Phenotypic variability observed in a Chinese patient cohort with biallelic variants in the genes.

PURPOSE

The neuronal ceroid lipofuscinoses (NCLs) comprise a group of inherited neurodegenerative disorders with thirteen NCL-disease causing genes ceroid lipofuscinosis neuronal ( identified. The purpose of this study was to describe the genetic and clinical characteristics of a cohort of Chinese patients harboring biallelic variants in the genes.

METHODS

We recruited 14 patients from 13 unrelated families who carried biallelic variants in the genes. All patients underwent ophthalmic and systematic evaluations, as well as comprehensive molecular genetic analyses. Reverse transcription polymerase chain reaction (RT-PCR) assays were performed to observe the effect of a novel non-canonical splice-site (NCSS) variant on pre-mRNA splicing. Eventually, eight patients were followed up.

RESULTS

We detected 21 variants in three genes (, , and ); 13 variants were novel. RT-PCR assays indicated that the NCSS variant c.963-13A>G changed the pre-mRNA splicing, thereby creating an in-frame indel variant p.(W321delinsCPNLR) in . Diagnoses of neuronal ceroid lipofuscinosis (NCL) and non-syndromic retinal dystrophy (RD) were established in eight patients and six patients, respectively. The patients with NCL showed clinical heterogeneity, from typical phenotypes of CLN3 or CLN7 disease to juvenile- or adult-onset CLN1 disease. All patients experienced early and severe visual loss. A retinal evaluation revealed specific macular striation in 12 of the 14 patients.

CONCLUSIONS

Patients with variants in the three genes exhibit varied clinical spectra, which might be related to their genotype. All patients presented relatively unique retinal alterations. Our findings point to a crucial need for genetic analysis for the early and accurate diagnosis of patients with NCL.