Mastermind Stories

Connecting Patients with Diagnoses

Rady Children’s Institute for Genomic Medicine

Mastermind Uncovers Baby’s Rare Immunodeficiency

When a child needs a genome-driven diagnosis fast, clinicians turn to Rady Children’s Institute for Genomic Medicine (RCIGM) in San Diego. More than 50 children’s hospitals nationwide rely on the Institute for ultra-rapid genetic analysis, diagnosis, and treatment recommendations.

Associate Lab Director Kasia Ellsworth sees the difference they make every day. “About 4% of children or neonates born in hospitals require critical care”, she said. “There they start interim empirical treatment, and a search for etiological diagnosis begins. We can expect that 20 to 50% of those kids will end up having a genetic diagnosis, and from many of those diagnoses we can devise precision treatment. That leads to lower mortality and long-term morbidity, shorter clinical stays, and decreased hospital costs.”

With young lives in the balance, time is of the essence. And RCIGM delivers; they have set the world speed record for WGS twice. For medically urgent cases, the Institute’s typical turnaround time from sample to preliminary diagnosis is less than three days.

The process starts at the referring hospital, where consent, enrollment, information gathering, and sample collection take place. At Rady Children’s Institute, the samples are sequenced in their CAP/CLIA certified laboratory. The data then goes through the bioinformatics pipeline using a variety of computational tools. The resulting data files are annotated, filtered, and interpreted using data analysis software.

Then, Dr. Ellsworth and her board certified colleagues step up to the final challenge. The analysis and interpretation team prioritizes variants with respect to phenotypes; curates the evidence for clinical relevance; and classifies them according to guidelines set forth by the ACMG (American College of Medical Genetics & Genomics). “This is where we spend a lot of time,” says Dr. Ellsworth. “By improving and automating some of the variant curation steps, we’re able to decrease turnaround time. That’s where Mastermind comes into play.”


The need for speed was evident when a week-old baby showed signs of an immune deficiency (SCID, or severe combined immunodeficiency): He was doing well in the neonatal ICU, but was at risk of developing severe recurrent viral bacterial and fungal infections, along with failure to thrive.

A blood sample obtained from the patient indicated an absence of T and B-cells, prompting a search for the genetic cause to confirm the diagnosis and better define the treatment strategy. Among the many genetic data-points that required review, they discovered a large deletion encompassing three exons within the DCLRE1C gene, which the OMIM (Online Mendelian Inheritance in Man) catalog confirmed is associated with autosomal recessive SCID.

Diligent further analysis revealed another anomaly within this gene: a single DNA letter change that changed a single molecular component of the protein encoded by this gene – otherwise known as a missense variant; these can be among the most challenging to interpret without direct evidence from previous cases or functional studies to support the variant’s role in causing disease. An immunologist noted that DCLRE1C is notoriously difficult to sequence. Could it be relevant to the case? A search for references characterizing the variant in previous cases in HGMD (the Human Gene Mutation Database) came up empty.

But where other research tools failed, Mastermind succeeded.

“When Mastermind indicated there was a single reference that had cited the exact variant found in our patient, we could then quickly access and read the data, which showed that in vivo and in vitro studies were performed”, said Dr. Ellsworth. “Rather than gene name, this variant was found in the literature under the protein’s name — Artemis. It turned out that this amino acid position is essential for the protein catalytic activities, and therefore we were able to evoke functional evidence for classification.”

Based on the patient’s clinical presentation and molecular findings, the RCIGM clinical team agreed on the patient’s diagnosis — crucially, prior to onset of severe symptoms. As a result, the baby’s medical treatment was adjusted to match the child’s disease-specific needs.

The result of this diagnostic journey? The baby is healthy and thriving.

Dr. Ellsworth said that this wasn’t the only time that Mastermind came through for her. In 11 recent cases, Mastermind handily beat out HGMD in five of them in terms of number of references, finding more information for 11 out of 23 genes. In contrast, HGMD never returned more references. She further reported that many of the references that Mastermind found “were very useful for classification of the variants that were ultimately noted in the clinical report.”

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Rare Genomics Institute

Single Research Paper Found in Mastermind Leads to Diagnosis

Getting a diagnosis for a rare disease is a long and often painful journey that can take an average of five years1 and hundreds of doctor visits. Sometimes, the answer never comes; conventional diagnostics does not always provide a diagnosis for diseases that are only found in one in a million or one in 10 million people. Because most rare diseases are genetic in nature, genomic DNA sequencing can be used to provide answers that conventional approaches cannot.

Most families affected with rare diseases are under financial strain, making access to genetic sequencing technologies difficult. Rare Genomics Institute (RG), a non-profit patient advocacy group, meets these patients at the end of their diagnostic odyssey – when all other means of diagnosis have failed and when financial resources are no longer available to continue the diagnostic process.

The Patient Research Services of the RG has created an ecosystem of leading technology partners and genetic experts from top research institutions around the world to give patients pro-bono access to world-class genomic sequencing, data analysis and interpretation services. Often, RG works with their partners and volunteer experts to re-analyze cases that have hit a dead end.

Recently, RG announced a strategic partnership with Genomenon, a Big Data genomics company that uses artificial intelligence to connect the genetic mutations buried in 30 million medical research publications with patient data obtained from genetic sequencing. Using technology that wasn’t available just a few years ago, Genomenon puts the research for over 4.1 million genomic variants at the scientist’s fingertips to make sure that no stone is left unturned in providing a comprehensive diagnosis.

In a recent case, a patient had their whole exome sequenced and analyzed by a leading genetics laboratory as part of their long diagnostic odyssey. The lab was unable to find any clinically relevant genetic mutations that could provide a diagnosis. That was where RG stepped in; Dr. Lipika Ray, a computational geneticist on the Patient Research Services team, reanalyzed the patient’s DNA, which included a search of the state-of-the-art Mastermind Genomic Search Engine.

With Mastermind, Dr. Ray was able to find a single research report in the scientific literature that matched the patient’s DNA data. The patient in the report shared similar symptoms with the patient being analyzed. With this finding, RG recommended that the patient be re-examined based on the diagnosis found in the scientific research.

“Sometimes there is only one research paper that can connect a patient’s DNA with a diagnosis. Searching through millions of research papers to find a patient’s genetic mutation can be like trying to find a needle in a haystack. With advanced AI techniques used by Genomenon, the needle can pop right into view.” said Dr. Ray. “I can say with certainty that without the findings obtained from Genomenon, I would not have been able to provide a diagnosis for this patient.”

“This case is the perfect example of the innovative opportunities we try to bring to rare disease patients that have been fighting for so long with no answer,” said Romina Ortiz, COO of Rare Genomics Institute.

Delay to diagnosis often results in inappropriate testing, treatments, or missed treatment opportunities, and is correlated with increased morbidity and mortality2,3,4,5. Genetic answers, like the one found in this case, can provide whole new avenues for these families.

It allows them to gain approval and coverage for referrals and testing with specialists to better treat or manage the disease. And in some cases, even cure their disease. At the same time, it immediately gives them something real to attribute their child’s disease to. It can give them a new community to participate in, where families with children that share similar mutations or disease can provide resources, recommendations or sometimes just someone that understands them.

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1. Angelis A, et al. Socio-economic burden of rare diseases: A systematic review of cost of illness evidence. Health Policy 2015; 119(7):964-79.

2. Limb L, Nutt S, Sen A. Experiences of rare diseases: an insight from patients and families. 2010.

3. Guffon N, Heron B, Chabrol B, Feillet F, Montauban V, Valayannopoulos V. Diagnosis, quality of life, and treatment of patients with Hunter syndrome in the French healthcare system: a retrospective observational study. Orphanet J Rare Dis. 2015;10:43 doi: 10.1186/s13023-015-0259-0

4. Wang RT, Silverstein Fadlon CA, Ulm JW, Jankovic I, Eskin A, Lu A, et al. Online self-report data for duchenne muscular dystrophy confirms natural history and can be used to assess for therapeutic benefits. PLoS Curr. 2014;6. pii:

5. Pierucci P, Lenato GM, Suppressa P, Lastella P, Triggiani V, Valerio R, et al. A long diagnostic delay in patients with Hereditary Haemorrhagic Telangiectasia: a questionnaire-based retrospective study. Orphanet J Rare Dis. 2012;7:33 doi: 10.1186/1750-1172-7-33

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