In the first ASHG 2014 concurrent invited session, the talks in “Beyond Mendel – Complexities of Simple Mendelian Disorders” were beautiful demonstrations of the progress that has been made in understanding the underlying genetics, processes, and mechanisms involved in diseases. The session highlighted the degree of complexity involved in classical Mendelian diseases or seemingly simple single-gene disorders. Even among diseases with high penetrant or well-known alleles and an identifiable pattern of inheritance, there are still differences in the severity or presentation of the diseases, age of disease onset, and aggressiveness in disease progression. So what causes these differences? If there is one allele or gene underlying the disease, why do we see incomplete penetrance, and differences among individuals in a family?
In the first talk of the session “Elucidating the contribution of CFTR allelic variation and modifier genes to phenotypic variation in cystic fibrosis” Dr. Jeenah Park from the Johns Hopkins University School of Medicine discussed factors modifying CF disease severity. In a study of 151 cystic fibrosis sibling pairs with at least one copy of the F508del allele, three MC3R variants were found to be associated with lung disease severity. Two of the alleles were associated with higher-than-average lung function, while one allele was associated with reduced lung function. Individuals without any of the three modifier alleles were found in the middle of the distribution. MC3R encodes melanocortin peptides which help to mediate lung anti-inflammatory responses, and Dr. Park concluded that this reduction of the airway inflammatory burden may prevent irretrievable lung damage. Thus, the protective effects of MC3R variants could potentially benefit all CF patients, regardless of CFTR phenotypes.
Highlighting the second talk in the session, clinical researcher Dr. Anna Rose from the UCL Institute of Ophthalmology discussed the vision disorder retinitis pigmentosa (RP). The disease typically appears in late adolescence or early adulthood as night blindness or peripheral vision loss, and becomes progressively more severe leading to overall blindness by the age of 50. Retinal degenerative diseases are some of the most heterogenous and complex, and researchers have found a significant genetic heterogeneity in RP (~60 genes and loci, with multiple modes of inheritance), with the dominant form caused by more than 25 genes. Six splicing factors are associated with the dominant form of RP, and 10% of cases were found to be associated with PRPF31. Within this subset, Rose and colleagues identified variant haploinsufficiency and phenotypic non-penetrance. Interestingly, given that PRPF31 is dominantly inherited, both symptomatic and non-symptomatic individuals within pedigrees were found to have the same underlying causal variant. However, symptomatic individuals expressed the mutated allele, while asymptomatic individuals carried the same mutation, but the wild type copy was the higher expressing allele. To understand the genetic factors that control expression of PRPF31, Dr. Rose found that there was a major cis-acting effect of an upstream minisatellite repeat (MSR1) element. When MSR1 was present as a CNV of four copies (MAF ~15% in European populations), the affect was protective, and individuals were asymptomatic. When present as a three-copy CNV, individuals progressed to disease, suggesting a molecular switch function that could have important implications for other conditions.
These examples demonstrate that even in diseases with well-defined genetic causes, multiple environmental and genomic factors may interact to modify the phenotype of disease. The regulation of expression in these diseases and in many others suggests that variation in promoters and other regulatory elements can be as important as the presence of the underlying disease variant. Likewise protective epistatic effects may also be useful in understanding disease pathology and provide a basis for therapy research.
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