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Sequencing Offers Diagnosis in Nearly 60 Percent of Infantile-Onset Nystagmus Cases

NEW YORK (GenomeWeb) – Next-generation sequencing was able to offer a diagnosis for nearly 60 percent of infantile nystagmus syndrome patients in a new study.

Nystagmus — in which the eyes make uncontrolled, repetitive movements — can be a sign of a number of different diseases, including Leber congenital amaurosis. But ophthalmic exams can be inconclusive or difficult to perform in young patients.

A team of researchers in South Korea assessed whether sequencing could help diagnose patients with infantile-onset nystagmus. As they reported in JAMA Ophthalmology today, Yonsei University's Jinu Han and his colleagues found that sequencing could home in on a molecular diagnosis for more than half the patients in their cohort. Further, sequencing led to a change in diagnosis for 10 patients.

"This study demonstrated that NGS has a potential role in early diagnosis of both familial and sporadic cases involving [infantile nystagmus syndrome]," Han and his colleagues wrote.

The researchers enrolled 48 patients of Korean ancestry with infantile nystagmus syndrome who presented consecutively to their clinic. Eight of the patients had a family history of nystagmus. All the patients underwent ophthalmic examinations, including electroretinography and optical coherence tomography, if possible, and had blood drawn for genetic analysis.

Most of the patients underwent genetic testing using a customized NGS panel that included 113 genes linked to infantile nystagmus syndrome in the literature and genetic databases such as OMIM. One patient underwent testing using the TruSight One sequencing panel. Sequencing was performed on the Illumina MiSeq sequencer and the researchers generated more than 8.4 million reads per sample, on average.

Han and his colleagues filtered the variants and used the guidelines set forth by the American College of Genetics and Genomics to classify them. The most commonly mutated genes were GUCY2D, PAX6, and GPR143.

The researchers uncovered pathogenic or likely pathogenic alleles in 36 of the patients in their study. All in all, a probable molecular diagnosis was made for 28 of the 48 patients, giving a molecular diagnostic rate of 58.3 percent. A possible molecular diagnosis was made in a further eight patients. Twelve cases were not resolved by sequencing.

For the 48 patients in the study, 15 had initially been presumed to have idiopathic infantile nystagmus, while 23 were thought at first to have Leber congenital amaurosis. Four of the others were diagnosed clinically with ocular albinism, three with a PAX6-related phenotype, and three with achromatopsia.

The sequencing results, however, changed the diagnoses of 10 patients. Of the 23 patients initially diagnosed with Leber congenital amaurosis, 16 kept that diagnosis after sequencing. Of the seven patients whose diagnosis changed, one was diagnosed with likely achromatopsia, one with Senior-Loken syndrome, and one with possible infantile cerebellar-retinal degeneration. Four patients' diagnoses were unresolved.

At the same time, three patients with initial idiopathic infantile nystagmus diagnoses received new diagnoses of Leber congenital amaurosis, the researchers reported.

"Therefore, early NGS testing will aid in differentiating LCA from other non-progressive diseases with nystagmus such as achromatopsia," the researchers wrote.

In a related commentary, Harvard Medical School's Janey Wiggs also noted that Han and his colleagues identified 11 patients who harbored mutations in genes for which gene therapies are currently under development. Those genes include GUCY2D, RPGRIP1, CEP290, and CNGB3. She added that the researchers also reported finding a homozygous WDR19 mutation in one patient that not only causes retinal dystrophy, but also renal disease.

"Collectively, these results suggest that the genetic testing of infants with nystagmus can provide information that improves diagnosis and risk assessment and points to possible opportunities for novel treatment," she wrote.