Candidate gene study of HOXB1 in autism spectrum disorder

Lucia A. Muscarella, Vito Guarnieri, Roberto Sacco, Paolo Curatolo, Barbara Manzi, Riccardo Alessandrelli, Grazia Giana, Roberto Militerni, Carmela Bravaccio, Carlo Lenti, Monica Saccani, Cindy Schneider, Raun Melmed, Leonardo D'Agruma, Antonio M. Persico

Research output: Contribution to journalArticle

Abstract

Background. 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. Methods. 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. Results. 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). Conclusions. 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.

Original languageEnglish
Article number9
JournalMolecular Autism
Volume1
Issue number1
DOIs
Publication statusPublished - 2010

Fingerprint

Alleles
Autistic Disorder
Genes
Head
Chromosomes
Population Control
Autism Spectrum Disorder
DNA Sequence Analysis
Morphogenesis
Brain Stem
Single Nucleotide Polymorphism
Exons
Parents
High Pressure Liquid Chromatography
Phenotype
Mutation
Growth

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Developmental Neuroscience
  • Developmental Biology
  • Molecular Biology

Cite this

Muscarella, L. A., Guarnieri, V., Sacco, R., Curatolo, P., Manzi, B., Alessandrelli, R., ... Persico, A. M. (2010). Candidate gene study of HOXB1 in autism spectrum disorder. Molecular Autism, 1(1), [9]. https://doi.org/10.1186/2040-2392-1-9

Candidate gene study of HOXB1 in autism spectrum disorder. / Muscarella, Lucia A.; Guarnieri, Vito; Sacco, Roberto; Curatolo, Paolo; Manzi, Barbara; Alessandrelli, Riccardo; Giana, Grazia; Militerni, Roberto; Bravaccio, Carmela; Lenti, Carlo; Saccani, Monica; Schneider, Cindy; Melmed, Raun; D'Agruma, Leonardo; Persico, Antonio M.

In: Molecular Autism, Vol. 1, No. 1, 9, 2010.

Research output: Contribution to journalArticle

Muscarella, LA, Guarnieri, V, Sacco, R, Curatolo, P, Manzi, B, Alessandrelli, R, Giana, G, Militerni, R, Bravaccio, C, Lenti, C, Saccani, M, Schneider, C, Melmed, R, D'Agruma, L & Persico, AM 2010, 'Candidate gene study of HOXB1 in autism spectrum disorder', Molecular Autism, vol. 1, no. 1, 9. https://doi.org/10.1186/2040-2392-1-9
Muscarella, Lucia A. ; Guarnieri, Vito ; Sacco, Roberto ; Curatolo, Paolo ; Manzi, Barbara ; Alessandrelli, Riccardo ; Giana, Grazia ; Militerni, Roberto ; Bravaccio, Carmela ; Lenti, Carlo ; Saccani, Monica ; Schneider, Cindy ; Melmed, Raun ; D'Agruma, Leonardo ; Persico, Antonio M. / Candidate gene study of HOXB1 in autism spectrum disorder. In: Molecular Autism. 2010 ; Vol. 1, No. 1.
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abstract = "Background. 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. Methods. 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. Results. 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). Conclusions. 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.",
author = "Muscarella, {Lucia A.} and Vito Guarnieri and Roberto Sacco and Paolo Curatolo and Barbara Manzi and Riccardo Alessandrelli and Grazia Giana and Roberto Militerni and Carmela Bravaccio and Carlo Lenti and Monica Saccani and Cindy Schneider and Raun Melmed and Leonardo D'Agruma and Persico, {Antonio M.}",
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T1 - Candidate gene study of HOXB1 in autism spectrum disorder

AU - Muscarella, Lucia A.

AU - Guarnieri, Vito

AU - Sacco, Roberto

AU - Curatolo, Paolo

AU - Manzi, Barbara

AU - Alessandrelli, Riccardo

AU - Giana, Grazia

AU - Militerni, Roberto

AU - Bravaccio, Carmela

AU - Lenti, Carlo

AU - Saccani, Monica

AU - Schneider, Cindy

AU - Melmed, Raun

AU - D'Agruma, Leonardo

AU - Persico, Antonio M.

PY - 2010

Y1 - 2010

N2 - Background. 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. Methods. 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. Results. 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). Conclusions. 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.

AB - Background. 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. Methods. 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. Results. 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). Conclusions. 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.

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