8/18/2014

1

Updates on care and research for children with developmental

disabilities and autism

Carlos A. Bacino, M.D.

Dept. of Molecular and Human Genetics

Baylor College of Medicine y

Texas Children’s Hospital

Houston, Texas, USA

Intellectual Disability

• A disability characterized by significant limitations both in intellectual functioning (IQ<70) and in adaptive behavior (everyday social and practical skills).

• Onset before the age of 18

• By definition affects 2% of the general population.

8/18/2014

2

Normal distribution

• The median of any “IQ” test is usually set at 100, and the standard deviation is set at 15

• For a normal distribution, ~95% of the population will fall between two standard deviations of the mean (70-130)

Intellectual Disability

• Characterized by below-average intelligence or mental ability

• Lack of skills necessary for day-to-day living • People with intellectual disabilities can and do learn new

skills, but they learn them more slowly Limitations in: • Intellectual functioning. Also known as IQ, this refers to a

person’s ability to learn, reason, make decisions, and solve problems.

• Adaptive behaviors. These are skills necessary for day-to-day life, such as being able to communicate effectively, interact with others, and take care of oneself.

8/18/2014

3

Causes of Developmental Disabilities

Chromosome problems: Down syndrome, VCFS, Williams syndrome, etc.

Cerebral palsy

Rare genetic problems: Fragile X syndrome, Angelman syndrome, Prader-Willi syndrome, etc.

Prenatal exposures, infections

Metabolic diseases

Unknown causes in 50% of cases

Identifiable genetic causes of ID

25% chromosomal aberrations 25% monogenic causes

~ 45% unknown

<5% teratogenic exposures

<5%perinatal complications

8/18/2014

4

Most common genetic causes of ID

• #1: Trisomy 21 (Down Syndrome), 1:650

• #2: Fragile X syndrome, 1:4000 (males), 1:8000 (females)

• #3: Rett syndrome, 1:8500 (females)

Clinical Description of Autism Spectrum

Disorders (ASDs)

First described by

Leo Kanner (1943); Hans Asperger (1944

Characterized by:

– Impairments in social interaction and communication

–Restricted, stereotyped patterns of behavior and

interests

–Moderate to severe language delay

–Onset before 3 years of age

Comorbid conditions:

Intellectual disabilities (25-70%); epilepsy (5–38%),

anxiety (11-85%)

8/18/2014

5

Autism spectrum disorders (ASD)

• ASD is estimated to affect 8.6–9.3 per 1,000 children (up to

8 years of age)

• CDC’s calculations: Of 4 million children born in the United

States each year, approximately 36,500 will eventually be

diagnosed with ASD. We can estimate that about 730,000

individuals between the ages of 0 to 21 have an ASD.

(MMWR, 2009 & http://www.cdc.gov)

No.

of A

SD

/1,0

00 c

hild

ren

ASD has a strong genetic basis

• Male predominance (M:F = 4-5:1)

• Concordance rate up to 96% in monozygotic twins

(9% in dizygotic twins)

• 10-15% of autism cases have an identifiable genetic condition or chromosomal problem

• Recurrence: 4% for girls, 7% boys (one affected), 25-50% if a second child is affected.

8/18/2014

6

Signs for Autism

• No words by age 2

• Poor eye contact

• No response to name being called

• Not playing with toys in the correct way

• Repetitive motor behaviors (hand flapping, spinning)

• Loss of any skills before age 3

Autism

Childhood Disintegrative Disorder

Asperger's Syndrome PDD-NOS

Autism Spectrum Disorder

8/18/2014

7

AUTISM VERY DIFFERENT GROUPS

• Syndromic, dysmorphic

• Higher fraction MR

• Genetic clinic series

• 25-30% findable mutations

• Male:female = ~2:1

• Essential, idiopathic, nondysmorphic

• Higher functioning

• +/- 10 % findable mutations

• Male:female = ~8:1

Syndromic Autism

Rett syndrome MECP2

16p11.2 del KCTD13

Angelman syndrome UBE3A

FraX syndrome FMR1

PTEN assoc. disorders PTEN

Tuberous sclerosis TSC1, TSC2

8/18/2014

8

Autism and Genetic Disorders

• Autism has been described in association with a number of genetic conditions including: – Rett syndrome, tuberous sclerosis, Angelman

Syndrome, Prader-Willi Syndrome, Down Syndrome, Fragile X syndrome, and 22q deletion syndromes.

How can a genetics doctor help you and your child? Questions:

• What is the diagnosis?

• What is the cause?

• What is going to happen in the future?

• What is the treatment?

8/18/2014

9

Normal Male Chromosomes

8/18/2014

10

Normal Female Chromosomes

47,XY,+21 Down Syndrome

8/18/2014

11

New testing

Called chromosome microarray

Can see much smaller chromosome or gene changes

Example

46,XY,der(14;21)(q10;q10),+21 Chromosome 21-specific plot

8/18/2014

12

Diagnosis and Counseling

If a diagnosis is made:

give information about the condition

possible medical complications

design a treatment plan

Offer counseling about chance for condition to occur in future children

Diagnosis and Counseling

Discuss reproductive options

Provide information about care before becoming pregnant: – take folic acid

– keep good control of diabetes

– stop drinking alcohol and smoking

Help with family support and coping

8/18/2014

13

Clinical Evaluations for Intellectual Disability & Autism

ADOS-G and ADI-R

Clinical evaluation for known syndromes

Special attention to facial features

Woods lamp evaluation (UV light)

Brain imaging studies: MRI and MR Spectroscopy

Laboratory Testing for ID & Autism

Chromosome microarray testing (array CGH) Urine organic acids Urine MPS Lactic acid Plasma aminoacids Acyl-carnitine profile Fragile-X testing in males DNA testing for PTEN mutations if macrocephaly

present (3-4 SD above the mean) MECP2 sequencing in females

PMID: 18414214 - Clinical genetics evaluation in identifying the etiology of autism spectrum disorders. Genetics in Medicine. 2008 Apr 10(4):301-5.

8/18/2014

14

Fragile X syndrome

• Intellectual disability mild to profound; autistic-like w/hand-flapping; repetitive, explosive, stuttering, stammering speech; seizures

• Develop large testes after puberty or by adulthood

• Mild connective tissue dysplasia - joint laxity

Fragile X syndrome

Other: large head size, large jaw, long face, large ears, pale blue irises of eyes, mitral prolapse in heart (valve in the heart)

Trinucleotide expansion disease

(expansion of genetic instruction) that causes gene non functional

- Diagnosis = Fragile X DNA testing

8/18/2014

15

Autism present in 15-30 % of patients with FraX

Classic Rett Syndrome

Normal development until 6-18 months, when child begins to regress:

-Head growth slows -Language skills disappear -Stereotypic movements

replace purposeful hand use -Autistic features appear, lose

ability to walk, seizures, breathing pattern not regular

8/18/2014

16

MeCP2 Region Duplications

• Changes in the MECP2 gene cause classic Rett Syndrome and can cause intellectual disabilities, autistic spectrum disorders

• Infantile hypotonia (low muscle tone)

• Significant speech/language delays

• Some also have seizures, autistic features, and progressive loss of walking ability

Deletions of 22q13.3

• Phelan-McDermid syndrome

• More than 50% of patients show autism or autistic-like behavior, and therefore it can be classified as a syndromic form of autism spectrum disorders

• Involving SHANK3

8/18/2014

17

Hypotonic facies, long smooth philtrum, nail dysplasia

SHANK3 and Autism

SHANK3 regulates the structural organization of dendritic spines and is a binding partner of neuroligins; genes encoding neuroligins are mutated in autism and Asperger syndrome

8/18/2014

18

GAIN on 15q11.2q13.1 and autism

• Nonspecific facial dysmorphic features

• Variable degree of language delay and developmental delay

• Autism-spectrum behavioral abnormalities

Patients with

7q11.23 dup

involving the

Williams syndrome

critical region

8/18/2014

19

An example – 16p11.2 deletions and duplications

One of the most common “copy number variants” associated to autism spectrum disorders

A deletion or duplication in 16p11.2 is identified in 1-2% of all patients with ASD

Can be “syndromic ASD”, but often “non-syndromic”

One mutation – multiple disorders

Autism ADHD

Bipolar

alcoholism

depression, suicide

alcoholism

ADHD

8/18/2014

20

Tuberous Sclerosis Complex

• Autosomal Dominant

• 1/6000 individuals

• 30% inherited

• 70% sporadic

• Marked Clinical Variability

TSC1 Hamartin

TSC2 Tuberin

Van Slegtenhorst M De Hoogt R, et al. Science 1997; 277:805-8

European Chromosome 16 Tuberous sclerosis Consortium. Cell 1993;75:1305-15

Tuberous sclerosis: Skin

• Achromic lesions

8/18/2014

21

Whole Exome Sequencing Testing

• There are ~ 22.000 genes in the genome

• There are a total of 180.000 exons in the human genome

• This allows detection of hundreds of mutations all at once

8/18/2014

22

What is an exome?

• Exons are the short, functionally important sequences of DNA which represent the regions in genes that are translated into protein

• The exome is 1.5-2 % of the whole genome, but makes up the part of the genome we best understand

8/18/2014 W H O L E E X O M E S E Q U E N C I N G 43

What is Whole Exome Sequencing (WES)?

• Test that “captures” or selects the coding regions or exons throughout the whole genome to then be sequenced nucleotide by nucleotide to a depth of coverage necessary to build a consensus sequence with high accuracy.

• This consensus sequence is then compared to standards and references of what is normal in the population

• Once identified through WES variations in an individual's DNA sequence can be related back to the individual's medical concerns in an effort to diagnose the cause of the medical disorder.

8/18/2014 W H O L E E X O M E S E Q U E N C I N G 44

8/18/2014

23

Goal of Clinical WES

• Obtaining a diagnostic result

• Improve preventive care through identification of medically actionable result

• Probable cost-effectiveness

8/18/2014 W H O L E E X O M E S E Q U E N C I N G 45

Exome Sequencing Studies in Autism

Potential Genes in Autism

• CHD8

• NTNG1

• KATNAL2

• GRIN2B

• LAMC3

• SCN1A

• SCN2A

Known Genes in Autism

• PTEN

• SHANK3

• MECP2

• NRXN1

• CNTNAP2

8/18/2014

24

Conclusions • Now able to find many more causes of developmental

disorders and autism with new chromosome microarray and metabolic studies

• Chromosome abnormalities are very common in developmental delay and autism (up to 1 in 100 liveborn babies)

• Technology continues to advance, what is next? Whole Exome Sequencing and Whole Genome Sequencing

• Discovery of genes, pathways involved in diseases is leading the way to new treatments

Back to the patients Why is it even worth knowing?

“Get an answer”

Chance of recurrence for future pregnancies

Find support groups – individuals with same genetic variant

Anticipatory guidance

Change medical follow-up and screening

Therapies and research

8/18/2014

25

Web Resources

• Genetic & Rare Diseases Information Center http://rarediseases.info.nih.gov/GARD

• Genetic Alliance: www.geneticalliance.org

• Texas Department of State Health Services: http://www.dshs.state.tx.us/genetics/pedi-genetics.shtm

• Chromosome Disorder Outreach: www.chromodisorder.org

• Unique http://www.rarechromo.org

Thank you

• This webinar has been possible thanks to Title V Funding from the Texas Department of State Health Services.

• Thank you to Rachel Moyer-Trimyer with DARS for facilitating this webinar.