Deletion 17q12 Is a Recurrent Copy Number Variant that Confers High Risk of Autism and Schizophrenia

Abstract

Autism spectrum disorders (ASD) and schizophrenia are neurodevelopmental disorders for which recent evidence indicates an important etiologic role for rare copy number variants (CNVs) and suggests common genetic mechanisms. We performed cytogenomic array analysis in a discovery sample of patients with neurodevelopmental disorders referred for clinical testing. We detected a recurrent 1.4 Mb deletion at 17q12, which harbors HNF1B, the gene responsible for renal cysts and diabetes syndrome (RCAD), in 18/15,749 patients, including several with ASD, but 0/4,519 controls. We identified additional shared phenotypic features among nine patients available for clinical assessment, including macrocephaly, characteristic facial features, renal anomalies, and neurocognitive impairments. In a large follow-up sample, the same deletion was identified in 2/1,182 ASD/neurocognitive impairment and in 4/6,340 schizophrenia patients, but in 0/47,929 controls (corrected p = 7.37 × 10⁻⁵). These data demonstrate that deletion 17q12 is a recurrent, pathogenic CNV that confers a very high risk for ASD and schizophrenia and show that one or more of the 15 genes in the deleted interval is dosage sensitive and essential for normal brain development and function. In addition, the phenotypic features of patients with this CNV are consistent with a contiguous gene syndrome that extends beyond RCAD, which is caused by HNF1B mutations only.

Towards a new point of view on the phenotype of patients with a 17q12 microdeletion syndrome

“…These three signs were not reported by Moreno-De-Luca et al 2 Moreover, others signs, mentioned by that author (down-slanting palpebral fissures, highly arched eyebrows, slightly depressed nasal bridge and malar flattening), were not significantly present in the patients of our deletion group. Contrary to Moreno-De-Luca et al , who consistently noticed macrocephaly, we only had one patient with this malformation.…”

“…Initially, the 17q12 microdeletion syndrome was reported to be free of neurological involvement,1 but more recent reports have shown that it is associated with frequent neurodevelopmental or psychiatric disorders. Table 1 summarises reported cases, an analysis of which appears to lend credence to Moreno-De-Luca et al ,2 who concluded in their study that this anomaly is ‘a recurrent copy number variant that confers high risk of autism and schizophrenia’ or other neuropsychological disorders.…”

“…Among the 14 other genes, LHX1 is an interesting candidate. This hypothesis, involving a gene expressed during brain development, has already been evoked in several publications,1 2 4 15 but tests have failed to confirm it so far 10. Further studies are needed to explore the possibility of other genes in the deleted region being involved in neurological disorders.…”

Risk factors for autism: translating genomic discoveries into diagnostics

“…It is noteworthy that CNVs at the 16p11.2 locus are also observed in schizophrenia ), childhood obesity Walters et al 2010) and increasingly in other disorders (Shinawi et al 2010). In another CNV-ascertained cohort, careful phenotypic follow-up of individuals with 17q12 deletions is revealing a large number with autism phenotypes (Moreno- De-Luca et al 2010). In addition to the need for genomic platforms on which to undertake studies of environmental risk factors (as discussed above), such genomic stratiWcation will be important for research into comparative eVectiveness of various intervention strategies and clinical trials-ushering in the potential for truly personalized medical care.…”

CNVinspector:a web-based tool for the interactive evaluation of copy number variations in single patients and in cohorts

“…Common diseases, such as schizophrenia,2 epilepsy3 and Parkinson's disease4 have been associated with CNVs, but their exact contribution to such complex traits is a matter of ongoing debate 5. In clinical genetics, however, genome-wide CNV analysis has become standard diagnostic practice for patients with developmental disorders, dysmorphic features or congenital anomalies 6…”