Chinese researchers used an advanced genetic sequencing technique to identify two new pathogenic variants of the CLN8 gene in a boy with suspected neuronal ceroid lipofuscinosis (NCL), or Batten disease.
Molecular diagnosis was delivered within three weeks, demonstrating the advantages of using genome sequencing for providing fast and accurate diagnosis, particularly suitable for pediatric disorders that are very heterogeneous such as NCLs.
The study, Identification of two novel null variants in CLN8by targeted next-generation sequencing: first report of a Chinese patient with neuronal ceroid lipofuscinosis due to CLN8 variants, was published in the journal BMC Medical Genetics.
NCLs are a group of heterogeneous disorders, with variable disease manifestations and onset of symptoms. Extensive genetic heterogeneity associated with NCL indicates that precise diagnosis of NCLs may rely mainly on molecular genetic testing.
More than 430 variations have been identified in the 13 candidate genes known to underlie NCLs, most of which have been registered in the NCL Mutation Database.
Reported variants are almost exclusively from Western patients, and very little is known about the clinical and genetic characteristics of subjects from other nationalities, including Chinese patients.
So far, 74 NCL patients have been attributed to the pathogenic variants in the CLN8 gene, and most patients are from Finland and Turkey.
The team identified two novel pathogenic variants in the CLN8 gene using targeted next-generation sequencing in an 8-year-old Chinese boy. The boy had clinical symptoms suspected of NCL, including intractable epilepsy, cognitive and motor decline, and progressive vision loss.
This was the first case report of NCL in Chine due to CLN8 variants. By using genome sequencing, researchers were able to provide an accurate and rapid diagnosis, completed within three weeks.
“Our findings expand the variant diversity of CLN8 and demonstrate the tremendous diagnosis value of targeted next-generation sequencing for pediatric NCLs,” researchers wrote.
Both CLN8 variants were interpreted as “pathogenic” according to the guidelines of the American College of Medical Genetics and Genomics (ACMG) and were null variants, meaning they were likely to produce nonfunctional and incomplete CLN8 proteins.
CLN8 variants are associated with two types of disease manifestations, one less-severe and the other more-severe. The first, also called epilepsy with mental retardation (EPMR) or Northern epilepsy, is characterized by normal development in early childhood, with onset of seizures between 5 and 10 years of age. The more severe trait, called late-infantile NCL (LI-NCL), has an earlier onset and more rapid progression.
By combining clinical information with genetic testing, the patient was accurately diagnosed as having a variant of LI-NCL.
The patient developed the first epilepsy attacks at the age of 4, and his cognitive function and vision progressively deteriorated thereafter.
Reviewing the NCL Mutation Database and the literature on patients with CLN8 variants, researchers found a correlation between the type of CLN8 variant and disease severity.
Patients carrying null variants and nonfunctional genes generally had earlier onset and more progressive disease than those with variants that reduced the expression or function of the gene.
The study underscores the value of genetic sequencing to diagnose the cause of intellectual disability in children, which can be due to complex and heterogeneous diseases, including NCLs.
“NCLs remain a challenge for neurologists, especially for the pediatric neurologist, because the clinical signs in young children or toddlers are subtle and often overlap with other congenital neurodegenerative diseases, such as mitochondrial disorders or early-onset Parkinsonism,” researchers wrote.
“Our report demonstrates the absolute diagnosis advantage of high-throughput genomic sequencing for pediatric neurodegenerative disease with high phenotypic and genetic heterogeneity, making patients move to the precise genotyping.” researchers concluded.