Chromosomal deletion at 22q11.2 may increase the risk of Parkinson’s disease, particularly early-onset Parkinson’s disease, according to research published online ahead of print March 23 in the Lancet Neurology.

The association between Parkinson’s disease and chromosome 22q11.2 deletion syndrome could be important for patient management, with implications for identifying and managing comorbidities as well as for genetic counseling, said Kin Y. Mok, PhD, of the Department of Molecular Neuroscience at the University College London Institute of Neurology and the Division of Life Science at Hong Kong University of Science and Technology, and colleagues.

Deletion at 22q11.2 is among the most common interstitial deletions in humans and one of the strongest genetic risk factors for schizophrenia, the authors noted. The clinical phenotype of chromosome 22q11.2 deletion syndrome varies widely and can include cleft palate, dysmorphic facial features, cardiac defects, skeletal deformities, and learning disabilities. The deletions are inherited from a parent in 5% to 10% of cases and occur de novo in the remainder of cases.

An observational study by Butcher et al found an increased frequency of Parkinson’s disease in patients with chromosome 22q11.2 deletion syndrome, compared with controls. Few patients with chromosome 22q11.2 deletion syndrome developed Parkinson’s disease, however, indicating that other factors play a role.

Four Genome-Wide Association Studies

To establish the frequency of deletions spanning the 22q11.2 locus in idiopathic Parkinson’s disease, Dr. Mok and colleagues screened data from the following four large independent genome-wide association studies: the UK Wellcome Trust Case Control Consortium 2 Parkinson’s disease, the Dutch Parkinson’s Disease Genetics Consortium, the US National Institute on Aging, and the International Parkinson’s Disease Genomics Consortium.

The investigators conducted case–control association analysis to compare the proportions of 22q11.2 deletions between groups. They used Fisher’s exact test for the independent case–control studies and the Mantel–Haenszel test for the meta-analyses. In addition, they retrieved clinical details from the medical records of patients with Parkinson’s disease who had 22q11.2 deletions.

In all, they included data from 9,387 patients with Parkinson’s disease and 13,863 controls in their analysis. Eight patients with Parkinson’ disease and none of the controls had 22q11.2 deletions. Age at onset was available for 8,451 of the patients with Parkinson’s disease, including all of those with 22q11.2 deletions. Age at onset was lower in patients carrying a 22q11.2 deletion, compared with patients with Parkinson’s disease who were not carrying a deletion (mean age at onset, 42.1 vs 60.3).In addition, a deletion was present in more patients with early-onset Parkinson’s disease than with late-onset Parkinson’s disease. “Of the 1,014 patients with Parkinson’s disease with age at onset younger than 45 years, five (0.49%) had 22q11.2 deletions, compared with three (0.04%) of 7,437 with an age at onset of 45 years or older,” the researchers said.

None of the patients with a deletion presented with a diagnosis of chromosome 22q11.2 deletion syndrome or schizophrenia. “With hindsight, some cases had other features suggestive of 22q11.2 deletion syndrome, such as hypocalcemia, depression, fatigue, mental retardation, and cleft palate,” the researchers said.

“Clinicians should bear this uncommon 22q11.2 deletion in mind when a patient presents with early-onset Parkinson’s disease,” said Dr. Mok and colleagues. “Carriers of a 22q11.2 deletion are prone to many other potential comorbidities, and clinicians should actively investigate for these comorbidities when managing a patient with a 22q11.2 deletion and Parkinson’s disease.”

Although the 22q11.2 deletion is associated with two neuropsychiatric disorders, schizophrenia and Parkinson’s disease, it is not clear whether the deletion “is a single common pathogenic pathway or whether separate genetic defects within the 22q11.2 deletion contribute to the differing phenotypes,” the authors said.

Findings May Reflect Ascertainment Bias

The findings are based on a retrospective, combined analysis of four studies that might be heterogeneous, and the methods of case referral in those studies could have led to ascertainment bias. For instance, although a history of schizoaffective disorder was not an explicit exclusion criterion in the recruitment of patients with Parkinson’s disease, the UK Brain Bank excludes patients with neuroleptic treatment at onset of Parkinson’s disease, the investigators said. Furthermore, psychiatrists or other specialists likely would manage patients who carry the deletion and have severe psychiatric or systemic illness, making those patients potentially less likely to be referred to neurology recruitment centers.

“We should approach their findings with cautious optimism,” said Eng-King Tan, MBBS, Senior Consultant Neurologist at the National Neuroscience Institute at Singapore General Hospital and Professor at Duke-National University of Singapore Medical School, in an accompanying commentary. “The estimated prevalence of 22q11.2 deletion syndrome in the general population (0.024%) and that of a 22q deletion among patients with early-onset Parkinson’s disease (0.49%) are low. Hence, any large-scale effect on screening in the general population of patients with Parkinson’s disease will be small.” In addition, fewer than 20 patients with coexistent 22q11.2 deletion syndrome and Parkinson’s disease have been identified so far, and it is not clear why only 3% of patients with the syndrome develop Parkinson’s disease, said Dr. Tan. Nevertheless, the study will heighten clinicians’ vigilance “in looking for features of 22q11.2 deletion syndrome in patients with early-onset Parkinson’s disease, and in carefully considering Parkinson’s disease as a differential diagnosis in patients with 22q11.2 deletion syndrome even if these patients are on antipsychotic drugs.”

—Jake Remaly

Chromosomal Deletion May Increase the Risk of Parkinson’s Disease