Using extended pedigrees to identify novel autism spectrum disorder (ASD) candidate genes

Marc Woodbury-Smith, Andrew D. Paterson, Bhooma Thiruvahindrapduram, Anath C. Lionel, Christian R. Marshall, Daniele Merico, Bridget A. Fernandez, Eric Duku, James S. Sutcliffe, Irene O’Conner, Christina Chrysler, Ann Thompson, Barbara Kellam, Kristiina Tammimies, Susan Walker, Ryan K. C. Yuen, Mohammed Uddin, Jennifer L. Howe, Morgan Parlier, Kathy Whitten, Peter Szatmari, Veronica J. Vieland, Joseph Piven, Stephen W. Scherer

Copy number variation has emerged as an important cause of phenotypic variation, particularly in relation to some complex disorders. Autism spectrum disorder (ASD) is one such disorder, in which evidence is emerging for an etiological role for some rare penetrant de novo and rare inherited copy number variants (CNVs). De novo variation, however, does not always explain the familial nature of ASD, leaving a gap in our knowledge concerning the heritable genetic causes of this disorder. Extended pedigrees, in which several members have ASD, provide an opportunity to investigate inherited genetic risk factors. In this current study, we recruited 19 extended ASD pedigrees, and, using the Illumina HumanOmni2.5 BeadChip, conducted genome-wide CNV interrogation. We found no definitive evidence of an etiological role for segregating CNVs in these pedigrees, and no evidence that linkage signals in these pedigrees are explained by segregating CNVs. However, a small number of putative de novo variants were transmitted from BAP parents to their ASD offspring, and evidence emerged for a rare duplication CNV at 11p13.3 harboring two putative 'developmental/neuropsychiatric' susceptibility gene(s), GSTP1 and NDUFV1.