Microduplications at the pseudoautosomal SHOX locus in autism spectrum disorders and related neurodevelopmental conditions. Issue 8 (12th April 2016)

• Record Type: Journal Article
• Authors: Tropeano, Maria; Howley, Deirdre; Gazzellone, Matthew J; Wilson, C Ellie; Ahn, Joo Wook; Stavropoulos, Dimitri J; Murphy, Clodagh M; Eis, Peggy S; Hatchwell, Eli; Dobson, Richard J B; Robertson, Dene; Holder, Muriel; Irving, Melita; Josifova, Dragana; Nehammer, Annelise; Ryten, Mina; Spain, Debbie; Pitts, Mark; Bramham, Jessica; Asherson, Philip; Curran, Sarah; Vassos, Evangelos; Breen, Gerome; Flinter, Frances; Ogilvie, Caroline Mackie; Collier, David A; Scherer, Stephen W; McAlonan, Grainne M; Murphy, Declan G
• Is Part Of: Journal of medical genetics. Volume 53:Issue 8(2016)
• Page Start: 536
• Page End: 547
• Publication Date: 2016-04-12
• Subjects: Neurodevelopment -- Copy number variation -- Dosage-sensitive gene -- Enhancer -- Female; Medical genetics -- Periodicals; 616.042
• DOI: 10.1136/jmedgenet-2015-103621
• Languages: English
• ISSNs: 1468-6244

Abstract

Abstract : Background: The pseudoautosomal short stature homeobox-containing ( SHOX ) gene encodes a homeodomain transcription factor involved in cell-cycle and growth regulation. SHOX / SHOX enhancers deletions cause short stature and skeletal abnormalities in a female-dominant fashion; duplications appear to be rare. Neurodevelopmental disorders (NDDs), such as autism spectrum disorders (ASDs), are complex disorders with high heritability and skewed sex ratio; several rare (<1% frequency) CNVs have been implicated in risk. Methods: We analysed data from a discovery series of 90 adult ASD cases, who underwent clinical genetic testing by array-comparative genomic hybridisation (CGH). Twenty-seven individuals harboured CNV abnormalities, including two unrelated females with microduplications affecting SHOX . To determine the prevalence of SHOX duplications and delineate their associated phenotypic spectrum, we subsequently examined array-CGH data from a follow-up sample of 26 574 patients, including 18 857 with NDD (3541 with ASD). Results: We found a significant enrichment of SHOX microduplications in the NDD cases (p=0.00036; OR 2.21) and, particularly, in those with ASD (p=9.18×10 −7 ; OR 3.63) compared with 12 594 population-based controls. SHOX duplications affecting the upstream or downstream enhancers were enriched only in females with NDD (p=0.0043; OR 2.69/p=0.00020; OR 7.20), but not in males (p=0.404; OR 1.38/p=0.096; OR 2.21). Conclusions: Microduplications at the SHOX locus are a low penetrance risk factor for ASD/NDD, with increased risk in both sexes. However, a concomitant duplication of SHOX enhancers may be required to trigger a NDD in females. Since specific SHOX isoforms are exclusively expressed in the developing foetal brain, this may reflect the pathogenic effect of altered SHOX protein dosage on neurodevelopment.