title: Reciprocal Relationship between Head Size, an Autism Endophenotype, and Gene Dosage at 19p13.12 Points to AKAP8 and AKAP8L.
abstract: Microcephaly and macrocephaly are overrepresented in individuals with autism and are thought to be disease-related risk factors or endophenotypes. Analysis of DNA microarray results from a family with a low functioning autistic child determined that the proband and two additional unaffected family members who carry a rare inherited 760 kb duplication of unknown clinical significance at 19p13.12 are macrocephalic. Consideration alongside overlapping deletion and duplication events in the literature provides support for a strong relationship between gene dosage at this locus and head size, with losses and gains associated with microcephaly (p=1.11x10(-11)) and macrocephaly (p=2.47x10(-11)), respectively. Data support A kinase anchor protein 8 and 8-like (AKAP8 and AKAP8L) as candidate genes involved in regulation of head growth, an interesting finding given previous work implicating the AKAP gene family in autism. Towards determination of which of AKAP8 and AKAP8L may be involved in the modulation of head size and risk for disease, we analyzed exome sequencing data for 693 autism families (2591 individuals) where head circumference data were available. No predicted loss of function variants were observed, precluding insights into relationship to head size, but highlighting strong evolutionary conservation. Taken together, findings support the idea that gene dosage at 19p13.12, and AKAP8 and/or AKAP8L in particular, play an important role in modulation of head size and may contribute to autism risk. Exome sequencing of the family also identified a rare inherited variant predicted to disrupt splicing of TPTE / PTEN2, a PTEN homologue, which may likewise contribute to both macrocephaly and autism risk.
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Nebel
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, United States of America; Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, United States of America; Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Jill
authors.initials: J
authors.lastname: Kirschen
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Jinlu
authors.initials: J
authors.lastname: Cai
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Young Jae
authors.initials: YJ
authors.lastname: Woo
authors.affiliation: Saul R. Korey Department of Neurology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, United States of America; Epilepsy Management Center, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, United States of America; Department of Pediatrics, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, United States of America.
authors.forename: Koshi
authors.initials: K
authors.lastname: Cherian
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, United States of America; Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Brett S
authors.initials: BS
authors.lastname: Abrahams
mesh_terms: D054758:A Kinase Anchor Proteins / Q000235:genetics*; D001321:Autistic Disorder / Q000150:complications / Q000235:genetics* / Q000473:pathology; D002675:Child, Preschool; D002888:Chromosomes, Human, Pair 19; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D059472:Exome; D018628:Gene Dosage; D020440:Gene Duplication; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D058627:Megalencephaly / Q000150:complications / Q000235:genetics*; D008831:Microcephaly / Q000150:complications / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D010375:Pedigree; D012307:Risk Factors
chemical_list: D054758:A Kinase Anchor Proteins; C485099:AKAP8 protein, human; C490117:AKAP8L protein, human; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins