Reciprocal relationship between head size, an autism endophenotype, and gene dosage at 19p13.12 points to AKAP8 and AKAP8L

Rebecca A. Nebel, Jill Kirschen, Jinlu Cai, Young Jae Woo, Koshi A. Cherian, Brett S. Abrahams

Research output: Contribution to journalArticle

11 Citations (Scopus)

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,aPTEN homologue, which may likewise contribute to both macrocephaly and autism risk.

Original languageEnglish (US)
Article numbere0129270
JournalPLoS One
Volume10
Issue number6
DOIs
StatePublished - Jun 15 2015

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Endophenotypes
gene dosage
Gene Dosage
Autistic Disorder
Genes
Head
Megalencephaly
Exome
A Kinase Anchor Proteins
Microcephaly
Modulation
head circumference
Microarrays
Conservation
protein kinases
Oligonucleotide Array Sequence Analysis
risk factors
genes
autism
DNA

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Reciprocal relationship between head size, an autism endophenotype, and gene dosage at 19p13.12 points to AKAP8 and AKAP8L. / Nebel, Rebecca A.; Kirschen, Jill; Cai, Jinlu; Woo, Young Jae; Cherian, Koshi A.; Abrahams, Brett S.

In: PLoS One, Vol. 10, No. 6, e0129270, 15.06.2015.

Research output: Contribution to journalArticle

Nebel, Rebecca A. ; Kirschen, Jill ; Cai, Jinlu ; Woo, Young Jae ; Cherian, Koshi A. ; Abrahams, Brett S. / Reciprocal relationship between head size, an autism endophenotype, and gene dosage at 19p13.12 points to AKAP8 and AKAP8L. In: PLoS One. 2015 ; Vol. 10, No. 6.
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