More on Autism Genetics and Genetic Testing

The January 28th AMED News reviews the recently published studies on the genetics of autism, about deletion and duplication of chromosome 16 in the New England Journal of Medicine and about CNTNAP2 as an autism susceptibility gene in the American Journal of Human Genetics. Speculating about genetic testing that might be developed from these studies, writer Victoria Stagg Elliott notes that

The challenge now facing researchers is to replicate these findings and determine their clinical utility. Genetic testing for this variation is possible and performed at some institutions. Those who conduct the screening say it can help children receive a confirmed autism diagnosis and improve access to educational services. The results also may suggest increased risk in subsequent children and give comfort to parents.

10% of autism cases are caused by genetic syndromes, such as fragile X or Prader-Willi syndromes.

“Mothers wonder, ‘Is there something I did while I was pregnant? What could I have done differently?’ This tells them that there’s nothing that the parent could have done differently, and that’s helpful information just in and of itself[my emphasis]” said David Miller, MD, PhD, assistant director of the Genetics Diagnostic Laboratory at Children’s Hospital Boston, one of the authors of the New England Journal of Medicine paper. He has been testing patients for this deletion or duplication for the past year.

An autism test is being offered by Children’s Hospital of Boston. Other scientists and doctors suggest a more cautious view about the new studies’ findings:

“This study has meaning and significance, but it’s still a tiny, little step forward. This is a very small percentage of kids,” said Patricia Manning-Courtney, MD, director of the Kelly O’Leary Center for Pervasive Developmental Disorders at Cincinnati Children’s Hospital Medical Center. “I’m not sure how we would apply this information clinically or what my next step would be. Everybody wants a biomarker for autism, but we’re already learning that there is not going to be one.

“Some experts question how specific these chromosomal abnormalities are to autism. For example, not all of the children with this genetic variation in the New England Journal of Medicine study had a diagnosis of autism. They were identified as having developmental delay or mental retardation. Some who had a diagnosis of autism also may have had some intellectual disability, although this is not clear from the paper.

“It would be interesting to know more details about the affected patients,” said Scott Myers, MD, a neurodevelopmental pediatrician at the Janet Weis Children’s Hospital in Danville, Pa. “I suspect that the more specific and common phenotypic aspect of 16p11.2 microdeletions or microduplications is intellectual disability. … If the 16p11.2 abnormalities are more specific for the autism phenotype, there should be a substantial number of affected individuals who have autism spectrum disorders without mental retardation.

“Doubt also was expressed because autism is considered an inherited genetic disease, and siblings of affected children tend to have a higher risk of developing it. The studies’ authors said the deletion and duplication of this genetic material is something that, for the most part, is not passed down by either parent and may occur during the formation of the egg or sperm, at conception or very early in fetal development.

But “it’s a pretty big leap to say [autism] is not inherited,” Dr. Manning-Courtney said.

The Children’s Hospital provides some more detail about the individuals in the study (emphases in italics are mine):

The Autism Consortium researchers scanned DNA samples from more than 3,000 children and families, of whom 1,441 were diagnosed with an ASD. Five individuals with ASDs had a chromosome 16 deletion. The deCODE team found the same deletion in three of 299 people. The Children’s researchers, using a high-resolution genomic copy-number variant analysis technique, designed by the hospital’s laboratory team for clinical use, tested close to 1,000 patient samples and found five more instances of the deletion among 512 patients referred for developmental delay and/or suspected ASDs.

In addition, the Children’s team identified four patients with a duplication, rather than a deletion, of the chromosome 16 region, a seeming paradox that is not uncommon in genetics. “Genes may need to be expressed at exactly the right level within particular tissues,” says David Miller, MD, PhD, assistant director of the Genetics Diagnostic Laboratory at Children’s and a coauthor on the paper. “Expressing them at half of the normal amount within the cells, or twice the normal amount, can throw things out of balance within a cell, especially if they’re involved in a complicated network where they’re interacting with other genes.”

The chromosome 16 deletion/duplication accounts for an estimated 1 percent of autism cases, adding to the roughly 15 percent of cases of autism with known genetic causes, says Miller, who is also a clinical geneticist and a member of the Consortium.

In light of the continued, seemingly constant, search to find some “cause” for autism, from lipstick traces to “something in the environment” (I am sure that someone will next identify global warming as a culprit), I’l reiterate Dr. David Miller’s statement: “‘Mothers wonder, ‘Is there something I did while I was pregnant? What could I have done differently?’ This tells them that there’s nothing that the parent could have done differently, and that’s helpful information just in and of itself.’”