Microduplications at the pseudoautosomal SHOX locus in autism spectrum disorders and related neurodevelopmental conditions

Maria Tropeano, Deirdre Howley, Matthew J Gazzellone, C Ellie Wilson, Joo Wook Ahn, Dimitri J Stavropoulos, Clodagh Murphy, Peggy S Eis, Eli Hatchwell, Richard J B Dobson, Dene Robertson, Muriel Holder, Melita Irving, Dragana Josifova, Annelise Nehammer, Mina Ryten, Debbie Spain, Mark Pitts, Jessica Bramham, Philip AshersonSarah Curran, Evangelos Vassos, Gerome Breen, Frances Flinter, Caroline Mackie Ogilvie, David A Collier, Stephen W Scherer, Grainne M Mcalonan, Declan G Murphy

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23 Citations (Scopus)


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.                                  

Original languageEnglish
JournalJournal of Medical Genetics
Early online date12 Apr 2016
Publication statusPublished - 2016


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