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Candidate gene study of HOXB1 in autism spectrum disorder

Lucia A Muscarella110, Vito Guarnieri1, Roberto Sacco23, Paolo Curatolo4, Barbara Manzi4, Riccardo Alessandrelli4, Grazia Giana4, Roberto Militerni5, Carmela Bravaccio6, Carlo Lenti7, Monica Saccani7, Cindy Schneider8, Raun Melmed9, Leonardo D'Agruma19* and Antonio M Persico23*

Author Affiliations

1 Medical Genetics Service, IRCCS 'Casa Sollievo dalla Sofferenza', San Giovanni Rotondo, FG, Italy

2 Laboratory of Molecular Psychiatry and Neurogenetics, University 'Campus Bio-Medico', Via Alvaro del Portillo 21, I-00128 Rome, Italy

3 Laboratory of Molecular Psychiatry and Psychiatric Genetics, Department of Experimental Neurosciences, IRCCS 'Fondazione Santa Lucia', Rome, Italy

4 Department of Child Neuropsychiatry, University of Rome 'Tor Vergata', Rome, Italy

5 Department of Child Neuropsychiatry, II University of Naples, Italy

6 Department of Pediatrics, University 'Federico II', Naples, Italy

7 Department of Child Neuropsychiatry, University of Milan, Milan, Italy

8 Center for Autism Research and Education, Phoenix, AZ, USA

9 Southwest Autism Research and Resource Center, Phoenix, AZ, USA

10 Current Address: Laboratory of Oncology, IRCCS 'Casa Sollievo della Sofferenza', San Giovanni Rotondo (FG), Italy

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Molecular Autism 2010, 1:9  doi:10.1186/2040-2392-1-9

Published: 25 May 2010



HOXB1 plays a major role in brainstem morphogenesis and could partly determine the cranial circumference in conjunction with HOXA1. In our sample, HOXA1 alleles significantly influence head growth rates both in autistic patients and in population controls. An initial report, suggesting that HOXB1 could confer autism vulnerability in interaction with HOXA1, was not confirmed by five small association studies.


Our sample includes 269 autistic individuals, belonging to 219 simplex and 28 multiplex families. A mutational analysis of the two exons and flanking intronic sequences of the HOXB1 gene was carried out in 84 autistic patients by denaturing high performance liquid chromatography, followed by DNA sequencing. Identified rare variants were then searched by a restriction analysis in 236 autistic patients and 325-345 controls. Case-control and family-based association studies were performed on two common variants in 169 Italian patients versus 184 Italian controls and in 247 trios.


We identified three common polymorphisms, rs72338773 [c.82insACAGCGCCC (INS/nINS)], rs12939811 [c.309A>T (Q103H)], and rs7207109 [c.450G>A (A150A)] and three rare variants, namely IVS1+63G>A, rs35115415 [c.702G>A (V234V)] and c.872_873delinsAA (S291N). SNPs rs72338773 and rs12939811 were not associated with autism, using either a case-control (alleles, exact P = 0.13) or a family-based design [transmission/disequilibrium test (TDT)χ2 = 1.774, P = 0.183]. The rare variants, all inherited from one of the parents, were present in two Italian and in two Caucasian-American families. Autistic probands in two families surprisingly inherited a distinct rare variant from each parent. The IVS1+63A allele was present in 3/690 control chromosomes, whereas rare alleles at rs35115415 and c.872_873delinsAA (S291N) were not found in 662 and 650 control chromosomes, respectively. The INS-T309 allele influenced head size, but its effect appears more modest and shows no interaction with HOXA1 alleles. The INS-T309 allele is also associated with more severe stereotypic behaviours, according to ADI-R scores (N = 60 patients, P < 0.01).


HOXB1 mutations do not represent a common cause of autism, nor do HOXB1 common variants play important roles in autism vulnerability. HOXB1 provides minor, albeit detectable contributions to head circumference in autistic patients, with HOXA1 displaying more prominent effects. HOXB1 variants may modulate the clinical phenotype, especially in the area of stereotypic behaviours.