title: The 22q11 PRODH/DGCR6 deletion is frequent in hyperprolinemic subjects but is not a strong risk factor for ASD.
abstract: The proline dehydrogenase (PRODH) gene maps to 22q11.2 in the region deleted in the velo-cardio-facial syndrome (VCFS). A moderate to severe reduction (>50%) in PRODH activity resulting from recessive deletions and/or missense mutations has been shown to cause type 1 hyperprolinemia (HPI). Autistic features have been reported as a common clinical manifestation of HPI. Here we studied the frequency of a recurrent small 22q11.2 deletion encompassing PRODH and the neighboring DGCR6 gene in three case-control studies, one comprising HPI patients (n = 83), and the other two comprising autism spectrum disorder (ASD) patients (total of n = 2800), analyzed with high-resolution microarrays. We found that the PRODH deletion is a strong risk factor for HPI (OR = 50.7; 95%CI = 7.5-2147) but not for ASD (P = 0.4, OR = 0.6-3.3). This result indicates either that the suggested association between ASD and HPI is spurious and results from a bias leading to the preferential inclusion of patients with autistic features in HPI series, or that HPI is present in only a very small subset of ASD patients. In this latter case, a very large sample size would be required to detect an association between the PRODH deletion and ASD in a case-control study.
authors.affiliation: Inserm U1079, Institute for Research and Innovation in Biomedicine, University of Rouen, France.
authors.forename: Anne Claire
authors.initials: AC
authors.lastname: Richard
authors.affiliation: Inserm U1079, Institute for Research and Innovation in Biomedicine, University of Rouen, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Rovelet-Lecrux
authors.affiliation: Inserm U1130, Neuroscience Paris Seine, Paris, France.|CNRS UMR 8246, Neuroscience Paris Seine, Paris, France.|Sorbonne Universités, UPMC Univ Paris 6, Institut de Biologie Paris-Seine, Paris, France.
authors.forename: Elsa
authors.initials: E
authors.lastname: Delaby
authors.affiliation: Inserm U1079, Institute for Research and Innovation in Biomedicine, University of Rouen, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Charbonnier
authors.affiliation: The Centre for Applied Genomics, and Program in Genetics and Genome Biology, the Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Bhooma
authors.initials: B
authors.lastname: Thiruvahindrapuram
authors.affiliation: Population Diagnostics, Inc., Melville, New York.
authors.forename: Eli
authors.initials: E
authors.lastname: Hatchwell
authors.affiliation: Population Diagnostics, Inc., Melville, New York.
authors.forename: Peggy S
authors.initials: PS
authors.lastname: Eis
authors.affiliation: Unité de neuropédiatrie et pathologie du développement, CHU Paris Est-Hôpital d'Enfants Armand-Trousseau, Paris, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Afenjar
authors.affiliation: Service de génétique médicale, CHU de Poitiers, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Gilbert Dussardier
authors.affiliation: The Centre for Applied Genomics, and Program in Genetics and Genome Biology, the Hospital for Sick Children, Toronto, Ontario, Canada.|McLaughlin Centre and Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Scherer
authors.affiliation: Inserm U1130, Neuroscience Paris Seine, Paris, France.|CNRS UMR 8246, Neuroscience Paris Seine, Paris, France.|Sorbonne Universités, UPMC Univ Paris 6, Institut de Biologie Paris-Seine, Paris, France.
authors.forename: Catalina
authors.initials: C
authors.lastname: Betancur
authors.affiliation: Inserm U1079, Institute for Research and Innovation in Biomedicine, University of Rouen, France.|Centre Hospitalier du Rouvray, Sotteville-lès-Rouen, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Campion
mesh_terms: D000328:Adult; D000592:Amino Acid Metabolism, Inborn Errors / Q000235:genetics*; D000067877:Autism Spectrum Disorder / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics*; D015331:Cohort Studies; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D009687:Nuclear Proteins; D011394:Proline Oxidase / Q000235:genetics*; D012307:Risk Factors
chemical_list: C101273:DGCR6 protein, human; D016326:Extracellular Matrix Proteins; D009687:Nuclear Proteins; D011394:Proline Oxidase; C582834:PRODH protein, human
keywords: 22q11.2 deletion; autism; copy number variant; hyperprolinemia; proline dehydrogenase