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.

Figure 1

17q12 Region Chromosome 17 schematic showing a close-up of 17q11.2-17q12, including selected genes and segmental duplications in the region, along with the results of four different autism linkage studies and one association study on male-only autism families (black squares [in Stone et al., black squares correspond to markers flanking the linkage peak and are connected by a dotted horizontal black line]). The recurrent 17q12 deletion found in our patients is depicted as a horizontal blue line, flanked by segmental duplications (blue shaded rectangles). The 180K cytogenomic array results of one of the patients are shown below.

Figure 2

Facial Phenotype of Patients with 17q12 Deletions Macrocephaly, epicanthal folds, downslanting palpebral fissures, arched and high eyebrows, slightly depressed nasal bridge, and malar flattening are the features shared most consistently among these patients. Profile pictures and photographs at different ages are provided when available, showing the progression of the phenotype over time.