What explains a patient’s genetic disease when no genetic cause is known?
Writer: Zohar Mendzelevski-Steinberg
Editor: Maddie Wigmore-Sykes
Art: Bella Peng
Only 20% of families with inherited early-onset breast cancer have a mutated version of BRCA1/2, the tumour suppressor genes best known for their involvement in breast cancer when silenced. Researchers have not been able to identify the cause of the other 80% of families’ heritable cancer until now – because they were looking in the wrong place.
Recent work by the Newman group at the University of Manchester has shown that BRCA1 promoters in the non-coding region of DNA are epigenetically silenced, leading to the effective silencing of BRCA1. They aren’t the only ones: across the globe, labs are discovering that in a range of diseases for which no genetic basis was previously known, epigenetic and genetic mutations to regulatory regions in the non-coding DNA are the cause. This ranges from cancer, to neurodevelopmental disorders, and to rare congenital diseases. In patients who present with only one risk allele for a recessive disorder, researchers are discovering non-coding DNA mutations which seriously reduce the expression of the remaining healthy allele. So, what do we know so far?
In the case of BRCA1, it appears that the promoters upstream of the BRCA1 gene are being hypermethylated, a heritable epigenetic modification which silences the promoter. This prevents transcription of the functional BRCA1 protein, a DNA repair protein which suppresses tumour formation, leaving only the dysfunctional allele to act in all cells of a patient’s body. In the case of muscle disorders, Cummings and other researchers found that mutations in introns (the non-coding DNA interspersed within genes, spliced out of the mature mRNA that codes for proteins) can disrupt normal splicing, producing malformed proteins. In severe collagen VI-related dystrophy, these introns promote their own inclusion in the final protein, altering the structure of specific collagen chains.
The rare syndrome thrombocytopenia with absent radii (TAR) reduces platelet numbers and causes severe bleeding. However, it is a recessive condition, and in many patients only one null allele has been inherited (i.e. an allele which is largely a deletion). The lack of activity from the remaining functional allele has been linked to mutations in both the regulatory region upstream of the key gene and in its first intron. In 2015, a similar story was unearthed in the case of congenital scoliosis – one risk allele and one functional allele with a mutated regulatory region resulted in recessive disease.
While many of the disorders for which non-coding mutations are relevant are rare, there are ground-breaking applications for treatment. In families with high cancer incidence, members can be tested for BRCA1 promoter methylation to inform their preventative treatment programmes. Large cohort studies can be employed to catalogue benign or damaging variants in non-coding genomic and epigenomic data so that we can catch genetic conditions early, when treatment is most effective. Personal genetic risk profiles can be compiled for patients which take into account the interactions between sections of DNA, allowing a future of exquisitely personalised treatments. Databases of this kind can also begin to teach us about the pathological mechanisms of diseases of which we still have a poor understanding of and even provide new drug targets. We have only begun to scratch the surface of what can go wrong with our non-coding DNA, but now that the causes are being unravelled, the hope for genetic treatment returns.