Новая гомозиготная мутация в гене ARL6IP1 - второй случай редкой спастической параплегии

Background. Hereditary spastic paraplegias (HSPs) are a large group of neurodegenerative disorders characterized by progressive lower limbs spasticity and weakness caused by a retrograde axonal degeneration of the corticospinal tracts. The considerable and constantly increasing number of HSP-associated genes (more than 80 different loci with 60 corresponding spastic paraplegia genes) complicates the diagnosis in every particular case, especially with a single reported occurrence like the autosomal recessive spastic paraplegia 61 (SPG61, OMIM: 615685). However, new sequencing methods allow to accelerate the process and find the molecular cause of the disease much more reliably, especially in families with rare HSPs. Aims. To describe a rare complicated early-onset HSP (SPG61) in a Dargin consanguineous family and find out its molecular genetical cause. Materials and methods: personal and family history analysis, neurological examination, electroencephalography, brain MRI, blood DNA extraction, whole exome sequencing (WES), WES data analysis, Sanger sequencing. Results. During a session of whole-exome sequencing and analysis, a new homozygous variant c.[92T>C];[92T>C] (p.[(Leu31Pro)];[(Leu31Pro)], NM_015161.1) has been discovered in exon 2 of the ARL6IP1 gene, which makes it the second variant found in this gene worldwide and the first one in Russia. Sanger sequencing of the patients’ and parents’ DNA confirmed the p.(Leu31Pro) variant status (homozygous in both patients and heterozygous in both parents) and its segregation with the disease status. Here we describe the clinical findings of the disease in this family and a clinical data comparison for two families with variants in the ARL6IP1 gene (described previously and studied in our laboratory). Conclusions. Our research broadens the diversity of symptoms associated with ARL6IP1 gene mutations. The discovered variant expands the causative mutation spectrum of complicated early-onset HSPs.