Advances in ASD Genetics: Creating Hope for Targeted Therapies

Daniel H Geschwind, MD PhD Professor of Neurology, Psychiatry and Human Genetics

UCLA School of Medicine

CART 2016 Symposium

Outline

• Introduction (Genetics and Autism). • What genes have been identified.

• What these genes mean for clinical practice and treatment.

• Disclosures: Dr. Geschwind consults for SynapDx, who are trying to develop biomarkers for ASD.

Evidence that autism has a genetic origin

• Twin Studies

– Twin studies show heritability average of 70%.

• Family studies.

– Risk to sibling ranges from 15-25x population

• Many genetic syndromes or known chromosomal disorders are associated with autism.

– Dozens of rare genetic syndromes or mutations have been identified

Phenotype = genotype + environment

Cognitive Function

Cerebral Structure

Gross Anatomy Microscopic

Molecular Chemical

Development

Genes Environment

Something happens

Autism Spectrum Condition

Levels of convergence in ASD

Genetic Variants Molecular Pathways

Biological Pathways Brain Regions/ Circuits

Approach: Moving from Genes to Pathways to Therapeutics

• Identify Genes.

• Human Patients.

• Mouse models.

• Human post mortem tissue.

• Human neural progenitors – primary neurons.

Therapeutics development

Find Genes

Model in animals

In vitro human models

Post mortem tissue

Geschwind and Konopka Nature 2009

Implications of Knowing Genetic Causes of Disease

• Knowing the genetic basis of the disorder has significant implications for treatment and recurrence risk. – new mutations vs. heritable (environment?) - recurrence risk! – How is it inherited (mendelian)? — counseling.

• Knowing the genetic basis of the disorder has potentially significant implications for prevention. – Gene - environment interactions. – Mechanism of mutation may be preventable. – Early Diagnosis and Intervention!!

Geschwind Cell 2008

Autism in the Individual

Stein et al. Neuron in press

Human Genetics: Terminology

23 pairs of chromosomes

In a particular part of the chromosome 5 there are many genes

Within a gene there are exons, introns, and SNPs (polymorphisms)

Single Nucleotide Polymorphism (SNP)

• If the SNP variant is >1% it is a polymorphism.

• If it is rare, it is more likely to be a mutation.

The human genome is rich in copy number variation (CNVs)

Lupski, NEJM, 2007 Some CNVs cause disease, others are benign

Visible chromosomal abnormalities are not common in ASD, but advances in technology allow detection of submicroscopic

chromosomal structural variants

a human

a human cell

23 pairs of chromosomes

23 from mother

23 from father

If these structural variations are greater than 1kb, they are called Copy Number Variants (CNV). Some are considered normal (we each have dozens), others are pathogenic.

Chromosomes

AU006504 – male, duplication 15q11-q13

A Microarray Nimblegen Oligo Array – 60mer / 6 kb

De Novo CNV Detectable by Microarray

• Sebat et al: 2-3% familial, 10% simplex.

• Marshall et al: 2% familial and 7% simplex.

• Simons consortium (State lab): All simplex.

Large de novo CNV: about 6%

Abrahams and Geschwind 2009

We can find genetic causes in 10-20% of cases currently

We can sequence an entire human genome for $2000.00

2012 Breakthrough: Genome Sequencing in ASD Families

• In 2012, 4 groups published the results of sequencing the coding genomes (exomes) of nearly 1000 patients with autism spectrum disorder. – Several dozen mutations were identified, including several observed

more than once. – However, with a few exceptions, most appear to increase risk for

ASD (about 6x), not cause ASD. – Even the 6 most frequent genes: CHD8, DYRK1A, GRIN2B, TBR1,

PTEN, and TBL1XR1 account < 1% of cases.

• Based on these studies, we estimate > 500 genes contribute to ASD in the population.

• A strong effect of paternal age on mutation rate and ASD is observed.

O’roak et al. 2012 Nature

Increasing Paternal Age is a risk, especially for de novo (new) mutations.

Many forms of genetic variation and modes of inheritance of ASD

22q11-13 del, CHD8, DYRK1A, SCN2A, ARID1B, ANK2, GRIN2B,

SYNGAP1, ADNP, TBR1, POGZ,

KATNAL2….

Smith Lemli Opitz

CNTNAP2… Timothy syndrome,

(del)16p11, (dup)15q11-13

Tuberous Sclerosis,

Fragile X, DMD Common Variation (MET? CNTNAP2?, SEMA5a?)

Genetic testing can currently identify approximately 20% of mutations contributing to ASD:

Clinical Microarray, Fragile X as first line, followed by Whole Exome Sequencing if first line negative

The Challenge

• Advances in genetics and genomics have identified many genes involved in susceptibility for ASD.

• These genes provide targets for mechanistic understanding and therapeutic development.

• However, these findings highlight extreme genetic heterogeneity, even in rare (Mendelian) disorders.

• Will we have to develop a specific treatment for each disorder, or will there be convergence in specific biological pathways, developmental stages/processes or brain circuitry?

When and where do autism genes act?

Developmental Dynamics

Laminar/Circuit Specificity: “Disconnectivity”

Parikshak et al.Cell 2013

Biological Processes for targeting therapy

Animal Models Cell Models Patient Tissue

Multiple Mouse Strains Multiple Mutations

Gene Expression

Peripheral Biomarkers

iPSC Human Neural Progenitors

Gene Expression Target Validation

Brain Peripheral Blood

Gene Expression

Sequencing

System Biology Integration

Identification of Novel Pathways

How do we develop therapeutics?

Implications of Knowing Genetic Causes of Disease

• Knowing the genetic basis of the disorder has significant implications for treatment and recurrence risk. – new mutations vs. heritable (environment?) - recurrence risk! – How is it inherited (mendelian)? — counseling.

• Knowing the genetic basis of the disorder has potentially significant implications for prevention. – Gene - environment interactions. – Mechanism of mutation may be preventable. – Early Diagnosis and Intervention!!

Many valid mouse models • Shank2/3 • TSC1/2 • MECP2 • PTEN • (dup)16p11 • CNTNAP2

KO-OXT KO-Saline

“The recent demonstrations in animal models that certain forms of neurodevelopmental

disorders associated with autism, such as Fragile X, tuberous sclerosis, and Rett syndrome,

can be largely reversed in adulthood represent a paradigm shift in our concept of developmental

disorders. Should these findings generalize to humans, genetically identified

pathway therapeutics would become the most important area of future treatment research

in ASD.”

Geschwind, Annu. Rev. Med. 2009

Convergent pathways

Protein Translation

Wnt signaling Synaptic signaling

“And then my health began to improve, thanks to a pill that targets a specific genetic mutation tied to my cancer. I began to

walk without a cane ….. A tiny drop of hope.”

SundayReview|Opinion How Long Have I Got Left? By PAUL KALANITHIJAN. 24, 2014

The Hope of Genetic Testing in Medicine

“For young people like me — I am 36 — given a diagnosis of cancer, there aren’t many words. “

Summary

• While ASD risk is largely genetic, its etiology is multi-factorial and very heterogeneous (The “Autisms”).

• Rare genetic variants contribute to at least 10% of cases, and may explain more (20%?). Genetic testing is warranted to identify these causes.

• Exome sequencing is a clinical test in ASD. Soon, whole genome sequencing will be a clinical test in ASD.

• Genetics provides a route to development of new therapies.

• Several animal and cell models are being developed based on genetic findings and will be used to develop innovative treatments

Thanks to those who do the work

UCLA Neurogenetics