Two compound heterozygous variants in the CLN8 gene are responsible for neuronal cereidolipofuscinoses disorder in a child: a case report

Abstract

Background: Neuronal Ceroid Lipofuscinosis (NCL) disorders, recognized as the primary cause of childhood dementia globally, constitute a spectrum of genetic abnormalities. CLN8, a subtype within NCL, is characterized by cognitive decline, motor impairment, and visual deterioration. This study focuses on an atypical case with congenital onset and a remarkably slow disease progression.

Methods: Whole-genome sequencing at 30× coverage was employed as part of a national genomics program to investigate the genetic underpinnings of rare diseases. This genomic approach aimed to challenge established classifications (vLINCL and EPMR) and explore the presence of a continuous phenotypic spectrum associated with CLN8.

Results: The whole-genome sequencing revealed two novel likely pathogenic mutations in the CLN8 gene on chromosome 8p23.3. These mutations were not previously associated with CLN8-related NCL. Contrary to established classifications (vLINCL and EPMR), our findings suggest a continuous phenotypic spectrum associated with CLN8. Pathological subcellular markers further validated the genomic insights.

Discussion: The identification of two previously undescribed likely pathogenic CLN8 gene mutations challenges traditional classifications and highlights a more nuanced phenotypic spectrum associated with CLN8. Our findings underscore the significance of genetic modifiers and interactions with unrelated genes in shaping variable phenotypic outcomes. The inclusion of pathological subcellular markers further strengthens the validity of our genomic insights. This research enhances our understanding of CLN8 disorders, emphasizing the need for comprehensive genomic analyses to elucidate the complexity of phenotypic presentations and guide tailored therapeutic strategies. The identification of new likely pathogenic mutations underscores the dynamic nature of CLN8-related NCL and the importance of individualized approaches to patient management.

Keywords: CLN8; ceroid lipofuscinosis; genomics; neurodegeneration; neurological disorders; whole genome sequencing.

Figure 1

Brain MRI. (A) Sagittal T1 sequences at two years old, and (B) nine years old. Progressive cerebellar and discrete cerebral atrophy are observed.

Figure 2

IGV view of the reads mapping onto the CLN8 gene (partial view). The two compound heterozygous variants are located (1728651 and 1728654). Blue and red bars mark the presence of a single nucleotide variant allele in the reads (light blue and red horizontal bars). Not all reads are shown (the coverage for the two variants is 35x). Reference genomic and protein sequences are shown below. The two variants are always in different reads, being aligned to different chromosomes (compound heterozygosity).

Figure 3

Electron microscopy. Abnormal intracellular deposits were observed in the skin's hypodermal fibroblast, consistent with the diagnosis of GRODs.