Advancing genomic technologies and clinical awareness accelerates discovery of disease-associated tandem repeat sequences

Abstract

Expansions of gene-specific DNA tandem repeats (TRs), first described in 1991 as a disease-causing mutation in humans, are now known to cause >60 phenotypes, not just disease, and not only in humans. TRs are a common form of genetic variation with biological consequences, observed, so far, in humans, dogs, plants, oysters, and yeast. Repeat diseases show atypical clinical features, genetic anticipation, and multiple and partially penetrant phenotypes among family members. Discovery of disease-causing repeat expansion loci accelerated through technological advances in DNA sequencing and computational analyses. Between 2019 and 2021, 17 new disease-causing TR expansions were reported, totaling 63 TR loci (>69 diseases), with a likelihood of more discoveries, and in more organisms. Recent and historical lessons reveal that properly assessed clinical presentations, coupled with genetic and biological awareness, can guide discovery of disease-causing unstable TRs. We highlight critical but underrecognized aspects of TR mutations. Repeat motifs may not be present in current reference genomes but will be in forthcoming gapless long-read references. Repeat motif size can be a single nucleotide to kilobases/unit. At a given locus, repeat motif sequence purity can vary with consequence. Pathogenic repeats can be "insertions" within nonpathogenic TRs. Expansions, contractions, and somatic length variations of TRs can have clinical/biological consequences. TR instabilities occur in humans and other organisms. TRs can be epigenetically modified and/or chromosomal fragile sites. We discuss the expanding field of disease-associated TR instabilities, highlighting prospects, clinical and genetic clues, tools, and challenges for further discoveries of disease-causing TR instabilities and understanding their biological and pathological impacts-a vista that is about to expand.

Figure 1.

Overview of disease-associated repeat discovery by year, with colored inserts specifying the major technological breakthroughs that were used to make these discoveries. (AD) Alzheimer disease, (ALS/FTD) amyotrophic lateral sclerosis/frontotemporal dementia, (ASD) autism spectrum disorder, (BAFME) benign adult familial myoclonic epilepsy, (BD) bipolar disorder, (BPES) blepharophimosis, ptosis, and epicanthus inversus syndrome, (CANVAS) cerebellar ataxia, neuropathy, vestibular areflexia syndrome, (CCD) cleidocranial dysplasia, (CCHS) congenital central hypoventilation syndrome, (DBQD2) Desbuquois dysplasia 2, (DM) myotonic dystrophy, (DRPLA) dentatorubropallidoluysian atrophy, (EDM1) multiple epiphyseal dysplasia, (EIEE1) epileptic encephalopathy, early infantile, 1, (EPM1) epilepsy, progressive myoclonus-1, (FECD3) Fuchs endothelial corneal dystrophy-3, (FRDA) Friedreich's ataxia, (FSHD) facioscapulohumeral muscular dystrophy, (FXTAS) fragile X ataxia/tremor syndrome, (GD) glutaminase deficiency, (HDL2) Huntington disease-like 2, (HFG) hand-foot-genital syndrome, (HPE5) holoprosencephaly 5, (LOAD) late-onset Alzheimer disease, (MJD) Machado-Joseph disease, (NIID) neuronal intranuclear inclusion disease, (OPDM) oculopharyngodistal myopathy, (OPMD) oculopharyngeal muscular dystrophy, (OPML) oculopharyngeal myopathy with leukoencephalopathy, (PSACH) pseudoachondroplasia, (RCPS) Richieri-Costa-Pereira syndrome, (SBMA) spinal bulbar muscular atrophy, (SCA) spinocerebellar ataxia, (SMD) skeletal muscle disease, (SPD1) synpolydactyly-1, (SCZ) schizophrenia, (XPD) X-linked dystonia-parkinsonism, (22q11DS) 22q11 deletion syndrome. It has been concluded that FAME, BAFME, FEME, FCTE, and ADCME are the same clinical entity even if genetically heterogeneous—we use the acronym BAFME here as it is the most used acronym associated with the disease. The nonfolate-sensitive rare fragile sites FRA10B and FRA16B, caused by expanded AT-rich repeats, are not listed herein (see Table 1).

Figure 2.

Proposed mechanisms through which disease-associated repeats may exert toxicity. Multiple mechanisms may be active at a single locus. (RAN) Repeat-associated non-ATG, (UTR) untranslated region.