Identification of a Novel Indel Variant in the DARS2 Gene in Russian Patients with Leukoencephalopathy with Brainstem and Spinal Cord Involvement and Lactate Elevation.

Autor:	Bostanova FM; Research Centre for Medical Genetics, 1 Moskvorechye St., 115522 Moscow, Russia., Tsygankova PG; Research Centre for Medical Genetics, 1 Moskvorechye St., 115522 Moscow, Russia., Larshina EA; Research Centre for Medical Genetics, 1 Moskvorechye St., 115522 Moscow, Russia., Nagornov IO; Research Centre for Medical Genetics, 1 Moskvorechye St., 115522 Moscow, Russia., Evseeva YV; Ekaterinburg Research Institute of Viral Infections, 620030 Yekaterinburg, Russia., Krutikhina IL; Kirov Regional Children's Clinical Hospital, 610050 Kirov, Russia., Dzhentemirova ME; State Budgetary Healthcare Institution 'Magadan Region Center for Maternal and Child Health', 685000 Magadan, Russia., Kashlakova MN; St. Petersburg State Budgetary Institution, City Polyclinic, No. 114, 197374 St. Petersburg, Russia., Petukhova MS; Research Centre for Medical Genetics, 1 Moskvorechye St., 115522 Moscow, Russia., Sharkova IV; Research Centre for Medical Genetics, 1 Moskvorechye St., 115522 Moscow, Russia., Zakharova EY; Research Centre for Medical Genetics, 1 Moskvorechye St., 115522 Moscow, Russia.
Jazyk:	angličtina
Zdroj:	Genes [Genes (Basel)] 2024 May 11; Vol. 15 (5). Date of Electronic Publication: 2024 May 11.
DOI:	10.3390/genes15050615
Abstrakt:	Background: Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation is an inherited disease caused by pathogenic biallelic variants in the gene DARS2 , which encodes mitochondrial aspartyl-tRNA synthetase. This disease is characterized by slowly progressive spastic gait, cerebellar symptoms, and leukoencephalopathy with brainstem and spinal cord involvement. Case Presentation: Peripheral blood samples were collected from four patients from four unrelated families to extract genomic DNA. All patients underwent partial exon analysis of the DARS2 gene using Sanger sequencing, which detected the c.228-21_228-20delinsC variant in a heterozygous state. Further DNA from three patients was analyzed using a next-generation sequencing-based custom AmpliSeq™ panel for 59 genes associated with leukodystrophies, and one of the patients underwent whole genome sequencing. We identified a novel pathogenic variant c.1675-1256_*115delinsGCAACATTTCGGCAACATTCCAACC in the DARS2 gene. Three patients (patients 1, 2, and 4) had slowly progressive cerebellar ataxia, and two patients (patients 1 and 2) had spasticity. In addition, two patients (patients 2 and 4) showed signs of axonal neuropathy, such as decreased tendon reflexes and loss of distal sensitivity. Three patients (patients 1, 2, and 3) also had learning difficulties. It should be noted the persistent presence of characteristic changes in brain MRI in all patients, which emphasizes its importance as the main diagnostic tool for suspicion and subsequent confirmation of LBSL. Conclusions : We found a novel indel variant in the DARS2 gene in four patients with LBSL and described their clinical and genetic characteristics. These results expand the mutational spectrum of LBSL and aim to improve the laboratory diagnosis of this form of leukodystrophy.
Databáze:	MEDLINE
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