Cytogenetic Array Testing Reveals Genome-Wide Abnormalities in Children With Autism

Oligonucleotide microarray analysis reveals a higher yield of abnormalities in children with autism than previously seen with other techniques.

LOUISVILLE—Microarray analysis and testing for fragile X syndrome revealed genetic abnormalities in 10% of children with autism, according to research presented at the 38th National Meeting of the Child Neurology Society. Christa Lese Martin, PhD, and colleagues studied 93 children (79 males) with autism spectrum disorders (ASD) between ages 2 and 7 who were enrolled in an ongoing, comprehensive project aimed at finding meaningful subtypes of autism.

The children underwent a panel of genetic testing, including high-resolution karyotype and fluorescence in situ hybridization (FISH) for 15q, fragile X testing, and array comparative genomic hybridization using the EmArray Cyto array, a custom array of 44,000 oligos designed by Emory Genetics Laboratory in Atlanta, to detect copy number imbalances across the genome.

“Our study demonstrates that clinical microarray—ie, cytogenetic array—testing to look for genome-wide deletions or duplications and fragile X testing is strongly indicated in individuals with ASD,” Dr. Martin, Associate Professor of Human Genetics, Emory University School of Medicine in Atlanta, told Neurology Reviews. “The combination of these two tests identifies a cause for ASD in approximately 10% of individuals. The identification of a cause for ASD not only provides a clinical diagnosis, but also provides the opportunity for accurate genetic counseling for the families.”

New ASD Loci Identified
The pathogenic abnormalities identified included fragile X syndrome, a 17p deletion of the Smith-Magenis region, an unbalanced translocation resulting in duplication of 2p and deletion of 9p, and 16p11.2 duplication syndrome. The children with imbalances had similar cognitive and behavioral profiles as the remainder of the sample and had no obvious clues suggesting any underlying genetic abnormalities, the investigators noted.

“Karyotype alone is not sensitive, and multiple FISH probes would be needed to identify the most common autism loci, greatly increasing cost while still missing the important opportunity to examine the rest of the genome,” reported Dr. Martin’s group. “Our results also demonstrate that genome-wide microarray technology has increased yield and provides more cost-effective testing.”

In addition, four subjects had fragile X mutations; one was a full mutation, one was a premutation, and two were grey zone mutations. “Full mutation fragile X is a relatively rare finding in autism samples,” the researchers noted. “But premutation and grey zone mutations are more common than would be expected in a general population sample.”

Array Analysis in Diagnosing ASD
“Cytogenetic array analysis and fragile X testing are currently offered in many clinical genetic laboratories and should be offered as part of the diagnostic workup in the evaluation of ASD,” asserted Dr. Martin, who co-leads the array services at Emory Genetics Laboratory. “In addition, since all of the cases examined in our study had normal G-banded chromosome analysis, but several clinically significant abnormalities were identified by array analysis, these data provide further support that the array should be used as the first-line cytogenetic test since this analysis can identify imbalances that are below the resolution of a routine karyotype.

“The yield of cytogenetic array testing in individuals with ASD is quite high—8% to 10% has now been reported from various studies,” she added. “This information is invaluable to families to alleviate their search for a cause in their children and counsel them appropriately on recurrence risks in their family.”

Oligonucleotide microarray analysis reveals a higher yield of abnormalities in children with autism than previously seen with other techniques.

LOUISVILLE—Microarray analysis and testing for fragile X syndrome revealed genetic abnormalities in 10% of children with autism, according to research presented at the 38th National Meeting of the Child Neurology Society. Christa Lese Martin, PhD, and colleagues studied 93 children (79 males) with autism spectrum disorders (ASD) between ages 2 and 7 who were enrolled in an ongoing, comprehensive project aimed at finding meaningful subtypes of autism.

The children underwent a panel of genetic testing, including high-resolution karyotype and fluorescence in situ hybridization (FISH) for 15q, fragile X testing, and array comparative genomic hybridization using the EmArray Cyto array, a custom array of 44,000 oligos designed by Emory Genetics Laboratory in Atlanta, to detect copy number imbalances across the genome.

“Our study demonstrates that clinical microarray—ie, cytogenetic array—testing to look for genome-wide deletions or duplications and fragile X testing is strongly indicated in individuals with ASD,” Dr. Martin, Associate Professor of Human Genetics, Emory University School of Medicine in Atlanta, told Neurology Reviews. “The combination of these two tests identifies a cause for ASD in approximately 10% of individuals. The identification of a cause for ASD not only provides a clinical diagnosis, but also provides the opportunity for accurate genetic counseling for the families.”

New ASD Loci Identified
The pathogenic abnormalities identified included fragile X syndrome, a 17p deletion of the Smith-Magenis region, an unbalanced translocation resulting in duplication of 2p and deletion of 9p, and 16p11.2 duplication syndrome. The children with imbalances had similar cognitive and behavioral profiles as the remainder of the sample and had no obvious clues suggesting any underlying genetic abnormalities, the investigators noted.

“Karyotype alone is not sensitive, and multiple FISH probes would be needed to identify the most common autism loci, greatly increasing cost while still missing the important opportunity to examine the rest of the genome,” reported Dr. Martin’s group. “Our results also demonstrate that genome-wide microarray technology has increased yield and provides more cost-effective testing.”

In addition, four subjects had fragile X mutations; one was a full mutation, one was a premutation, and two were grey zone mutations. “Full mutation fragile X is a relatively rare finding in autism samples,” the researchers noted. “But premutation and grey zone mutations are more common than would be expected in a general population sample.”

Array Analysis in Diagnosing ASD
“Cytogenetic array analysis and fragile X testing are currently offered in many clinical genetic laboratories and should be offered as part of the diagnostic workup in the evaluation of ASD,” asserted Dr. Martin, who co-leads the array services at Emory Genetics Laboratory. “In addition, since all of the cases examined in our study had normal G-banded chromosome analysis, but several clinically significant abnormalities were identified by array analysis, these data provide further support that the array should be used as the first-line cytogenetic test since this analysis can identify imbalances that are below the resolution of a routine karyotype.

“The yield of cytogenetic array testing in individuals with ASD is quite high—8% to 10% has now been reported from various studies,” she added. “This information is invaluable to families to alleviate their search for a cause in their children and counsel them appropriately on recurrence risks in their family.”

Oligonucleotide microarray analysis reveals a higher yield of abnormalities in children with autism than previously seen with other techniques.

LOUISVILLE—Microarray analysis and testing for fragile X syndrome revealed genetic abnormalities in 10% of children with autism, according to research presented at the 38th National Meeting of the Child Neurology Society. Christa Lese Martin, PhD, and colleagues studied 93 children (79 males) with autism spectrum disorders (ASD) between ages 2 and 7 who were enrolled in an ongoing, comprehensive project aimed at finding meaningful subtypes of autism.

The children underwent a panel of genetic testing, including high-resolution karyotype and fluorescence in situ hybridization (FISH) for 15q, fragile X testing, and array comparative genomic hybridization using the EmArray Cyto array, a custom array of 44,000 oligos designed by Emory Genetics Laboratory in Atlanta, to detect copy number imbalances across the genome.

“Our study demonstrates that clinical microarray—ie, cytogenetic array—testing to look for genome-wide deletions or duplications and fragile X testing is strongly indicated in individuals with ASD,” Dr. Martin, Associate Professor of Human Genetics, Emory University School of Medicine in Atlanta, told Neurology Reviews. “The combination of these two tests identifies a cause for ASD in approximately 10% of individuals. The identification of a cause for ASD not only provides a clinical diagnosis, but also provides the opportunity for accurate genetic counseling for the families.”

New ASD Loci Identified
The pathogenic abnormalities identified included fragile X syndrome, a 17p deletion of the Smith-Magenis region, an unbalanced translocation resulting in duplication of 2p and deletion of 9p, and 16p11.2 duplication syndrome. The children with imbalances had similar cognitive and behavioral profiles as the remainder of the sample and had no obvious clues suggesting any underlying genetic abnormalities, the investigators noted.

“Karyotype alone is not sensitive, and multiple FISH probes would be needed to identify the most common autism loci, greatly increasing cost while still missing the important opportunity to examine the rest of the genome,” reported Dr. Martin’s group. “Our results also demonstrate that genome-wide microarray technology has increased yield and provides more cost-effective testing.”

In addition, four subjects had fragile X mutations; one was a full mutation, one was a premutation, and two were grey zone mutations. “Full mutation fragile X is a relatively rare finding in autism samples,” the researchers noted. “But premutation and grey zone mutations are more common than would be expected in a general population sample.”

Array Analysis in Diagnosing ASD
“Cytogenetic array analysis and fragile X testing are currently offered in many clinical genetic laboratories and should be offered as part of the diagnostic workup in the evaluation of ASD,” asserted Dr. Martin, who co-leads the array services at Emory Genetics Laboratory. “In addition, since all of the cases examined in our study had normal G-banded chromosome analysis, but several clinically significant abnormalities were identified by array analysis, these data provide further support that the array should be used as the first-line cytogenetic test since this analysis can identify imbalances that are below the resolution of a routine karyotype.

“The yield of cytogenetic array testing in individuals with ASD is quite high—8% to 10% has now been reported from various studies,” she added. “This information is invaluable to families to alleviate their search for a cause in their children and counsel them appropriately on recurrence risks in their family.”