30 years of repeat expansion disorders: What have we learned and what are the remaining challenges?

• Published in: American journal of human genetics Vol. 108; no. 5; pp. 764 - 785
• Main Authors: Depienne, Christel, Mandel, Jean-Louis
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.05.2021; Elsevier (Cell Press); Elsevier
• Subjects: Anticipation, Genetic; Biomedical Research - trends; Founder Effect; Genes, Dominant; Genes, Recessive; Genome, Human - genetics; Human health and pathology; Humans; Life Sciences; Review; Time Factors; Trinucleotide Repeat Expansion - genetics
• ISSN: 0002-9297; 1537-6605; 1537-6605
• DOI: 10.1016/j.ajhg.2021.03.011

Tandem repeats represent one of the most abundant class of variations in human genomes, which are polymorphic by nature and become highly unstable in a length-dependent manner. The expansion of repeat length across generations is a well-established process that results in human disorders mainly affecting the central nervous system. At least 50 disorders associated with expansion loci have been described to date, with half recognized only in the last ten years, as prior methodological difficulties limited their identification. These limitations still apply to the current widely used molecular diagnostic methods (exome or gene panels) and thus result in missed diagnosis detrimental to affected individuals and their families, especially for disorders that are very rare and/or clinically not recognizable. Most of these disorders have been identified through family-driven approaches and many others likely remain to be identified. The recent development of long-read technologies provides a unique opportunity to systematically investigate the contribution of tandem repeats and repeat expansions to the genetic architecture of human disorders. In this review, we summarize the current and most recent knowledge about the genetics of repeat expansion disorders and the diversity of their pathophysiological mechanisms and outline the perspectives of developing personalized treatments in the future. Tandem repeats represent one of the most abundant class of variations in human genomes, which are polymorphic by nature and become highly unstable in a length-dependent manner. The expansion of repeat length across generations is a well-established process that results in human disorders mainly affecting the central nervous system. At least 50 disorders associated with expansion loci have been described to date, with half recognized only in the last ten years, as prior methodological difficulties limited their identification. These limitations still apply to the current widely used molecular diagnostic methods (exome or gene panels) and thus result in missed diagnosis detrimental to affected individuals and their families, especially for disorders that are very rare and/or clinically not recognizable. Most of these disorders have been identified through family-driven approaches and many others likely remain to be identified. The recent development of long-read technologies provides a unique opportunity to systematically investigate the contribution of tandem repeats and repeat expansions to the genetic architecture of human disorders. In this review, we summarize the current and most recent knowledge about the genetics of repeat expansion disorders and the diversity of their pathophysiological mechanisms and outline the perspectives of developing personalized treatments in the future.