By: Barbara Woldin
Whole-exome sequencing and his parent’s unwavering tenacity finally led Bertrand Might, now almost 7, to a diagnosis—an extremely rare genetic disease (only 18 other diagnosed cases in the world) called N-glycanase deficiency, or NGLY1 for short.
It all began when Bertrand was around 1 month old and his parents Matt and Cristina noticed he was “jiggly” and was seemingly under duress most of the time. By 6 months, he had little to no motor control and Matt and Cristina knew something was very wrong with their son, describing their emotions as fear— visceral fear. “Parents naturally have high hopes for their children,” Matt says and “To have those hopes clawed away in slow motion is devastating.”
Initially diagnosed with ataxia-telangiectasia, a movement disorder which was subsequently ruled out, baby Bertrand underwent a battery of tests before, months later, doctors finally concluded he most likely had a metabolic disorder—one of more than 700 inborn errors of metabolism. This meant that he had a missing or faulty enzyme whose normal function is to break down and remove toxic compounds from the body or produce energy inside cells. But which enzyme was it? It was like looking for a needle in a haystack, but Bertrand’s parents set out to hunt down their son’s killer, as Matt describes it in his blog. 
Enzymes are proteins, which are large molecules made up of amino acids; there are approximately 1300 of these proteins in every human cell. Each of these enzymes has a particular function and when one is missing, its “job” doesn’t get done. Often, this results in the accumulation of toxic compounds in affected organs in the body or brain, causing a constellation of symptoms.
When Bertrand was 15 months old, a break came—oligosaccharides (sugar molecules) were found in his urine. Within weeks of finding the sugar molecules, Matt and Cristina had begun further blood testing on their son, which narrowed the list down to about 18 known ultra-rare disorders, but most of them were fatal or, at best, life-shortening. Then they met with Dr. Vandana Shashi at Duke University and began working with the genetics team there.
When Bertrand was 3 years old, the family enrolled in a small pilot study using whole-exome sequencing along with 11 other patient families whose child also had an undiagnosed disorder. At the time of the study, Bertrand’s symptoms were developmental delay, multifocal epilepsy, involuntary movements, abnormal liver function, and absent tears. By then, Bertrand’s parents were at the end of their rope, having exhausted a myriad number of tests to no avail. Would the pilot study be revealing? It was—when Bertrand was 41⁄2 years old, a call from Duke University said the exome study had concluded, and they had an answer—the NGLY1 gene could be the cause. This was a game-changing discovery because the gene had not been implicated in any condition before.
The Mights’ epic journey came to resolution with the results of the study which has since been published in the Journal of Medical Genetics.  Cristina and Matt each carried a different mutant NGLY1 gene; Matt had a nonsense (or stop) mutation in exon 8 and Cristina, a frame-shift (a point mutation involving either an insertion or deletion) in the last exon. Consequently, each of them produces only about half the normal amount of N-Glycanase 1. Bertrand got both mutant genes, meaning he lacks the ability to produce the NGLY1 enzyme. This enzyme is important in deglycosylating misfolded proteins, allowing them to be recycled into their constituent amino acids. As a result, Bertrand’s cells have been accumulating misfolded glycoproteins. This new disorder, N- Glycanase 1 deficiency or NGLY1, is known as a congenital disorder of glycosylation.
Armed with this knowledge, Matt used social media to find other parents who had children with similar symptoms. That’s when he met Matt Wilsey, whose daughter Grace also shed no tears and was eventually diagnosed with NGLY1 as well. By then, interest in the gene had piqued and another study was conducted with eight patients with NGLY1, including Bertrand and Grace. When the study was published in the journal Genetics in Medicine , Might and Wilsey wrote a commentary (an open access supplement) from a parent’s perspective, which accompanied the article. The commentary stated, “Families of children with serious genetic diseases often enter a diagnostic odyssey, moving from gene to gene in the hope of finding an explanation for the condition.”  And that’s where next-generation sequencing (NGS) comes into play.
However, unlike whole-genome sequencing which analyzes a person’s whole genome, whole-exome sequencing is more targeted and searches the entire portion of the protein-coding sequences of the genome only (about 2 percent of a person’s DNA), omitting introns and noncoding DNA; this makes it cheaper, quicker, and less labor-intensive. The combination of exome sequencing and family engagement through social media creates a new model, whereby, the two Matts explain, “Families, patients, and scientists work jointly to find new patients, confirm or refute hypotheses, exchange clinical information, enhance collaboration methods, and support research toward understanding and treatment.” This approach is truly the wave of the future in medical diagnostics for rare genetic diseases.
Thanks in part to this model, Matt Might says, “We've been able to sponsor a postdoc in Dr. Hudson Freeze's lab at the Sanford Burnham Medical Research Institute to do basic research on understanding the glycobiology of NGLY1 deficiency and another NGLY1 family is sponsoring an international network of researchers taking a variety of approaches to solve the problem.” The National Institutes of Health (NIH) is also conducting a massive study of all known NGLY1 patients to better understand the disorder, as well as the role and nature of the NGLY1 protein itself. Aside from the NIH study, much of the research was made possible from crowdfunding.
Crowdfunding is the practice of funding a project or venture by raising many small amounts of money from a large number of people, typically via the Internet. Matt says that together with the Wilsey family, “We've been able to support Dr. Hudson Freeze's lab in part through print sales of my Illustrated Guide to a Ph.D. And, friends and family have helped support the lion's share of the research effort.”
Today, at almost 7 years old, Bertrand is developmentally at the stage of a 6-8 month old. “He can hold a bottle to feed
himself and can reach a sitting position and stay sitting,” Matt continues on to say, “Bertrand communicates his emotions very well. It's obvious when he's happy or sad or hungry or in pain. For interacting with others and the world, Bertrand uses his eyes and broad gestures to indicate intent. He's been happy and healthy, and he's engaging in new kinds of advanced physical therapy, including exoskeletons that allow him to practice walking with an adjustable degree of assistance.” When asked what the hardest part of caring for a child with a rare disease is, he replied simply, “The world was not built for wheelchairs.” Despite the draining rollercoaster ride the Mights have had to endure, their love for Bertrand and the joy he brings to them is obvious and has sustained them. Matt describes his most treasured moment with Bertrand:
On a blog post from 2011, Matt ended with a promise he and Cristina made to Bertrand: “Of course, we will do everything possible for him. And, if that fails, we'll try the impossible.” That’s the power of a parent’s love, which often transcends the power of medicine.
 Might M. Hunting down my son’s killer. http://matt.might.net/articles/my-sonskiller/ Accessed August 2, 2014.
 Need AC, Shashi V, Hitomi Y, et al. Clinical application of exome sequencing in undiagnosed genetic conditions. J Med Genet 2012;49:353e361. doi:10.1136/jmedgenet-2012-100819.
 Enns GM, Shashi V, Bainbridge M. Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum-associated degradation pathway. Genet Med. 2014 Mar 20. doi: 10.1038/gim.2014.22. [Epub ahead of print]
 Might M, Wisley M. The shifting model in clinical diagnostics: how next-generation sequencing and families are altering the way rare diseases are discovered, studied, and treated. Genet Med. 2014 Mar 20. doi: 10.1038/gim.2014.23. [Epub ahead of print]