Mosaicism in Short Tandem Repeat Disorders: A Clinical Perspective

Fragile X, Huntington disease, and myotonic dystrophy type 1 are prototypical examples of human disorders caused by short tandem repeat variation, repetitive nucleotide stretches that are highly mutable both in the germline and somatic tissue. As short tandem repeats are unstable, they can expand, contract, and acquire and lose epigenetic marks in somatic tissue. This means within an individual, the genotype and epigenetic state at these loci can vary considerably from cell to cell. This somatic mosaicism may play a key role in clinical pathogenesis, and yet, our understanding of mosaicism in driving clinical phenotypes in short tandem repeat disorders is only just emerging. This review focuses on these three relatively well-studied examples where, given the advent of new technologies and bioinformatic approaches, a critical role for mosaicism is coming into focus both with respect to cellular physiology and clinical phenotypes.