Abstract
Purpose :
To determine the causative variants in CLN3 gene in juvenile neuron ceroid lipofuscinosis (JNCL) complicated with heart malfunction and isolated cone-rod dystrophy (CORD) respectively and to analysis the correlation between the phenotypes and the pathogenic variants.
Methods :
Visual acuity (BCVA), fundus photography, optical coherence tomography (SS-OCT), visual field, and electroretinogram (ERG) were performed in three affected individuals from two families diagnosed with JNCL and isolated CORD respectively. Peripheral blood was collected from three patients and six family members. Total genomic DNA was extracted and whole exome sequencing was performed on the probands. Bioinformatics analysis, Sanger sequencing and co-separation verification were performed. The pathogenicity of the variants was carried out according to the ACMG guidelines. 3-D protein structure was predicted.
Results :
All patients showed vision loss in both eyes. OCT revealed thinning, atrophic, and disorganized macular in all patients. Patients in the family F1 also showed epilepsy and abnormal cardiac function, while the patient in family F2 presented only retinal malfunction. We detected two compound heterozygous variants of the CLN3 gene in the two families, including a missense variant c.982G>C (p.Ala328Pro), a splicing variant c.963-13A>G and two nonsense variant c.104G>A (p.Trp35X) and c.263C>G (p.Ser88X). c.963-13A>G, c.104G>A (p.Trp35X) and c.263C>G (p.Ser88X) were novel variants. In addition, we detected a novel nonsense variant c.2526C>G (p.Tyr842X) in MYBPC3 in family F1. Sanger sequencing and co-segregation analysis showed that the five variants co-segregated with phenotype in the two families. Conservation analysis showed that three CLN3 protein residues (Trp35, Ser88, Ala328) were highly conserved in different species. According to ACMG guidelines, four of the variants were likely pathogenic (c.104G>A, c.263C>G and c.982G>C in CLN3, c.2526C>G in MYBPC3), and one was uncertain significance variant (c.963-13A>G in CLN3). Protein structure was modified by the variants.
Conclusions :
Four compound heterozygous variants in CLN3 and a heterozygous MYBPC3 variant were identified in a JNCL with heart malfunction.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.