After years of searching for a diagnosis, Jill Viles was diagnosed with Emery-Dreifuss Muscular Dystrophy (EDMD), a rare form of muscular dystrophy that affected her and some of her family. However, whilst Jill experienced muscle wasting from a young age, some of her siblings - who were also diagnosed with EDMD - experienced some increased musculature. A search for the cause of this difference in phenotypes led Jill to Congenica, whose clinical scientists found a shared mutation in SMAD7, a modifier gene involved in the TGF-β signalling pathway that may be the cause of the differing phenotypes (or ‘symptom’). This information is now been used by researchers in the University of Iowa to further research the underlying causes of EDMD.
Jill’s Early Life
Confirming the Diagnosis
Jill spent hours of her free time at university reading all the medical journals she could find on muscular dystrophy. One such article spoke of two brothers who had been diagnosed with Emery-Dreifuss Muscular Dystrophy, or EDMD - a rare form of MD characterised by muscle weakness and wasting, stiff joints, and heart-rhythm irregularities. Recognising the same symptoms she had experienced throughout her own life, Jill hypothesised that this may be the very same disease that she also suffered from. “It was like finding a picture of family” she later said, “and you just know they’re family.” Jill shared this hypothesis with her family. This led her father to visit a clinician for previously overlooked heart issues - another symptom of EDMD. Whilst reticent at first, the clinician agreed to fit a heart rate monitor for a day. At times, his pulse dropped below 30 bpm. He was immediately fitted with a pacemaker, saving his life.
It was like finding a picture of family
Jill later reached out to Italian researchers who were conducting a genetic study of EDMD who, after four years, finally gave her some genetic answers - she and her siblings had a mutation in the LMNA (or ‘Lamin A’) gene, a protein-coding gene linked to diseases that affect muscle and fat, including EDMD. This finally confirmed the cause of Jill’s condition, but it still did not explain her siblings’ differing symptoms; but years had passed, and Jill continued with her life. She got married and had a son – who did not share her condition – and the questions were left unanswered.
Congenica Joins the Quest for Answers
Years later, after hearing of Jill’s story on This American Life, Craig Taylor, VP of Business Development at Congenica, realised that his company may be able to help Jill in her quest.
Craig shared Jill’s story with Congenica’s clinical team, who persuaded company leadership to donate whole genome sequencing and analysis services not only for Jill, but also her siblings, to help get to the bottom of what was causing their phenotypes.
Samples from Jill and her siblings were processed
using a whole-genome sequence secondary analysis pipeline.
The results were loaded into Sapientia for analysis and variants
were reviewed by Congenica’s Clinical Team.
Congenica’s expert team were able to explore Jill’s case in depth by using their diagnostic decision support platform, Sapientia. Sapientia provides a web-based platform for accessing genetic analysis tools, scientific literature and genetic variant databases. Like Jill, Congenica’s experts thought there might be an underlying genetic explanation for the different phenotypes seen within Jill’s family and aimed to sequence the genomes of Jill and her family members to discern if a second disorder was responsible for the different muscular phenotypes seen in the family. The Congenica team knew that finding causal variants can be challenging in families because siblings naturally share a large proportion of genetic variance, so knowing where to focus the search would be challenging.
Investigating with Sapientia
First, the team reconfirmed that Jill and her siblings had the LMNA mutation linked to EDMD. The diagram below shows this confirmation in Sapientia, with Jill and all 3 of her siblings sharing the same G -> C mutation in the gene.
A patient story of diaganosis and discovery
Next, the team explored variants that are present in Jill and her brother who do not display hypermusculature, but not present in her brother and sister who do, and vice versa, looking specifically at genes associated with neuromuscular conditions, including EDMD. But they did not identify any variants that would suggest a second disorder.
To confirm Jill’s diagnosis, the team applied a gene panel that sorted out genes linked to specific
muscular phenotypes, including POMT1, POMT2, LMNA, and LAMA2. They applied population-
frequency data to filter out common variants and return only variants that are either absent
or extremely rare frequency within the general population. In addition to this, the team applied an
additional series of filters related to variant consequence.
The team found the likely causative variant was a heterozygous missense variant, LMNA
NM_170707 c.1580G>C. With this data on hand, they then applied the ACMG Guidelines and created
a fully-auditable decision trail within Sapientia. Ultimately, they reconfirmed the lamin A/C
mutation in Jill and her three siblings.
Investigating with Sapientia
The team member couldn’t help but draw parallels between the vast differences in musculature shown by Jill and her siblings. She questioned whether a similar mutation might be at play in humans and urged the team back home to explore mutations in the TGF-β pathway.
The team applied a gene panel to examine the many genes involved in the TGF- β pathway, searching for variants and once again looking for commonality between the two groups of siblings. The analysis uncovered a mutation in SMAD7 that was common to Jill and her brother, while absent from her the brother and sister who displayed excess muscle growth. A literature search showed that several other studies have suggested that SMAD7 enhances skeletal muscle differentiation and is required for the formation of muscular tissue3,4,5,6,7. Upon review, the Congenica team determined there was sufficient evidence pointing to the SMAD7 mutation, and a potential modifying gene had been found.
The SMAD7 variant was also absent from a large population dataset (gnomAD) used as a reference
by the team in their analysis. The amino acid is conserved down to zebrafish. The ExAC
database from the Broad Institute indicates a missense constraint score of 3.87, suggesting that
missense variance is not well tolerated in this gene.
The potential role of SMAD7 as a modifier gene continues to be explored as time goes on.Specifically, Dr. Lori Wallrath of University of Iowa is trying to discern whether the presence of this mutation is a situation unique to Jill’s family or if there are mutations in this gene present in others with EDMD, particularly those at the severe end of the spectrum.
You don’t see companies doing stuff like this. Congenica’s intervention led
Dr. Wallrath was inspired to reach out to Jill after hearing of Congenica’s gesture. She remarked, “You don’t see companies doing stuff like this. Congenica’s intervention led to the breakthroughs we are pursuing, which we
wouldn’t have seen otherwise.”
Dr. Wallrath has developed Drosophila and mouse models to study over- and
under-expression of the gene in different tissues. Additionally, she is collaborating
with her colleague, Dr. Benjamin Darbro, and Jill to form a cohort study to further
examine the implications of these findings.
What the Future Holds
If you would like to hear more from Jill herself, you can view our webinar, where Jill tells her story in her own words, and Congenica’s clinical scientists explain how they came to meet Jill, and find the potential modifier for her condition: https://www.congenica.com/webinar-discovering-missing-link-rare-disease-athlete/
1. Epstein D. The DIY Scientist, the Olympian, and the Mutated Gene: How a woman whose muscles disappeared discovered she shared a disease with a muscle-bound Olympic medalist. ProPublica. Originally published: January 15, 2016.
2. Congenica On Demand Webinar: Discovering the Missing Link Between my Rare Disease and an Olympic Athlete. Available at: https://www.congenica.com/webinar-discovering- missing-link-rare-disease-athlete/
3. Zhu et al. 2004. Myostatin signalling through SMAD2, SMAD3 and SMAD4 is regulated by the inhibitory SMAD7 by a negative feedbackmechanism. Cytokine 26:262–272.
4. Kollias et al. 2006. SMAD7 promotes and enhances skeletal muscle differentiation. Mol Cell Biol 26(16): 6248-6260.
5. Cohen et al. 2015. Genetic disruption of SMAD7 impairs skeletal muscle growth and regeneration. J Physiol. 593(Pt 11): 2479–2497.
6. Hua et al. 2016. SMAD7, an antagonist of TGF-beta signalling, is a candidate of prenatal skeletal muscle development and weaning weightin pigs. Mol Biol Rep. 43(4):241-51.
7. Winbanks et al 2016. SMAD7 gene delivery prevents muscle wasting associated with cancer cachexia in mice. Sci Transl Med. 8(348): 348ra98.
Rare Revolution Editor