Expanding the clinical phenotype of DYNC1H1 -associated mutations: a Chinese family with autosomal dominant complex hereditary spastic paraplegia

Hereditary spastic paraplegias (HSPs) are a clinically and genetically heterogeneous group of neurodegenerative diseases. To date, at least 84 distinct loci (SPGs) and 67 causative genes have been identified. Even though the number of known causative genes is constantly increasing, a substantial portion of patients remains without a molecular diagnosis. Variants in the dynein, cytoplasmic 1, heavy chain 1(DYNC1H1)gene have been reported to cause a range of neurogenetic diseases, including spinal muscular atrophy (SMA), Charcot-Marie-Tooth disease (CMT), and cortical malformations. This study aims to characterize the clinical spectrum of DYNC1H1-related disorders by reporting a rare missense variant (c.13763 C > T, p.Thr4588Met) identified in a Chinese family with autosomal dominant (AD) complex HSP. The affected individuals underwent a comprehensive neurological evaluation, including assessment of clinical features, laboratory testing, brain magnetic resonance imaging (MRI), and electrophysiological studies. The repetition/deletions in the SPAST, ATL1 gene were detected using multiplex ligation-dependent probe analysis (MLPA). Whole-exome sequencing (WES) was performed to identify the disease-causing mutation in the proband, which was subsequently validated by Sanger sequencing in the proband and his parents. In silico analysis was performed to predict the pathogenicity of the identified mutations. A heterozygous missense variant (c.13763 C > T, p.Thr4588Met) in the DYNC1H1 gene was identified, which was classified as likely pathogenic according to ACMG guidelines. The family was affected by autosomal dominant complex HSP, presenting with marked spastic paraplegia and ataxia. In silico analyses (e.g., using PolyPhen-2, PROVEAN, Mutation Taster, and CADD) indicated a deleterious effect on protein function. This study reports a rare DYNC1H1 variant associated with autosomal dominant (AD) complex HSP, expanding the mutational and phenotypic spectrum of DYNC1H1-related disorders.