TY - JOUR
T1 - A large-scale survey of the novel 15q24 microdeletion syndrome in autism spectrum disorders identifies an atypical deletion that narrows the critical region
AU - McInnes, L.
AU - Nakamine, Alisa
AU - Pilorge, Marion
AU - Brandt, Tracy
AU - Jiménez González, Patricia
AU - Fallas, Marietha
AU - Manghi, Elina
AU - Edelmann, Lisa
AU - Glessner, Joseph
AU - Hakonarson, Hakon
AU - Betancur, Catalina
AU - Buxbaum, Joseph
N1 - Funding Information:
This work was supported by NINDS (LAM, grant R01 043540), the Seaver Foundation (LAM and JDB) and a grant from the General Clinical Research Center at the Mount Sinai School of Medicine, and by the Seed Grant Program of The Charles R. Bronfman Institute for Personalized Medicine. The microarray work and analysis of the Costa Rican sample were supported by grant U24 NS 052108. We thank Safiana Katz for her careful processing of immortalized cell lines. We also thank Dr. Rafael Jimenez from the Bioethical Board and Dr. Abdon Castro, president of the Fundación Pro Hospital Nacional de Niños Dr. Carlos Sáenz Herrera. Above all, we are grateful to the family of patient AU008, and all the other families who have participated in our study, to the Autism Parents’ Association of San José, Costa Rica and to the families contributing to and supporting AGRE. We also appreciate the help of Dr. Nagahide Takahashi with qPCR experiments and Ana Tryfon and Lauren Pepa with accessing clinical data. Written consent for publication was obtained from the parents of patient AU008.
PY - 2010
Y1 - 2010
N2 - Background. The 15q24 microdeletion syndrome has been recently described as a recurrent, submicroscopic genomic imbalance found in individuals with intellectual disability, typical facial appearance, hypotonia, and digital and genital abnormalities. Gene dosage abnormalities, including copy number variations (CNVs), have been identified in a significant fraction of individuals with autism spectrum disorders (ASDs). In this study we surveyed two ASD cohorts for 15q24 abnormalities to assess the frequency of genomic imbalances in this interval. Methods. We screened 173 unrelated subjects with ASD from the Central Valley of Costa Rica and 1336 subjects with ASD from 785 independent families registered with the Autism Genetic Resource Exchange (AGRE) for CNVs across 15q24 using oligonucleotide arrays. Rearrangements were confirmed by array comparative genomic hybridization and quantitative PCR. Results. Among the patients from Costa Rica, an atypical de novo deletion of 3.06 Mb in 15q23-q24.1 was detected in a boy with autism sharing many features with the other 13 subjects with the 15q24 microdeletion syndrome described to date. He exhibited intellectual disability, constant smiling, characteristic facial features (high anterior hairline, broad medial eyebrows, epicanthal folds, hypertelorism, full lower lip and protuberant, posteriorly rotated ears), single palmar crease, toe syndactyly and congenital nystagmus. The deletion breakpoints are atypical and lie outside previously characterized low copy repeats (69,838-72,897 Mb). Genotyping data revealed that the deletion had occurred in the paternal chromosome. Among the AGRE families, no large 15q24 deletions were observed. Conclusions. From the current and previous studies, deletions in the 15q24 region represent rare causes of ASDs with an estimated frequency of 0.1 to 0.2% in individuals ascertained for ASDs, although the proportion might be higher in sporadic cases. These rates compare with a frequency of about 0.3% in patients ascertained for unexplained intellectual disability and congenital anomalies. This atypical deletion reduces the minimal interval for the syndrome from 1.75 Mb to 766 kb, implicating a reduced number of genes (15 versus 38). Sequencing of genes in the 15q24 interval in large ASD and intellectual disability samples may identify mutations of etiologic importance in the development of these disorders.
AB - Background. The 15q24 microdeletion syndrome has been recently described as a recurrent, submicroscopic genomic imbalance found in individuals with intellectual disability, typical facial appearance, hypotonia, and digital and genital abnormalities. Gene dosage abnormalities, including copy number variations (CNVs), have been identified in a significant fraction of individuals with autism spectrum disorders (ASDs). In this study we surveyed two ASD cohorts for 15q24 abnormalities to assess the frequency of genomic imbalances in this interval. Methods. We screened 173 unrelated subjects with ASD from the Central Valley of Costa Rica and 1336 subjects with ASD from 785 independent families registered with the Autism Genetic Resource Exchange (AGRE) for CNVs across 15q24 using oligonucleotide arrays. Rearrangements were confirmed by array comparative genomic hybridization and quantitative PCR. Results. Among the patients from Costa Rica, an atypical de novo deletion of 3.06 Mb in 15q23-q24.1 was detected in a boy with autism sharing many features with the other 13 subjects with the 15q24 microdeletion syndrome described to date. He exhibited intellectual disability, constant smiling, characteristic facial features (high anterior hairline, broad medial eyebrows, epicanthal folds, hypertelorism, full lower lip and protuberant, posteriorly rotated ears), single palmar crease, toe syndactyly and congenital nystagmus. The deletion breakpoints are atypical and lie outside previously characterized low copy repeats (69,838-72,897 Mb). Genotyping data revealed that the deletion had occurred in the paternal chromosome. Among the AGRE families, no large 15q24 deletions were observed. Conclusions. From the current and previous studies, deletions in the 15q24 region represent rare causes of ASDs with an estimated frequency of 0.1 to 0.2% in individuals ascertained for ASDs, although the proportion might be higher in sporadic cases. These rates compare with a frequency of about 0.3% in patients ascertained for unexplained intellectual disability and congenital anomalies. This atypical deletion reduces the minimal interval for the syndrome from 1.75 Mb to 766 kb, implicating a reduced number of genes (15 versus 38). Sequencing of genes in the 15q24 interval in large ASD and intellectual disability samples may identify mutations of etiologic importance in the development of these disorders.
UR - http://www.scopus.com/inward/record.url?scp=77956367695&partnerID=8YFLogxK
U2 - 10.1186/2040-2392-1-5
DO - 10.1186/2040-2392-1-5
M3 - Article
AN - SCOPUS:77956367695
SN - 2040-2392
VL - 1
JO - Molecular Autism
JF - Molecular Autism
IS - 1
M1 - 5
ER -