teenager. “Beth” is severely developmentally delayed, has never spoken, and still wears diapers. Yet “Beth” is mobile and responds to her environment with pure delight and angelic simplicity. Her parents love her deeply.
“Beth” requires much extra care and opportunities for my friend to perfect her sense of self-sacrifice. When she was small, her mother took her to every type of doctor hoping to figure out what was wrong. She has yet to receive a diagnosis for her only child.
I am amazed that no doctor has ever suggested WGS. Will my friend ever receive a diagnosis for her daughter? I believe that she will if “Beth’s” problem is genetic in origin, and when the cost WGS is no longer prohibitive, even if “Beth” has a one of kind problem.
It may be impossible to ameliorate “Beth’s” problem as the dedicated mother in the wonderful movie, Lorenzo’s Oil, was able to do with the help of an elderly British chemist. But the first step is getting that precious diagnosis—answering the question of why, why my child?
Nancy@NancyMillerLatimer.com has worked in scientific research and development for 27 years. She blogs at NeuronalBeauty.BlogSpot.com
Published in The WCP 10.11.12