Diagnostic Yield and Genotype-Phenotype Correlations of Clinical Exome Sequencing in Hereditary Spastic Paraparesis:...

Hereditary spastic paraparesis (HSP) encompasses a genetically and clinically heterogeneous group of neurodegenerative disorders, primarily characterized by progressive lower limb spasticity and weakness of the lower limbs. Although more than 80 genes have been associated with HSP, achieving definite genetic diagnosis remains challenging, limiting effective patient care, genetic counseling, and understanding of genotype-phenotype correlations. This study aimed to investigate the diagnostic yield of clinical exome sequencing (CES) in a cohort of Spanish individuals with suspected HSP and to explore genotype-phenotype correlations.

A total of 139 non-related Spanish individuals with HSP underwent standardized clinical evaluation and CES. Genetic analyses were performed using a virtual panel containing 129 HSP-associated genes, complemented by phenotype-driven filtering through the Human Phenotype Ontology. Statistical analyses were performed on core clinical and paraclinical features.

After clinical review, 108 index cases were included. Male patients were slightly more represented and mean age at onset was 33 years. Pure HSP forms were more prevalent. The most frequent presenting symptoms were gait disturbance and recurrent falls. A genetic diagnosis was achieved in 57 patients (52,8%), with SPAST and SPG7 being the most frequently mutated genes. In total, pathogenic/likely pathogenic variants were identified across 21 genes, including 8 novel variants. HSP with autosomal recessive inheritance was more common than autosomal dominant (29 vs. 25 cases), while dominant/recessive X-linked disease forms were rare (3 cases).

CES combined with HPO-based filtering is an effective strategy for achieving genetic diagnosis in patients with suspicion of HSP.