Application of a Clinical Workflow May Lead to Increased Diagnostic Precision in Hereditary Spastic Paraplegias and Cerebellar Ataxias: A Single Center Experience

Vittorio Riso,Gabriella Silvestri,Filippo Santorelli,Ginevra Zanni,Maria Pomponi,Alessia Perna,Lorena Travaglini,Tommaso Nicoletti,Melissa Barghigiani,Salvatore Rossi,Alessandra Tessa,Chiara Aiello

doi:10.3390/brainsci11020246

Abstract

The molecular characterization of Hereditary Spastic Paraplegias (HSP) and inherited cerebellar ataxias (CA) is challenged by their clinical and molecular heterogeneity. The recent application of Next Generation Sequencing (NGS) technologies is increasing the diagnostic rate, which can be influenced by patients’ selection. To assess if a clinical diagnosis of CA/HSP received in a third-level reference center might impact the molecular diagnostic yield, we retrospectively evaluated the molecular diagnostic rate reached in our center on 192 unrelated families (90 HSP and 102 CA) (i) before NGS and (ii) with the use of NGS gene panels. Overall, 46.3% of families received a genetic diagnosis by first-tier individual gene screening: 43.3% HSP and 50% spinocerebellar ataxias (SCA). The diagnostic rate was 56.7% in AD-HSP, 55.5% in AR-HSP, and 21.2% in sporadic HSP. On the other hand, 75% AD-, 52% AR- and 33% sporadic CA were diagnosed. So far, 32 patients (24 CA and 8 HSP) were further assessed by NGS gene panels, and 34.4% were diagnosed, including 29.2% CA and 50% HSP patients. Eleven novel gene variants classified as (likely) pathogenic were identified. Our results support the role of experienced clinicians in the diagnostic assessment and the clinical research of CA and HSP even in the next generation era.

Highlights

IntroductionUntil a few years ago, the diagnostic route of Hereditary Spastic Paraplegias (HSPs) and cerebellar ataxias (CA) was time-consuming, cost expensive and challenging in many cases because of their clinical and genetical heterogeneity
39/90 (43.3%) Hereditary Spastic Paraplegias (HSP) probands were genetically characterized (Table 1 and Figure 3); the diagnostic rate was 56.7% in autosomal dominant (AD)-HSP (17/30 families), and SPG4 was the most frequent form (16/17), with a novel SPG10 pathogenic variant found in one family [34]
Regarding Autosomal recessive (AR)-HSP, a genetic diagnosis was made in 15/27 families (55.5%): in the SPG11

Summary

Introduction

Until a few years ago, the diagnostic route of Hereditary Spastic Paraplegias (HSPs) and cerebellar ataxias (CA) was time-consuming, cost expensive and challenging in many cases because of their clinical and genetical heterogeneity. At least 64 genes (the SPastic Gait/Gene or SPG genes) have been characterized, and further HSP loci have been mapped [1,2,3,4,5,6,7]. Most autosomal dominant (AD)-HSPs are pure, and SPG4, due to mutations in SPAST, is the most common genetic variant [1,2,3]. Autosomal recessive (AR)-HSPs are mostly complicated and more heterogeneous than Mutations in ATL1 (SPG3A), REEP1 (SPG31), and KIF5A (SPG10) are relatively frequent; when combined with SPG4, these forms account for about 50–60% of AD-HSP families [8,9,10].

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