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

Daniel Moreno‐De‐Luca ,Luann Weik,Kim Uhas,Lisa Guy,David H Ledbetter,Troy J Gliem,Stephen T Warren,Charlotte Boni,Todd Ackley,Arthur R Brothman,Erin B Kaminsky,Denae M Golden,Swaroop Aradhya,Ram Iyer,Diane L Pickering,Warren G Sanger,Laurie A Demmer,Scott M Myers,Emily Aston,Bonnie Anne Salbert,Chantal F Morel,John A Crolla,Ashadeep Chandrareddy,Melanie E Care,Shuwen Huang,Eva W.C Chow,Urvashi Surti,Erik C Thorland,Amy T Pakula,Jennifer G Mullé ,Nancy Eisenhauer ,Stephan Sanders ,Margaret P Adam ,Christa Lese Martin ,John Barber

doi:10.1016/j.ajhg.2010.10.004

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.

Highlights

Autism is the most severe end of a spectrum of neurodevelopmental conditions collectively known as autism spectrum disorders (ASD [MIM 209850]), which include Asperger syndrome and pervasive developmental disorder not otherwise specified (PDD-NOS)
Discovery Sample 17q12 Deletion Identified in a Clinical Testing Setting We identified 18 patients with the same 17q12 deletion (13 males and 5 females) out of the 15,749 we assessed within the International Standards for Cytogenomic Arrays (ISCA) consortium
We chose to focus on the 17q12 deletion given that among this discovery sample, we observed an empirical association between this recurrent copy number variants (CNVs) and autism as a referral diagnosis (4 out of the 16 patients with referring diagnosis information were sent for Autism spectrum disorders (ASD))

Summary

Introduction

Autism is the most severe end of a spectrum of neurodevelopmental conditions collectively known as autism spectrum disorders (ASD [MIM 209850]), which include Asperger syndrome and pervasive developmental disorder not otherwise specified (PDD-NOS). Affecting males four times as often as females, the prevalence of autism is considered to be 1 in 500 individuals, rising to 1 in 110 when all ASD are included.[1]. With a prevalence of 1 in 100 to 1 in 200, the disorder typically comes to clinical attention when frank ‘‘positive’’ psychotic symptoms (hallucinations, delusions, disordered thinking, and bizarre behavior) or ‘‘negative’’ symptoms (profound social withdrawal, anhedonia, or apathy) emerge during late adolescence or early adulthood. Males are affected 1.4 times as often as females, and the age of onset is typically somewhat earlier, and course of illness more severe, in males.[2]

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Conclusion