ACC: Callosal Agenesis as a Window into Common Neurodevelopmental Disorders

Abstract: The corpus callosum – the largest fiber tract in the human brain, connects and integrates the two
cerebral hemispheres. Agenesis of the corpus callosum (ACC) with an incidence of 1 in 2,000 occurs in rare
syndromes and in common neurodevelopmental disorders (NDD) including epilepsy, intellectual disability (ID),
autism spectrum disorder (ASD), cerebral palsy and schizophrenia. Collectively these affect more than 5% of
the population and constitute a major public health concern. Recent evidence including from our team, points
to the importance of genetic etiologies. Our whole exome efforts in this grant’s initial submission identified 70
ACC genes that reached genome-wide significance, of which many of which are strong novel candidate genes
that need further validation. Based on population estimates, we expect that several hundred additional genes
will cause ACC. To discover the full range of ACC genetics and to make progress using model systems, we
bring together an outstanding investigative team that has made significant contributions to the biology of ACC.
Together we will advance gene discovery, and tackle key questions on CC development. To do so we will:
Aim 1: Identify novel de novo genetic causes of ACC and NDD. To do so, we will recruit, obtain clinical
data and conduct WES for 1000+ ACC trios from UCSF and collaborators. We will also receive genetic
information from 2000+ trios from the two largest commercial exome sequencing laboratories in the US,
GeneDx and Invitae. We will also leverage the community’s gene discovery efforts using MatchMaker, and
work with the IRC5 (international research consortium for the corpus callosum and cerebral connectivity:
www.IRC5.org), which the PI’s co-founded. These combined efforts will ensure robust novel gene discovery.
Aim #2: Discover genetic causes of ACC beyond germline de novo coding variants. In addition to gene
discovery above, we hypothesize that many ACC cases are caused by mutations in complex genomic regions.
We will initially focus on Aicardi syndrome, a highly complex yet distinctive brain malformation disorder. We will
conduct short-read deep WGS from affected brain tissue (6 in hand) and other tissues, collaborating with the
Broad Mendelian Genome Center, to perform long-read sequencing to resolve complex genomic architecture
and other difficult to sequence regions. We will also utilize the same work flow to tackle gene discovery in
similarly phenotypically unified conditions in particular focusing on multiplex cases.
Aim #3: Engage in functional confirmation and analysis of ACC candidate genes. During our current
cycle, we have made significant progress studying the biology C12ORF57. In this proposal, we will advance
this directly, by 1. Studying the protein interaction network for C12ORF57 and CAMKIV. We will also study the
signaling pathways that link CAMKIV to the transcription factor CREB and to regulation of AMPA receptors, the
key glutamatergic receptors for excitatory neural transmission. This work may have critical implications for
treatment strategies in epilepsy and possibly disorders of cognition.

Grant Number: 5R01NS058721-16
NIH Institute/Center: NIH
Principal Investigator: Emanuela Argilli