11q24.2-25 micro-rearrangements in autism spectrum disorders: Relation to brain structures.
Jacobsen syndrome (JS) is characterized by intellectual disability and higher risk for autism spectrum disorders (ASD). All patients with JS are carriers of contiguous de novo deletions of 11q24.2-25, but the causative genes remain unknown. Within the critical interval, we hypothesized that haploinsufficiency of the neuronal cell adhesion molecule Neurotrimin (NTM) might increase the risk for ASD and could affect brain structure volumes. We searched for deleterious mutations affecting NTM in 1256 ASD patients and 1287 controls, using SNP arrays, and by direct sequencing of 250 ASD patients and 180 controls. We compared our results to those obtained from independent cohorts of ASD patients and controls. We identified two patients with Copy Number Variants (CNV) encompassing NTM, one with a large de novo deletion, and a clinical phenotype of JS (including macrocephaly), and a second with a paternally inherited duplication, not consistent with JS. Interestingly, no similar CNVs were observed in controls. We did not observe enrichment for deleterious NTM mutations in our cohort. We then explored if the macrocephaly in the patient with JS was associated with a homogeneous increase of brain structures volumes using automatic segmentation. Compared to subjects without NTM micro-rearrangements (n=188), the patient had an increased volume of the sub-cortical structures but a decrease of the occipital gray matter. Finally our explorations could not incriminate NTM as a susceptibility gene for ASD, but provides new information on the impact of the 11q24.2-25 deletion on brain anatomy.
Human Genetics and Cognitive Functions, Institut Pasteur, Paris, France.|CNRS URA 2182, Institut Pasteur, Paris, France.|Department of Child Psychiatry, Robert Debré Hospital, APHP, Paris, France.
Anna
A
Maruani
Human Genetics and Cognitive Functions, Institut Pasteur, Paris, France.|CNRS URA 2182, Institut Pasteur, Paris, France.
Guillaume
G
Huguet
Human Genetics and Cognitive Functions, Institut Pasteur, Paris, France.|CNRS URA 2182, Institut Pasteur, Paris, France.|Department of Child Psychiatry, Robert Debré Hospital, APHP, Paris, France.
Anita
A
Beggiato
Department of Radiology, Robert Debré Hospital, APHP, Paris, France.
Monique
M
ElMaleh
Human Genetics and Cognitive Functions, Institut Pasteur, Paris, France.|CNRS URA 2182, Institut Pasteur, Paris, France.
Roberto
R
Toro
Human Genetics and Cognitive Functions, Institut Pasteur, Paris, France.|CNRS URA 2182, Institut Pasteur, Paris, France.
Claire S
CS
Leblond
Human Genetics and Cognitive Functions, Institut Pasteur, Paris, France.|CNRS URA 2182, Institut Pasteur, Paris, France.
Alexandre
A
Mathieu
Department of Child Psychiatry, Robert Debré Hospital, APHP, Paris, France.
Frederique
F
Amsellem
Human Genetics and Cognitive Functions, Institut Pasteur, Paris, France.|CNRS URA 2182, Institut Pasteur, Paris, France.
Nathalie
N
Lemière
Department of Human Genetics, Robert Debré Hospital, APHP, Paris, France.
Alain
A
Verloes
INSERM U955, Team 15, Faculty of Medicine, Creteil, France.|Department of Adult Psychiatry, Henri Mondor-Albert Chenevier Hospitals AP-HP, Creteil, France.|Fondation FondaMental, French National Science Foundation, Creteil, France.
Marion
M
Leboyer
Gillberg Neuropsychiatry Centre, Gothenburg University, Göteborg, Sweden.|Saint George's Hospital Medical School, London, United Kingdom.
Christopher
C
Gillberg
Human Genetics and Cognitive Functions, Institut Pasteur, Paris, France.|CNRS URA 2182, Institut Pasteur, Paris, France.|Diderot Paris 7, University Paris, Paris, France.
Thomas
T
Bourgeron
Human Genetics and Cognitive Functions, Institut Pasteur, Paris, France.|CNRS URA 2182, Institut Pasteur, Paris, France.|Department of Child Psychiatry, Robert Debré Hospital, APHP, Paris, France.|Fondation FondaMental, French National Science Foundation, Creteil, France.
Richard
R
Delorme
D000328:Adult; D000067877:Autism Spectrum Disorder / Q000235:genetics*; D001921:Brain / Q000002:abnormalities / Q000503:physiopathology; D016022:Case-Control Studies; D002869:Chromosome Aberrations; D002880:Chromosomes, Human, Pair 11; D056915:DNA Copy Number Variations; D005260:Female; D058851:GPI-Linked Proteins / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D054868:Jacobsen Distal 11q Deletion Syndrome / Q000209:etiology / Q000235:genetics; D008279:Magnetic Resonance Imaging; D008297:Male; D058627:Megalencephaly / Q000235:genetics; D009154:Mutation; D019006:Neural Cell Adhesion Molecules / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy
D058851:GPI-Linked Proteins; D019006:Neural Cell Adhesion Molecules; C092530:neurotrimin
Jacobsen syndrome; autism; brain; gene; macrocephaly