Abstract
BACKGROUND: Autism spectrum disorders (ASDs) are characterized by social, communication, and behavioral deficits and complex genetic etiology. A recent study of 517 ASD families implicated DOCK4 by single nucleotide polymorphism (SNP) association and a microdeletion in an affected sibling pair. METHODS: The DOCK4 microdeletion on 7q31.1 was further characterized in this family using QuantiSNP analysis of 1M SNP array data and reverse transcription polymerase chain reaction. Extended family members were tested by polymerase chain reaction amplification of junction fragments. DOCK4 dosage was measured in additional samples using SNP arrays. Since QuantiSNP analysis identified a novel CNTNAP5 microdeletion in the same affected sibling pair, this gene was sequenced in 143 additional ASD families. Further polymerase chain reaction-restriction fragment length polymorphism analysis included 380 ASD cases and suitable control subjects. RESULTS: The maternally inherited microdeletion encompassed chr7:110,663,978-111,257,682 and led to a DOCK4-IMMP2L fusion transcript. It was also detected in five extended family members with no ASD. However, six of nine individuals with this microdeletion had poor reading ability, which prompted us to screen 606 other dyslexia cases. This led to the identification of a second DOCK4 microdeletion co-segregating with dyslexia. Assessment of genomic background in the original ASD family detected a paternal 2q14.3 microdeletion disrupting CNTNAP5 that was also transmitted to both affected siblings. Analysis of other ASD cohorts revealed four additional rare missense changes in CNTNAP5. No exonic deletions of DOCK4 or CNTNAP5 were seen in 2091 control subjects. CONCLUSIONS: This study highlights two new risk factors for ASD and dyslexia and demonstrates the importance of performing a high-resolution assessment of genomic background, even after detection of a rare and likely damaging microdeletion using a targeted approach.