Genetic Landscape of Opsoclonus-Myoclonus-Ataxia Syndrome in Children

Abstract

Background: Opsoclonus-myoclonus-ataxia syndrome (OMAS) is a rare neurological disorder, with involuntary rapid saccadic conjugate eye movements as one of characteristics, primarily affecting the cerebellum. While the exact pathogenesis remains unclear, genetic and autoimmune factors have been suggested to contribute to its development.

Methods: We enrolled patients diagnosed with OMAS before the age of 18 years at a pediatric neuroimmunology clinic in Boston, United States, using the 2004 Genoa Criteria. Whole genome sequencing was conducted for the patients and their biological parents in all cases, with one case including an unaffected twin sibling.

Results: De novo germline variants (DNVs) in probands were identified and validated and analyses of structural variants, recessive variants in neuroimmune-associated genes, and high-resolution human leukocyte antigen (HLA) typing were performed. Our study included 42 patients, 23 of whom had neuroblastoma. We found 12 confirmed DNVs in protein-coding regions in nine patients (29.0% of 31 from 30 trios and 1 quartet). Ten patients (23.8% of 42) had rare homozygous or compound heterozygous variants known to alter protein function, affecting 11 genes. Notably, the major histocompatibility complex, class II, DR beta 1 (HLA-DRB1) ∗01 allele was observed in 27 out of 84 (32.1%) alleles in the patients, significantly higher than that in the general population (chi-square test, P < 0.0001). In one case, a potential genetic modifier of OMAS with severe cerebellar atrophy was identified, associated with a protein-truncating DNV in the CACNA2D2 gene.

Conclusions: This first genome sequencing study reveals potential genetic contributors to OMAS, implicating polygenic predisposition-with HLA-DRB1∗01 as a possible factor-combined with nongenetic risk factors like neuroblastoma.

Keywords: Compound heterozygous; De novo germline variants; Linked-reads genome sequencing; Opsoclonus-myoclonus-ataxia syndrome; Recessive.

Figure 1.. Overview of the Variant Prioritization Pipeline.

This figure depicts the workflows for identifying disease-associated variants in 30 trios, 1 quartet, and 11 unrelated patients. Pedigree charts represent the inheritance patterns, with squares for males, circles for females, and filled symbols indicating affected individuals. Genotypes are indicated as “0|0” for homozygous reference, “0|1” for heterozygous, and “1|1” for homozygous variant. De novo germline variants are identified by examining loci where both parents have “0|0”, and the proband has “0|1” in the trios. For the quartet with monozygotic twins, de novo variants are selected only if they are observed exclusively in the affected twin (top panel). Pedigree charts also show affected individuals with homozygous variants (“1|1”) inherited from carrier parents (“0|1”). These variants are very rare (MAF < 0.001) or novel in the population database and have nonsynonymous effects with reported disease-associated phenotypes in ClinVar (middle panel). Additionally, pedigree charts illustrate cases where the proband has two different heterozygous variants (“0|1”) inherited from each parent, resulting in a compound heterozygous genotype (“1|0”, “0|1”). These variants are also very rare or novel and have nonsynonymous effects with reported disease associations in ClinVar. Inheritance from each parent is confirmed with phased genome sequencing intervals (bottom panel). MAF: Minor Allele Frequency.

Figure 2.. Truncating de novo germline variant in the CACNA2D2 gene.

A. Sanger sequencing chromatograms showing the ENST00000479551.1:c.2874del (p.Gly950AlafsTer66) de novo variant in the affected individual. The chromatograms illustrate the genetic sequence of the mother (M), father (F), and proband (P). B. Structural brain magnetic resonance imaging of the patient with the de novo germline variant in the CACNA2D2 gene. T1-weighted sagittal (left panel) and T2-weighted axial (right panel) views show severe cerebellar atrophy.