The History of Gene Hunting in Hereditary Spinocerebellar Degeneration: Lessons From the Past and Future Perspectives.

Ashraf Yahia,Giovanni Stevanin

doi:10.3389/fgene.2021.638730

Abstract

Hereditary spinocerebellar degeneration (SCD) encompasses an expanding list of rare diseases with a broad clinical and genetic heterogeneity, complicating their diagnosis and management in daily clinical practice. Correct diagnosis is a pillar for precision medicine, a branch of medicine that promises to flourish with the progressive improvements in studying the human genome. Discovering the genes causing novel Mendelian phenotypes contributes to precision medicine by diagnosing subsets of patients with previously undiagnosed conditions, guiding the management of these patients and their families, and enabling the discovery of more causes of Mendelian diseases. This new knowledge provides insight into the biological processes involved in health and disease, including the more common complex disorders. This review discusses the evolution of the clinical and genetic approaches used to diagnose hereditary SCD and the potential of new tools for future discoveries.

Highlights

Hereditary forms of spastic paraplegia (SPG), cerebellar ataxia (CA), spastic ataxia, and spinocerebellar ataxia (SCA) are distinct clinical entities caused by related mechanisms and encompassing a continuum of phenotypes known as hereditary spinocerebellar degenerations (SCDs; Parodi et al, 2018)
Among the 56% (123/220) of known SCD subtypes identified by approaches that involved linkage analysis, a good example of its diagnostic utility is the study by Novarino et al (2014) that reported 15 novel causative genes in consanguineous families with various forms of SPG; they used single nucleotide polymorphism (SNP) markerbased homozygosity to filter and prioritize the exome data
whole-exome sequencing (WES) is dominating SCD gene discovery and we can expect that whole-genome sequencing (WGS) will dominate the discovery of the genes causing Mendelian diseases in the future, probably within integrated multi-omics strategies to reduce the number of candidate variants (Posey, 2019; Kerr et al, 2020)

Summary

INTRODUCTION

Hereditary forms of spastic paraplegia (SPG), cerebellar ataxia (CA), spastic ataxia, and spinocerebellar ataxia (SCA) are distinct clinical entities caused by related mechanisms and encompassing a continuum of phenotypes known as hereditary spinocerebellar degenerations (SCDs; Parodi et al, 2018). Homozygosity mapping in consanguineous cases, were the primary approaches for identifying genes and loci associated with Mendelian diseases (Lipner and Greenberg, 2018) These methods were developed in the 1980s thanks to improvements in detection of genetic markers and their assignment in chromosomal maps. Among the 56% (123/220) of known SCD subtypes identified by approaches that involved linkage analysis, a good example of its diagnostic utility is the study by Novarino et al (2014) that reported 15 novel causative genes in consanguineous families with various forms of SPG; they used SNP markerbased homozygosity to filter and prioritize the exome data. Longread WGS is probably a promising new tool for diagnosing genetic diseases for the near future with great hope on detection of nucleotide repeats as well (Posey, 2019; Wenger et al, 2019)

Findings

DISCUSSION AND FUTURE

CONCLUSION