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Case Reports
. 2020 Jul;8(7):e1228.
doi: 10.1002/mgg3.1228. Epub 2020 May 15.

Neuronal ceroid lipofuscinosis in the Russian population: Two novel mutations and the prevalence of heterozygous carriers

Anastasiya A Kozina  1   2 , Elena G Okuneva  3 , Natalia V Baryshnikova  2   3 , Olga B Kondakova  4 , Ekaterina A Nikolaeva  5 , Inessa D Fedoniuk  6 , Svetlana V Mikhailova  6 , Anna Y Krasnenko  3 , Ivan F Stetsenko  3 , Nikolay A Plotnikov  3 , Olesia I Klimchuk  3 , Yaroslav V Popov  3 , Ekaterina I Surkova  3 , Peter A Shatalov  3   5 , Alexander S Rakitko  3   7 , Valery V Ilinsky  1   2   3   8
Affiliations
Case Reports

Neuronal ceroid lipofuscinosis in the Russian population: Two novel mutations and the prevalence of heterozygous carriers

Anastasiya A Kozina et al. Mol Genet Genomic Med. 2020 Jul.

Abstract

Background: Neuronal ceroid lipofuscinoses (NCLs) are a group of neurodegenerative disorders characterized by an accumulation of lipofuscin in the body's tissues. NCLs are associated with variable age of onset and progressive symptoms including seizures, psychomotor decline, and loss of vision.

Methods: We describe the clinical and molecular characteristics of four Russian patients with NCL (one female and three males, with ages ranging from 4 to 5 years). The clinical features of these patients include cognitive and motor deterioration, seizures, stereotypies, and magnetic resonance imaging signs of brain atrophy. Exome sequencing was performed to identify the genetic variants of patients with NCL. Additionally, we tested 6,396 healthy Russians for NCL alleles.

Results: We identified five distinct mutations in four NCL-associated genes of which two mutations are novel. These include a novel homozygous frameshift mutation in the CLN6 gene, a compound heterozygous missense mutation in the KCTD7 gene, and previously known mutations in KCTD7, TPP1, and MFSD8 genes. Furthermore, we estimated the Russian population carrier frequency of pathogenic and likely pathogenic variants in 13 genes associated with different types of NCL.

Conclusion: Our study expands the spectrum of mutations in lipofuscinosis. This is the first study to describe the molecular basis of NCLs in Russia and has profound and numerous clinical implications for diagnosis, genetic counseling, genotype-phenotype correlations, and prognosis.

Keywords: NCL; exome sequencing; heterozygous carrier; neuronal ceroid lipofuscinosis.

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Conflict of interest statement

AAK, EGO, NVB, AYK, IFS, NAP, OIK, YVP, EIS, PAS, ASR, and VVI are employees of Genotek Ltd. The authors declare that they have no other competing interests.

Figures

FIGURE 1
FIGURE 1
Chromatograms of novel mutations identified in the study. (a) Patient 2 was homozygous for CLN6 (NM_017882.2) mutation c.396dupT (p.Val133fs). (b) Patient 4 was compound heterozygous for KCTD7 (NM_153033.4) mutations c.190A>G (p.Thr64Ala) and c.337T>C (p.Ser113Pro). The first mutation was previously reported, the second mutation is novel. R and Y are IUPAC ambiguity codes that mean A+G and C+T, respectively
FIGURE 2
FIGURE 2
The number of heterozygous carriers with variants in NCL‐associated genes in the Russian population. The analysis presents variants for which the allele frequency is <1%. The pathogenicity status of the mutation was assessed according to the ACMG criteria and ClinVar database. ACMG, American College of Medical Genetics and Genomics; NCL, neuronal ceroid lipofuscinosis
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