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

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.

Clinical and genetic characterization of a Taiwanese cohort with spastic paraparesis combined with cerebellar involvement

“…In addition, half of the cases with molecular diagnosis could be confirmed before implementation of WES. It has been demonstrated that by integrating mode of inheritance and pertinent clinical data, disease-related genetic testing followed by multigene panels may improve diagnostic yield for HSP and HCA (22). Furthermore, this and our study suggest that the integrated testing flowchart not only helps to guide a time and cost-efficient molecular testing in the new generation sequencing era, but also facilitates genotype-phenotype correlation in diagnosing the heterogeneous neurogenetic disorders.…”

NGS in Hereditary Ataxia: When Rare Becomes Frequent

“…However, the outcomes achieved combining in silico and 3D-modeling studies allowed us to speculate on the potential causative role of the other variants (i.e., those whose 3D protein structure was not available) Interestingly, the SCAR genes considered to be frequent in the pre-NGS era (e.g., ATM, SETX, and APTX) were less common than expected in our cohort, or even absent (i.e., SACS). This could be related to the prevalently retrospective nature of our study, in which patients with peculiar phenotypes, such as those resembling ataxia-telangectasia, ataxia with oculomotor apraxia, and autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), underwent direct Sanger sequencing prior to inclusion [105].…”

Next-Generation Sequencing Technologies and Neurogenetic Diseases

“…A retrospective study published in 2021 estimated the diagnostic yield in 124 SCA patients from 102 families in Italy, with a reported total diagnosis rate of 52%. AD-SCA patients had the highest diagnostic yield (64.5%) among the SCA cases, of which the most frequent subtype was SCA2, followed by SCA1, SCA3, SCA6, and SCA7 [53]. Furthermore, the genetic epidemiology of SCA, like that of any rare disease, is affected by founder effect.…”