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A Novel Deletion Variant in Cln3 With Highly Variable Expressivity Is Responsible for Juvenile Neuronal Ceroid Lipofuscinoses Publisher Pubmed



Gilani N1, 2 ; Razmara E3 ; Ozaslan M1 ; Abdulzahra IK4 ; Arzhang S5 ; Tavasoli AR6 ; Garshasbi M3
Authors
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Authors Affiliations
  1. 1. Department of Biology, Gaziantep University, Gaziantep, Turkey
  2. 2. Farabi Molecular Laboratory, Irbil, Iraq
  3. 3. Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
  4. 4. Kurdistan College of Medicine, Irbil, Iraq
  5. 5. School of Medicine, Shahrekord University of Medical Science, Shahrekord, Iran
  6. 6. Myelin Disorders Clinic, Pediatric Neurology Division, Children′s Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran

Source: Acta Neurologica Belgica Published:2021


Abstract

Mutations in CLN3 (OMIM: 607042) are associated with juvenile neuronal ceroid lipofuscinoses (JNCL)—a rare neurodegenerative disease with early retinal degeneration and progressive neurologic deterioration. The study aimed to determine the underlying genetic factors justifying the NCL phenotype in a large Iraqi consanguineous family. Four affected individuals with an initial diagnosis of NCL were recruited. By doing neuroimaging and also pertinent clinical examinations, e.g. fundus examination, due to heterogeneity of neurodevelopmental disorders, the proband was subjected to the paired-end whole-exome sequencing to identify underlying genetic factors. The candidate variant was also confirmed by Sanger sequencing. Various in silico predictions were used to show the pathogenicity of the variant. This study revealed a novel homozygous frameshift variant—NM_000086.2: c.1127del; p.(Leu376Argfs*15)—in the exon 14 of the CLN3 gene as the most likely disease-causing variant. Three out of 4 patients showed bilateral vision loss (< 7 years) and retinal degeneration with macular changes in both eyes. Electroencephalography demonstrated the loss of normal posterior alpha rhythm and also low amplitude multifocal slow waves. Brain magnetic resonance imaging of the patients with a high degree of deterioration showed mild cerebral and cerebellar cortical atrophy, mild ventriculomegaly, thinning of the corpus callosum and vermis, and non-specific periventricular white matter signal changes in the occipital area. The novel biallelic deletion variant of CLN3 was identified that most probably led to JNCL with variable expressivity of the phenotype. This study also expanded our understanding of the clinical and genetic spectrum of JNCL. © 2021, Belgian Neurological Society.
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