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Rare Disease or Rare Success: A Tale of Two Genomes

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When Congenica heard how an Iowa woman with a severe muscle wasting disease had not only diagnosed the genetic basis of her condition, but also realised it was linked it to a muscle-bound phenotype exhibited by Canadian Olympic hurdler Priscilla Lopes-Schliep, the company was inspired and wanted to see if they could help.

Jill Viles was delighted to hear of Congenica’s interest and their offer to help by sequencing her genome and those of her family in order to understand more about the rare muscle-wasting disease that affects her family - Emery-Dreifuss Muscular Dystrophy (EDMD). The hope is that this work will enable improved diagnosis and treatments for others patients with the condition.

During her undergraduate studies, Jill spent approximately 25 hours a week of her own time researching the disease. Eventually she found photographs of patients with Emery-Dreifuss and realised that the descriptions of the symptoms were very similar to those of herself and her family. This discovery also alerted her to the fact that her father and brother were at a higher risk of cardiac failure, a recognised feature of EDMD. Her father was immediately fitted with a pacemaker and her brother is receiving one later this year.

As a 19-year old, Jill had already uncovered a considerable amount of evidence that her family suffered from EDMD, but doctors were still very reluctant to issue a definitive diagnosis. Jill took matters into her own hands and contacted an Italian research team that was working on EDMD. Jill collected blood samples from her family and shipped them to the researchers in Italy. It took a further four years before the team was able to confirm Jill’s diagnosis in 1999.

The underlying pathogenic mutation was identified in the lamin A (LMNA) gene. Mutations in this gene cause a spectrum of disorders and further research by Jill, this time as an intern at the Johns Hopkins School of Medicine, identified that her condition was a form of the fat-wasting disease known as partial lipodystrophy. This blocks the body from storing fat in some areas, especially the arms and legs.

In some cases, mutations in this pathway cause the patient to have excess muscle growth, which was a feature of Jill’s father, who had characteristic ‘Popeye’ arms. Jill’s sister has similar features, and at a conference on lipodystrophy, she learned about a female Olympic sprinter who had very little fat. However, this elite athlete, Priscilla Lopes-Schliep, also had unusually large muscles. Jill began researching once again and was able to confirm that Priscilla was indeed missing fat in the same unique places around her body as Jill and her family. Jill was convinced that both she and Priscilla had a LMNA mutation, but that additional genetic modifier mutations gave the pair drastically different body types.

Jill eventually got in contact with Priscilla with the help of David Epstein, an investigative reporter and former senior writer at Sports Illustrated. The two have since become close friends, with Priscilla deciding to undergo genetic testing at the University of Texas Southwestern Medical Center, Dallas. There, Dr Abhimanyu Garg, a recognised expert in lipodystrophy, was able to confirm Jill’s prediction that she and Priscilla had different mutations in the same LMNA gene.

Moreover, he also discovered that Priscilla was at risk from a dangerously high level of triglycerides, prompting her to seek immediate treatment. This was the second time that Jill’s persistence had potentially saved a life – first that of her father and now an Olympic bronze medallist.

Phil Beales, MD, Professor of Genetics and Genomic Medicine, University College London, and Congenica’s co-founder and Clinical Director, says: “We will use our expertise in the interpretation of genetic and genomic data and rare disease diagnosis to try to identify specific DNA sequences that ‘modify’ the way that LMNA mutations can cause drastically different clinical phenotypes. I think it’s a long shot that we’ll find anything, as it is a small number of genomes to analyse, but if we don’t look, we won’t know - we may get lucky.”

Congenica is covering all the costs of whole genome sequencing, analysis, and interpretation for Jill and her four affected family members. The company will then provide its software to Dr Garg and his team to enable them to do their own analysis on not only Jill’s family, but also on any other relevant patient cohorts. Once this is completed, Dr Garg, Jill and Congenica will collaborate on next steps.

Jill comments: “It will be fascinating to have this information, as we know of cases in which doctors have sequenced DNA from two members of the same family and found identical mutations – but one is healthy while the other shows symptoms. Understanding why this happens could help us find treatments for the condition.”

Jill is determined to help other patients with this potentially devastating disease and to that end is raising money with a GoFundMe campaign to support further research.

Jill adds: “These very rare mutations are spread out in patients all over the world, and it’s a really slow ordeal to have individual doctors studying them. I see a future where families can have a single blood test to diagnose their condition.

“If the information is readily available through a platform, like Congenica’s Sapientia, the dozens of specialists and researchers will be better equipped to identify lipodystrophy or Emery-Dreifuss in their own labs. Then their patients won’t have to hunt through research papers and track down experts for answers.”

Jill Viles’ GoFundMe Campaign: https://www.gofundme.com/yyhtu45g

Jill Viles’ story in ProPublica: https://www.propublica.org/article/muscular-dystrophy-patient-olympic-medalist-same-genetic-mutation