Spectrinopathies in rare neurological and neuromuscular diseases : large-scale efforts towards the identification of novel molecular causes

Field: Biochemistry, Genetics and Molecular Biology (Life Sciences)

Rare inherited neurological and neuromuscular diseases affect the central nervous system, peripheral nervous system, and skeletal muscles.About 80% of rare diseases are estimated to have an underlying genetic etiology, yet only approximately 50% of patients receive a genetic diagnosis, which is often described as the diagnostic gap.Determining the genetic cause of patients' disease ends their often years-long diagnostic odyssey, has important consequences regarding the genetic counselling to be offered to patients, enables the availability of pre-implantation diagnostic testing, and increasingly so, determines access to clinical trials and gene-specific therapies.From a research point of view, closing the diagnostic gap has great impact on the discovery of critical neuronal and neuromuscular pathways, oftentimes leading to overarching pathomechanisms between inherited and acquired neuropathies and resulting in shared therapy development.The overall aim of this PhD thesis is to gain novel insights into the genetic architecture of rare inherited neurological and neuromuscular diseases, including spinocerebellar ataxia (SCA), hereditary spastic paraplegia (HSP), inherited peripheral neuropathies and inherited myopathies.The overall objective can be divided into two main parts: [1] the application of large-scale variant identification, using both 'classical' single-nucleotide variant identification and a novel bio-informatic approach to identify copy number variation in whole exome sequencing and [2] the characterization of the phenotypical spectrum associated with mutations in the SPTAN1 gene, identified using the approaches of [1].SPTAN1 mutations display an intriguingly wide phenotypical spectrum.Prior to this thesis, SPTAN1-associated diseases included epileptic syndromes, intellectual disability, and hereditary motor neuropathy.Chapter 2 describes the identification of de novo and dominantly inherited SPTAN1 variants as a cause of HSP and SCA, thereby widening the central nervous system phenotypes associated with SPTAN1 variants.This study relied on the screening of more than 10,000 NGS datasets with a relevant phenotype, indicative of the efforts currently needed to find genetic causes for rare diseases.Chapter 3 describes a large-scale approach to identify Copy Number Variants (CNVs) in repurposed Whole Exome Sequencing (WES).This analysis was performed within the setting of the Solve-RD consortium, enabling participation of 42 research groups across Europe studying rare inherited diseases.Three different CNV calling algorithms are compared in the study, which was limited to a pre-defined set of diseaseassociated genes to reduce the variant interpretation burden on submitting centers.Chapter 4 presents a deeper dive into one of the families identified using the techniques described in Chapter 3, where we show that a 9q34 deletion including the full SPTAN1 gene is causative of a myopathy phenotype.This identification not only provided a genetic diagnosis to a long-standing unsolved family, but also further defines the SPTAN1 associated phenotypical spectrum to include myopathy.A general discussion of this thesis is presented in Chapter 5, with a focus on the commonalities in pathomechanisms underlying rare inherited neurological and neuromuscular diseases, the large-scale data sharing necessary to identify novel causes for rare inherited diseases and current challenges that remain to implement novel upcoming technologies like long read and short read whole genome sequencing.Een discussie van dit proefschrift wordt gepresenteerd in Hoofdstuk 5, met de nadruk op de overeenkomsten in de pathomechanismen die ten grondslag liggen aan zeldzame erfelijke neurologische en neuromusculaire ziekten, het op grote schaal delen van gegevens die nodig zijn om nieuwe oorzaken voor zeldzame erfelijke ziekten te identificeren en de huidige uitdagingen die nog resteren vooraleer nieuwe technologieën zoals short read en long read whole genome sequencing klaar zijn voor implementatie.