The Increasing Importance of Duplications of Chromosome 15q11.2-q13 in Autism Spectrum Disorders

It is becoming increasingly apparent that segmental aneuploidy for the proximal long arm of chromosome 15 is a major etiologic contributor to autism (AUT) and autism spectrum disorders (ASD).  The region is rich with large, complex low copy repeats (LCR) that facilitate a multitude of different deletions and duplications of typically stereotyped blocks of genomic material.  The first copy number variants (CNV) of this region recognized in ASD were duplications, that primarily take two forms: interstitial duplications [int dup(15)] that lead to segmental trisomy for the involved genomic region and supernumerary isodicentric [idic (15)]chromosomes that lead to tetrasomy or mixed trisomy/tetrasomy.  The critical region for this dup(15) phenotype overlaps the Prader Willi-Angelman Critical region and familial cases of interstitial duplications indicate that maternally derived duplication chromosomes that confer the autism risk.  The dup(15) syndrome phenotype also variable cognitive impairment, hypotonia, subtle dysmorphic features and seizures.  Despite the relative frequency of this diagnosis among the ASD population (1-3%), dup(15) syndrome often goes unrecognized in part because the dysmorphic features are subtle and behavioral/cognitive profile of the syndrome is not well defined.  In 1999, we initiated a study of dup(15) in ASD, applying a combination of molecular and cytogenetic approaches to examine the duplication chromosomes and performing systematic cognitive and behavioral testing on a cohort individuals with confirmed duplications. These studies reveal an extremely high rate of AUT and ASD in this population, although notably, the phenotype is not fully penetrant.  In addition, we find dramatic variation in overall function based on measures of cognition and adaptive behaviors.  There appears to be a dosage effect on phenotype, with higher cognitive scores and adaptive function for individuals with interstitial duplications (trisomy) compared to those tetrasomy and hexasomy.  Importantly, examination of gene expression in brain in two individuals with idic(15) indicated that the level of gene expression did not equate to copy number and in one case, there was an apparent misregulation of paternally expressed genes in association with clinical features reminiscent of Prader Willi syndrome.  In this educational session, I will provide an overview of the molecular and cytogenetics of the dup(15) syndromes, and describe the clinical and behavioral characteristics of syndrome based on a cross-sectional study of 64 cases of individuals with dup(15) syndrome who have undergone systematic assessment of cognition, autism diagnosis, and adaptive function.  I will also briefly describe the recently identified chromosome 15q13.3 deletion syndrome