15q Duplication associated with autism in a multiplex family with a familial cryptic translocation t(14;15)(q11.2;q13.3) detected using array-CGH.

Authors: M Koochek, C Harvard, MJ Hildebrand, M Van Allen, H Winger, E Mickelson, JJA Holden, E Rajcan-Separovic, MES Lewis

Published in: Clinical Genetics 69: 124-134, 2006.

Research Summary Prepared By: Dr. Jeanette Holden

Maryam Koochek, a trainee in our ASPIRE training program, (www.AutismTraining.ca) utilized some of the many genetic samples that have been sent to us. A preliminary description of her findings can be found below.

The study’s purpose:

As part of our research into identifying genes associated with susceptibility to ASDs, we carried out a study that involves examining all parts of all chromosomes for small deletions and/or duplications that might help us understand the variable phenotypes (appearances and behaviours) associated with ASDs. If we found the same small changes in the chromosomes in several individuals with autism, then we believe that we will have identified a region of the chromosome that has one or more genes that contribute to autism or that make an individual susceptible to developing autistic behaviours. The method that we used to identify these deletions and duplications is called array-CGH or array based comparative genomic hybridization.

Who participated & what did participation involve?

In this study, we identified a family with a girl and her maternal aunt, both with autism and intellectual disability, who had an abnormal chromosome 14. This was not visible using routine methods for studying the chromosomes – in fact, from regular chromosome studies, it was concluded that both had normal chromosomes. However, when array-CGH was used to study the DNA from the young girl, it was found that she had three copies of a specific region of chromosome 15, near the centromere, and only one copy of a specific region of chromosome 14, also near the centromere. By doing additional special chromosome studies, we were able to show that the top part of one of the chromosome 14s was, in fact, a small part of chromosome 15. Both the girl and her aunt had this abnormal chromosome and thus 3 copies of a region of chromosome 15 that has previously been found to be associated with autism. In the majority of these other cases, the extra dose of this region of chromosome 15 is found on a very tiny extra chromosome, most frequently having two extra doses of the genes in this small region of the chromosome. The girl’s mother and her grandmother both had what is called a translocation – a small part of chromosome 15 was present on one of the chromosome 14’s and a small part of chromosome 14 was present on one of the chromosome 15’s. The mother and grandmother are said to be “carriers of a balanced translocation” – that is, there is nothing extra or missing. However, the girl and her aunt are missing a part of chromosome 14 and have an extra part of chromosome 15.

What our results showed:

This is a very unusual case and, because it would have been impossible to detect using standard chromosome studies, we suggested that studies should be done to determine whether a similar change is present when there is recurrence of autism in siblings or when there are two or more generations with autism in the family, especially when there are clinical features resembling the subjects in our study. These findings include a high forehead and deep-set eyes, down-slanting eyes, and a broad nasal root and bridge.

We sincerely thank you for your participation in this important area of research, and invite you to read the abstract of our study on pubmed.

Maryam Koochek
MSc Candidate
University of British Columbia

Evica Rajcan-Separovic, PhD
Assistant Professor,
Department of Pathology (Cytogenetics),
University of British Columbia

Suzanne Lewis, MD, FRCPC, FCCMG
Clinical Associate Professor
Department of Medical Genetics,
University of British Columbia