Chromosomal deletion at 22q11.2 and Parkinson's disease
Authors: Eng-King Tan
Journal: The Lancet Neurology (2016)

Chromosome 22q11.2 deletion syndrome is a group of heterogeneous disorders characterised by a deletion near the middle of chromosome 22 at a location designated q11.2. The clinical phenotype varies widely, with multiple system involvement. Well-recognised features include cleft palate, dysmorphic facial features, cardiac defects, skeletal deformities, developmental delays, and learning disabilities.1Hacıhamdioğlu B Hacıhamdioğlu D Delil K 22q11 deletion syndrome: current perspective.Appl Clin Genet. 2015; 8: 123-132Crossref PubMed Scopus (53) Google Scholar Many affected people are identified at a young age. These patients are at an increased risk of developing schizophrenia and other mental disorders, and have a reduced lifespan. Despite the multiple system involvement, an association between 22q11.2 deletion syndrome and Parkinson's disease was not suspected until the publication of independent case reports of co-occurrence of parkinsonism in patients with 22q11.2 deletion syndrome.2Zaleski C Bassett AS Tam K Shugar AL Chow EW McPherson E The co-occurrence of early onset Parkinson disease and 22q11.2 deletion syndrome.Am J Med Genet A. 2009; 149A: 525-528Crossref PubMed Scopus (39) Google Scholar, 3Ogaki K Ross OA Chromosome 22q11.2 deletion may contain a locus for recessive early-onset Parkinson's disease.Parkinsonism Relat Disord. 2014; 20: 945-946Summary Full Text Full Text PDF PubMed Scopus (8) Google Scholar Interest in this possible link increased after Butcher and colleagues4Butcher NJ Kiehl TR Hazrati LN et al.Association between early-onset Parkinson disease and 22q11.2 deletion syndrome: identification of a novel genetic form of Parkinson disease and its clinical implications.JAMA Neurol. 2013; 70: 1359-1366Crossref PubMed Scopus (111) Google Scholar reported four patients with early-onset Parkinson's disease in their study of 159 adults with 22q11.2 deletion syndrome. They found that the use of antipsychotics in these patients delayed diagnosis of Parkinson's disease by up to a decade and typical Lewy bodies were present in two of three patients at post mortem. All of the nine reported cases with 22q11.2 deletion syndrome in the published work so far had age at onset of Parkinson's disease of younger than 50 years.4Butcher NJ Kiehl TR Hazrati LN et al.Association between early-onset Parkinson disease and 22q11.2 deletion syndrome: identification of a novel genetic form of Parkinson disease and its clinical implications.JAMA Neurol. 2013; 70: 1359-1366Crossref PubMed Scopus (111) Google Scholar, 5Mok KY Sheerin U Simón-Sánchez J et al.Deletions at 22q11.2 in idiopathic Parkinson's disease: a retrospective combined analysis of genome-wide association data.Lancet Neurol. 2016; (published online March 23.)http://dx.doi.org/10.1016/S1474-4422(16)00071-5PubMed Google Scholar, 6Foo JN Liu JJ Tan EK Whole-genome and whole-exome sequencing in neurological diseases.Nat Rev Neurol. 2012; 8: 508-517Crossref PubMed Scopus (87) Google Scholar In The Lancet Neurology, Kin Mok and colleagues5Mok KY Sheerin U Simón-Sánchez J et al.Deletions at 22q11.2 in idiopathic Parkinson's disease: a retrospective combined analysis of genome-wide association data.Lancet Neurol. 2016; (published online March 23.)http://dx.doi.org/10.1016/S1474-4422(16)00071-5PubMed Google Scholar examined the opposite association; that is, they looked for deletions at 22q11.2 in four independent case-control Parkinson's disease datasets from different European populations. They did array-based copy number variation analyses of data from 9387 patients with Parkinson's disease and 13 863 controls. They found a significant increase of the common 3 Mb deletion (associated with 22q11.2 deletion syndrome) in Parkinson's disease (eight cases) compared with controls (no cases; p=0·00082). The deletions were associated with disease age at onset, with 0·49% frequency in patients with early-onset Parkinson's disease (<45 years) compared with 0·04% frequency in those with an age of onset of 45 years or older (p=0·005). These findings corroborate those from previous case reports2Zaleski C Bassett AS Tam K Shugar AL Chow EW McPherson E The co-occurrence of early onset Parkinson disease and 22q11.2 deletion syndrome.Am J Med Genet A. 2009; 149A: 525-528Crossref PubMed Scopus (39) Google Scholar, 3Ogaki K Ross OA Chromosome 22q11.2 deletion may contain a locus for recessive early-onset Parkinson's disease.Parkinsonism Relat Disord. 2014; 20: 945-946Summary Full Text Full Text PDF PubMed Scopus (8) Google Scholar and provide further support for an association between 22q11.2 deletion syndrome and Parkinson's disease, especially in patients with early-onset disease. Although an association does not prove causality, it provides impetus to look for a novel Parkinson's disease gene within the deleted region. Missense mutations of pathogenic genes have been well described in Parkinson's disease.6Foo JN Liu JJ Tan EK Whole-genome and whole-exome sequencing in neurological diseases.Nat Rev Neurol. 2012; 8: 508-517Crossref PubMed Scopus (87) Google Scholar, 7Tan EK Rare and common LRRK2 exonic variants in Parkinson's disease.Lancet Neurol. 2011; 10: 869-870Summary Full Text Full Text PDF PubMed Scopus (5) Google Scholar Additionally, copy number variants involving recessive (eg, PARKIN, PINK1) and dominant genes (SNCA) have also been implicated in familial Parkinson's disease. Whether haploinsufficiency of a single gene or a group of genes in the 22q11.2 region is responsible for the development of Parkinson's disease remains unknown. This could be investigated by knocking down individual genes or studying the effect of deletion mutants in neuronal cultures. Further validation in animal models (ie, gene knockdown) could be done to verify dopaminergic neuronal loss and other pathological features of Parkinson's disease. Deep sequencing of genes in the remaining hemizygous allele to identify mutations might identify novel recessive causative genes, although this might be challenging since these patients generally do not have a positive family history (most are carriers of de-novo mutations). A combination of a deletion and a mutation in the opposite allele or with other epigenetic factors is another possibility. Some of the candidate genes within this region (eg, COMT, DGCR8, and SEPT5) are possible causative genes because of their interaction with known Parkinson's disease genes or dopaminergic pathways. Although Mok and colleagues highlight the possible clinical effects (eg, screening and genetic counselling) of their findings, we should approach their findings with cautious optimism. First, both 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. Second, including the present study, the number of patients identified with coexistent 22q11.2 deletion syndrome and Parkinson's disease is still low (<20). Phenotype characterisation of these patients is still scarce. Three of the six cases in the present study had previous psychiatric or cognitive problems, but these diagnoses seemed to be based on historical information, and comprehensive neuropsychological testing, systematic screening, and details regarding treatment complications were not available. Third, we do not know why only 3% of patients with 22q11.2 deletion syndrome develop Parkinson's disease6Foo JN Liu JJ Tan EK Whole-genome and whole-exome sequencing in neurological diseases.Nat Rev Neurol. 2012; 8: 508-517Crossref PubMed Scopus (87) Google Scholar and whether there are any specific clinically useful warning signs and factors that might affect penetrance in patients who might develop parkinsonian symptoms subsequently. Despite many missing connections in the pathophysiological link between 22q11.2 deletion syndrome and Parkinson's disease, the present study will certainly raise clinicians' awareness and heighten their vigilance in looking for features of 22q11.2 deletion syndrome in patients with early-onset Parkinson's disease, and carefully considering Parkinson's disease as a differential diagnosis in patients with 22q11.2 deletion syndrome even if these patients are on antipsychotic drugs. Further functional experiments, replication studies in independent clinical cohorts, and identification of additional cases with chromosomal deletion sizes other than the 3 Mb region will shed more light on this interesting association. I declare no competing interests. Deletions at 22q11.2 in idiopathic Parkinson's disease: a combined analysis of genome-wide association dataClinicians should be alert to the possibility of 22q11.2 deletions in patients with Parkinson's disease who have early presentation or features associated with the chromosome 22q11.2 deletion syndrome, or both. Full-Text PDF Open Access