Genetic and symptomatic variations in Myotonic Dystrophy Type 1

Myotonic dystrophy type 1 (DM1) is an extremely variable genetic disorder showing an autosomal dominant inheritance that is characterised by myotonia, insulin resistance, cardiac conduction defects and cataracts. It is caused by a trinucleotide repeat expansion of CTG sequence located in the 3’-untranslated region of the dystrophia myotonica-protein kinase (DMPK) gene on chromosome 19 at q13.3. The severity of symptoms ranges from mild adult onset to severe congenital form. A characteristic clinical feature of DM1 is anticipation phenomenon where disease severity increases and age of onset decreases over successive generations. The DM1 mutation is highly unstable in both the germline and soma, and showed to be an age-dependent, tissue-specific (skeletal muscles comprised the largest allele length of approximately thousand units) and expansion biased. The unaffected level of the repeat sequence falls between ~5-37 repeats whereas the disease associated range starts from ~50 repeats, reaching several thousand units. These properties account for the observed anticipation and contribute toward the tissue-specificity and progressive nature of the symptoms. The manifested phenotypes, symptoms severity and age at onset are extremely variable within and between families. This is mostly accounted for by the progenitor allele length (PAL) passed on from affected parents in addition to the level of somatic instability over time. Though, recent data have shown that additional sequence variations (CCG, CGG variant repeats) within the repeat and immediate flanking DNA are associated with additional symptomatic variation, modified stability and delayed age of onset. Furthermore, individual specific genetic factors have shown to be clustered within and between families as a heritable trait. Therefore, it has been verified that PAL, in addition to individual specific genetic variations are the main modifier of disease onset. More recently, it has been observed that mismatch repair (