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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??). 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.

SUBMITTER: Moreno-De-Luca D

PROVIDER: S-EPMC2978962 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Deletion 17q12 is a recurrent copy number variant that confers high risk of autism and schizophrenia.

Moreno-De-Luca Daniel D Mulle Jennifer G JG Kaminsky Erin B EB Sanders Stephan J SJ Myers Scott M SM Adam Margaret P MP Pakula Amy T AT Eisenhauer Nancy J NJ Uhas Kim K Weik LuAnn L Guy Lisa L Care Melanie E ME Morel Chantal F CF Boni Charlotte C Salbert Bonnie Anne BA Chandrareddy Ashadeep A Demmer Laurie A LA Chow Eva W C EW Surti Urvashi U Aradhya Swaroop S Pickering Diane L DL Golden Denae M DM Sanger Warren G WG Aston Emily E Brothman Arthur R AR Gliem Troy J TJ Thorland Erik C EC Ackley Todd T Iyer Ram R Huang Shuwen S Barber John C JC Crolla John A JA Warren Stephen T ST Martin Christa L CL Ledbetter David H DH

American journal of human genetics 20101104 5

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), ...[more]

PMID: 21055719

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Project description:BackgroundAutism spectrum disorders and schizophrenia have been associated with an overlapping set of copy number variant loci, but the nature and degree of overlap in copy number variants (deletions compared to duplications) between these two disorders remains unclear.MethodsWe systematically evaluated three lines of evidence: (1) the statistical bases for associations of autism spectrum disorders and schizophrenia with a set of the primary CNVs thus far investigated, from previous studies; (2) data from case series studies on the occurrence of these CNVs in autism spectrum disorders, especially among children, and (3) data on the extent to which the CNVs were associated with intellectual disability and developmental, speech, or language delays. We also conducted new analyses of existing data on these CNVs in autism by pooling data from seven case control studies.ResultsFour of the CNVs considered, dup 1q21.1, dup 15q11-q13, del 16p11.2, and dup 22q11.21, showed clear statistical evidence as autism risk factors, whereas eight CNVs, del 1q21.1, del 3q29, del 15q11.2, del 15q13.3, dup 16p11.2, dup 16p13.1, del 17p12, and del 22q11.21, were strongly statistically supported as risk factors for schizophrenia. Three of the CNVs, dup 1q21.1, dup 16p11.2, and dup 16p13.1, exhibited statistical support as risk factors for both autism and schizophrenia, although for each of these CNVs statistical significance was nominal for tests involving one of the two disorders. For the CNVs that were statistically associated with schizophrenia but were not statistically associated with autism, a notable number of children with the CNVs have been diagnosed with autism or ASD; children with these CNVs also demonstrate a high incidence of intellectual disability and developmental, speech, or language delays.ConclusionsThese findings suggest that although CNV loci notably overlap between autism and schizophrenia, the degree of strongly statistically supported overlap in specific CNVs at these loci remains limited. These analyses also suggest that relatively severe premorbidity to CNV-associated schizophrenia in children may sometimes be diagnosed as autism spectrum disorder.

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Deletion 17q12 is a recurrent copy number variant that confers high risk of autism and schizophrenia.

Publications

Deletion 17q12 is a recurrent copy number variant that confers high risk of autism and schizophrenia.

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