Genetic Test Can Provide Definitive Diagnosis of Batten Disease, Canadian Study Suggests

Sanger sequencing — a conventional genetic test useful to identify mutations in disease-associated genes — can effectively help to provide a definitive diagnosis of Batten disease, according to a Canadian study.

The research also highlighted that the presence of cognitive decline, loss of previously acquired skills, progressive visual problems, and brain atrophy are significant symptoms of Batten disease and should drive clinicians to confirm a diagnosis through Sanger sequencing.

The study, “High diagnostic yield of direct Sanger sequencing in the diagnosis of neuronal ceroid lipofuscinoses,” was published in the journal JIMD Reports.

Batten disease, also known as neuronal ceroid lipofuscinosis (NCL), is the most common group of pediatric neurodegenerative disorders, characterized by progressive intellectual and motor deterioration, seizures, and vision loss.

To date, 13 different types of Batten disease — caused by mutations in at least 13 different genes — have been identified. The most common forms of Batten disease are CLN3 disease, a juvenile form of the disease, and CLN2 disease, a late infantile form.

While most mutations in these genes are associated with a particular disease type, some result in variable symptoms, disease onset, severity, and progression. Thus, genetic testing is the most reliable way to determine exactly which type a person has.

Conventional Sanger sequencing is used to detect mutations in genes associated with diseases, but its role in diagnosing Batten disease has not been studied to date.

Therefore, researchers at the Genome Diagnostics Laboratory at the Hospital for Sick Children (SickKids), in Canada, set out to determine whether Sanger sequencing could provide a definitive diagnosis of Batten disease in patients suspected of having the disease.

The Genome Diagnostics Laboratory, formerly known as the Molecular Genetics Laboratory, is one of the reference laboratories in Canada that provides Sanger sequencing for eight of the 13 genes associated with Batten disease.

The researchers retrospectively reviewed the electronic data of the laboratory’s database for results of genetic tests related to Batten disease-associated genes.

A total of 693 people underwent Sanger sequencing of Batten-associated genes between April 2004 and April 2018, including 343 people with symptoms suggestive of the disease to confirm a clinical diagnosis, seven fetuses for prenatal diagnosis, and 343 family members to test if they carried any of those mutations.

Sanger sequencing confirmed the diagnosis of Batten disease in 91 (27%) of the 343 people with suggestive symptoms, which corresponded to 22% of all families with symptomatic children. These diagnosed patients had a total of 52 different mutations in seven Batten-associated genes, including 11 new mutations.

The most common type of Batten disease was CLN2 disease (33 patients), followed by CLN3 disease (17 patients); CLN1 (infantile Batten disease), CLN6, and CLN7 diseases (each with 10 patients); CLN5 disease (seven patients); and CLN8 disease (four patients).

Clinical data was available for 33 patients diagnosed with Batten disease and for 76 people with suggestive symptoms but who did not have the disease. By comparing the data of these two groups of patients, the researchers found that the presence of cognitive decline, loss of previously acquired skills, progressive visual problems, and brain atrophy were highly suggestive of Batten disease.

These symptoms “should warrant physicians to investigate NCL using direct Sanger sequencing of the [Batten-associated genes],” the researchers wrote.

They also noted that the combination of normal features in eye or skin biopsies with the absence of mutations in Batten-associated genes are sufficient to exclude a diagnosis of Batten disease.

Notably, some non-classical features among diagnosed patients included a juvenile (instead of infantile) onset in 71% of patients with CLN1 disease, and an adult (instead of a childhood) onset in 75% of those with CLN6 disease.

These findings suggest that Batten disease should be considered in some cases with non-typical symptoms, the researchers said, and that advanced genetic tests may help identify more patients with non-classical Batten disease, including tests that can identify mutations in multiple genes simultaneously (next generation sequencing) or analyses of a person’s whole set of genes (whole exome sequencing).