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Inside the Lab Bioinformatics, Genetics and epigenetics, Omics, Clinical care, Screening and monitoring, Technology and innovation, Precision medicine

A Patient Is More Than a Price Tag

At a Glance

  • Intellectual developmental disorders (IDD) are prevalent and burdensome – but those caused by inborn errors of metabolism can often be treated if diagnosed using techniques like genome-wide sequencing
  • An initial study applying whole exome sequencing resulted in diagnoses for 68 percent of participants, as well as identification of new genes and disorders
  • In a subset of these patients, diagnoses allowed for targeted treatments to improve developmental and health outcomes
  • Genomic sequencing holds promise for IDD and other conditions, but researchers, pathologists, clinicians, bioinformaticians and patients must work together for it to succeed

Intellectual developmental disorders (IDD) are both prevalent and burdensome. With one in 40 people affected – and often experiencing additional symptoms like epilepsy or behavioral disturbances – IDD results in significant social and economic costs, making identifying and treating as many as possible a major goal. But with hundreds of known disorders and an estimated 95 million patients with cases of unknown cause (1), how can we take on the task of diagnosing the exact cause of IDD?

We know that many inborn errors of metabolism (IEMs) – monogenic defects causing enzyme deficiencies that result in energy depletion and toxin accumulation – can cause altered intellectual development. In cases where the error can be treated (for instance by medical diets, vitamins or medications), we see improvements not only to development, but also to psychiatric, neurological and systemic health. In an attempt to bring these benefits to as many IDD patients as possible, we investigated the diagnostic potential of genome-wide sequencing – and hit the jackpot. Of the 41 families enrolled in our study, all of whom experienced IDD and metabolic changes due to rare mystery conditions, we were able to identify the precise genetic causes in 28. We also discovered 11 new disease genes and several new phenotypic manifestations of previously known disorders (2). Most importantly, in four out of 10 cases, knowing the diagnosis allowed us to start treatment that improved their daily lives and health. It’s a wonderful start to large-scale DNA investigations of IDD, and one we anticipate expanding upon in years to come – because the more we can learn about the genetics of brain function, the better placed we are to change the lives of patients and families dealing with IDD.

Screenshots of the Treatable-ID app.
Selection strategy

The focus of our work was on patients with both IDD and biochemical or metabolic abnormalities, because the combination is suggestive of a genetic cause that is potentially amenable to treatment. We call those inborn errors of metabolism. Our patient selection criteria for genome‐wide sequencing included either confirmed IDD or a strong indication of future IDD development, as well as a metabolic phenotype of unknown origin. Because ours is a research‐based study focused on discovering novel rare genetic disorders and clinical manifestations, another important patient selection criterion was that previous genetic and biochemical (deep phenotype) testing done in a clinical setting had been elaborate, but had not yielded a diagnosis. In our cohort of patients, the underlying genetic defects were mainly due either to novel genes or to known genes with novel phenotypes – confirming that our patient selection criteria are useful for enriching gene discovery.

Genome-wide sequencing offers efficient and timely profiling of patients’ whole exomes and genomes – and, with exquisite data interpretation, can yield a definitive diagnoses.

But one thing that may be too easily forgotten is that good research isn’t the only marker of success. For our patients and their families, early diagnosis is of paramount importance to ensure they receive the right treatment at the right time. And not just that – it also provides an answer and a prognosis, avoids unnecessary further testing, and enables accurate genetic counseling. Genome‐wide sequencing offers efficient and timely profiling of patients’ whole exomes and genomes – and, with exquisite data interpretation, can yield a definite diagnosis in a very timely manner. In our opinion, any child with IDD deserves a thorough workup, including a chromosome microarray and Treatable Intellectual Disability Endeavor (TIDE, tidebc.org) first-tier metabolic testing. If those tests are negative – or if the patient needs a diagnosis faster than they can deliver one – then we think it’s entirely warranted to use genome-wide sequencing as a first-line test. That’s easier said than done, because availability is still an issue, but we believe that every patient deserves access to whatever diagnostic tools are needed. Of course, not every patient will receive a diagnosis; at the moment, about half will remain undiagnosed even with genome-wide sequencing, but as knowledge and expertise grows, these numbers will change for the better.

Winning the cost argument

An “ideal” patient for exome sequencing is one with a suspected rare monogenic disorder for whom thorough clinical phenotyping data is available. In our work in particular, we focus on whole exome sequencing (WES) in patients with unexplained IDD and metabolic phenotypes of likely genetic origin. Whole genome sequencing (WGS) has an even broader target population, because it’s also capable of revealing copy number variants. What do all of these tests have in common? They can’t occur in isolation – experts must be available to help analyze and interpret the bioinformatics findings. Too many patients receive test results they don’t understand, and even the doctors ordering the tests may lack the specialist education to explain the results fully. Patients should never be provided with genetic information without the guidance to help them understand its implications.

Of course, expertise can cost money – and when a test requires close collaboration between several members of a multidisciplinary team, it’s easy to question whether or not it’s cost-effective in the clinic. In our experience, the price tag on genome‐wide sequencing is only about one-tenth of the total cost of the diagnostic odyssey – but the benefit can be greater than that of any other expenditure. Patients and families are better-placed than anyone else to see how the speed and timeliness of sequencing impacts diagnosis and patient management, especially if we’re then able to treat the disease in question. For them, it’s life-changing, and that simple fact makes the test worth the cost.

A genomic journey of discovery

In our study’s cohort of IDD patients, we identified 11 novel genes implicated in human disease, and from that starting point, we were able to define several new disorders. For instance, we identified a form of hyperammonemia due to carbonic anhydrase VA deficiency in patients with defective CA5A genes – a deficiency amenable to treatment with carglumic acid and an emergency protocol (3). We also discovered epileptic encephalopathy due to N-acetylneuraminic acid phosphate synthase deficiency, and showed using model organisms that this deficiency is amenable to treatment with early supplementation of sialic acid, a sugar present in breast milk and other food products (4). And what of the other nine genes? Thus far, we’ve been able to ascribe to them two novel, potentially treatable disorders due to GOT2 and ACACB deficiencies, as well as seven candidate novel disorders.

The current best estimate for the total number of rare genetic disorders is approximately 7,000 – though the true number may be a bit higher (and only a subset of these are neurometabolic diseases). Given that as many as an estimated 50 percent of genes underlying known Mendelian phenotypes are still unknown, we anticipate that, in coming years, many more new disorders will be uncovered using genome-wide sequencing. As a matter of fact, we’re already working on that – the number of patients we have analyzed using this technology since publishing our initial study findings has tripled, and so have the discoveries we’ve made. Understanding the pathways and disease mechanisms for both metabolic and non-metabolic genetic conditions is important – it allows us to explore new treatment options, something that is already happening for conditions like Rett syndrome, Fragile X syndrome, and tuberous sclerosis.

We aim to continue discovering novel neurometabolic diseases using genome-wide sequencing, but we hope to place more focus on WGS rather than WES now that we’re approaching the era of the US$1,000 genome. We’ll also be expanding our novel gene discovery approach further to include other neurodevelopmental conditions like atypical cerebral palsy. Not only that, but we’re hoping to move into multiple –omics technologies (like transcriptomics and epigenomics) to identify genetic modifiers and better understand the phenotypic variability in patients with rare metabolic disorders. Ultimately, we hope that this combination of approaches will improve patient management, increase the predictability of disease outcomes, and help us to identify metabolic targets for future treatment.

Testimonials from users of the Treatable-ID app (see box “Simplifying Sequences: Treatable-ID”).

Simplifying Sequences: Treatable-ID

By Maja Tarailo-Graovac and Clara van Karnebeek

We have developed an app for clinicians called Treatable-ID (treatable-id.org), which we hope will enhance early diagnosis of treatable inborn errors in patients with IDD. The app provides information on the different IEMs and allows users to search by signs and symptoms – useful for narrowing down the differential diagnosis and fine-tuning second-tier testing on the TIDE protocol. It can be used in two ways: either to scrutinize the WES/WGS data for variants in the encoding genes during bioinformatics analysis or to identify the biochemical test of choice for a given variant. Right now, we’re seeing hundreds of users – from trainees to specialists – on the app’s website every day, and over 8,000 downloads per year worldwide. It’s even used in the American Board of Medical Genetics and Genomics teaching curriculum! As we discover new treatable diagnoses, we plan to keep Treatable-ID updated so that it’s always a complete, easily accessed resource for healthcare providers.

Collaboration in the clinic

How might genome-wide sequencing change the clinical laboratory’s day-to-day routine? We think it’s already doing so – and that the changes will keep happening. Single tests will slowly disappear as sequencing takes their place; it’s an ongoing process for monogenic diseases, but in the future, we expect the same for polygenic and multifactorial diseases. And genomics can impact more than just diagnosis and counseling; four out of 10 patients can receive treatment tailored to the underlying condition once identified (2)! As genetic analysis assumes an ever more critical role, teamwork between pathologists, bioinformaticians, clinicians and genetic counselors will be key for success. This is truly “big data,” and the more conditions and secondary findings we encounter, the more complex and challenging it becomes. We need well-informed, collaborative interpretation of that data, and we need to ensure that vital phenotypic information isn’t overlooked in our eagerness for genotypic data. In short, we need smart –omics!

That’s the key message we want to send to pathologists and laboratory medicine professionals working in the IDD field: that it’s vital to have close collaboration between experts in multiple disciplines in the era of –omics medicine. We attribute the success of our approach to efficient and extensive communication between the physicians who performed the deep phenotyping, the bioinformaticians who developed a semi-automated gene discovery pipeline and performed data interpretation, the laboratory scientists who performed experimental validations, the clinicians who developed improved treatment strategies based on our diagnoses, and – of course – the patient and family affected by the disorder. With this collaborative, multidisciplinary approach serving as a model, the future of genomic medicine is bright!

Maja Tarailo-Graovac is a research associate in the Wasserman laboratory at the University of British Columbia’s (UBC) Centre for Molecular Medicine and Therapeutics (CMMT), Vancouver, Canada.

Clara van Karnebeek is a principal investigator at CMMT and an Assistant Professor in the Division of Biochemical Diseases, Department of Pediatrics, at the UBC’s Faculty of Medicine.

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  1. Global Burden of Disease Study 2013 Collaborators, “Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013”, Lancet, 386, 743–800 (2015). PMID: 26063472.
  2. M Tarailo-Graovac et al., “Exome sequencing and the management of neurometabolic disorders”, N Engl J Med, 374, 2246–2255 (2016). PMID: 27276562.
  3. CD van Karnebeek et al., “Mitochondrial carbonic anhydrase VA deficiency resulting from CA5A alterations presents with hyperammonemia in early childhood”, Am J Hum Genet, 94, 453–461 (2014). PMID: 24530203.
  4. CD van Karnebeek et al., “NANS-mediated synthesis of sialic acid is required for brain and skeletal development”, Nat Genet, 48, 777–784 (2016). PMID: 27213289.
About the Authors
Clara van Karnebeek

Clara van Karnebeek is a principal investigator at CMMT and an Assistant Professor in the Division of Biochemical Diseases, Department of Pediatrics, at the UBC’s Faculty of Medicine.


Maja Tarailo-Graovac

Maja Tarailo-Graovac is a research associate in the Wasserman laboratory at the University of British Columbia’s (UBC) Centre for Molecular Medicine and Therapeutics (CMMT), Vancouver, Canada.

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