Mosaicism in Short Tandem Repeat Disorders: A Clinical Perspective

Abstract

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.

Keywords: DMPK; FMR1; HTT; Huntington disease; fragile X; genomic mosaicism; methylation mosaicism; myotonic dystrophy type 1; short tandem repeats.

Figure 1

Genetic location and short tandem repeat motif associated with example disorders. The majority of known STR disorders are found within the exonic and intronic regions of the affected gene. Disorders of interest for this review are distinguished in bold. FMR1; #300624, NOTCH2NLC; #603472, PPP2R2B; #604326, GLS; #618412, HTT; #143100, ATN1; #125370, AR; #313200, ATXN1; #164400, ATXN2; #183090, ATXN3; #109150, CACNA1A; #183086, ATXN7; #164500, TBP; #607136, FXN; #229300, CNBP; #602668, ATXN10; #603516, BEAN1; #117210, NOP56; #614153, TCF4; #613267, C9orf72; #105550, DMPK; #160900, ATXN8OS/ATXN8; #608768. # = Phenotype MIM number..

Figure 2

Illustration of the impact of STR instability over generations and the clinical significance of STR mosaicism that can be found within individuals. (A) Example pedigree demonstrating expansion across generations, particularly in the female germline for fragile X. (B) Mosaicism in the brain can impact clinical phenotypes of neurological disorders, while germline variation impacts generational changes, which can lead to differential expansion in sperm (HD) and egg cells (fragile X, DM1) depending on the specific STR. The right panel demonstrates the function of different brain regions, which could theoretically be impacted by clonal variation. (C) Somatic mosaicism, in some cases such as Huntington disease, may be developmentally dependent and cell-type-specific but not necessarily tied to proliferative status.