Autism and Developmental Delay
Developed by Dr. Judith Allanson, Ms. Shawna Morrison and Dr. June Carroll
Last updated Nov 2014
Disclaimer
• This presentation is for educational purposes only and should
not be used as a substitute for clinical judgement. GEC-KO
aims to aid the practicing clinician by providing informed
opinions regarding genetic services that have been developed
in a rigorous and evidence-based manner. Physicians must use
their own clinical judgement in addition to published articles
and the information presented herein. GEC-KO assumes no
responsibility or liability resulting from the use of information
contained herein.
Objectives
• Following this session the learner will be able to:
– Refer to their local genetics centre and/or order genetic
testing appropriately for autism/developmental delay
(ASD/DD)
– Set appropriate expectations for a family referred for
genetic consultation regarding a child with ASD/DD
– Discuss the pros and cons of first tier genetic testing for
ASD/DD
– Find high quality genomics educational resources
appropriate for primary care
Case
You have known the Spencer family for several years. They have
a 4 year old daughter, Alice, who is healthy and very bright. Their
son, Aidan, was born 2 years ago. He has normal stature and a
slightly large head. During his first year, his parents noticed that,
compared to his sister, he was floppy, with more balance and
coordination difficulties; he did not establish a sleep pattern well
and had lots of early morning wakening. He is a very busy boy
and seems hypersensitive to noise. They are most concerned
about delayed language acquisition that is becoming more
obvious as time passes.
Family history
Carl
A&W
Benjamin
A&W
Cathy
A&W
Barb
A&W
Beverly
A&W
4
The Spencers, their siblings
and parents are all healthy.
Alice
A&W
Cameron
A&W
Coral
A&W
Brett
A&W
Brenda
A&W
2
Aidan
• Floppy
• Balance & coordination difficulties
• Difficulty establishing sleep pattern
• Hypersensitive to noise
• Language delay
What do I need to know about the genetics
of autism spectrum disorder (ASD)?
• ASDs are considered genetically-influenced neurodevelopmental disorders with evidence pointing to
dysfunction at the level of the synapse
• There is extensive genetic heterogeneity and perhaps
hundreds of genetic variants involved
• A specific genetic etiology can be found in about 15%
of individuals with a diagnosis of ASD
Identifying genetic causes of autism
Test
Pick up rate
Chromosomal microarray (CMA)*
~10-20% of children with ASD will be found
to have a chromosomal micro-deletion or
micro-duplication (Copy Number Variant
[CNV])
Fragile X syndrome testing [FMR1 gene testing]
20% of boys with FXS meet the diagnostic criteria
for autism
1-6%
Other rarer single gene conditions [testing a
specific gene] or chromosome differences that
may be seen on karyotype
5%
Metabolic
<1%
• Newer genetic testing modalities may increase yield to 30-40%
Chromosomal Microarray (CMA)
•
CMA is a technology used to determine if there are small extra (micro-duplication)
or missing (micro-deletion) pieces of genetic information. These gains and losses
are called copy number variants (CNVs). A CNV can be: of no medical
consequence; pathogenic, resulting in physical and/or intellectual consequences;
or protective against disease (e.g. HIV infection).
Reference DNA from control
labeled Red
Test DNA from patient
labeled Green
Denature the DNA (separate the strands) and Hybridize to slide
Areas of loss (deletion)
Glass microarray slide
Computer scans and
analyzes signal outputs
Area of gain (duplication)
Who should be offered genetic testing?
• Any child with autistic features should first be assessed by a
general or developmental pediatrician, and specialized autism
testing used to provide a definitive diagnosis
– Examples: Autism Diagnostic Observation Schedule [ADOS], Autism
Diagnostic Interview [ADI]
• If autism is confirmed, a genetics referral should be offered
• The genetics assessment will look for unusual physical
features that might point to a syndrome or specific single
gene disorder. These are most commonly found when the
patient has “autism-plus” or complex ASD, with overgrowth,
very large head, seizure disorder, muscle weakness or ataxia,
cognitive regression, pigmentary abnormalities, or multiple
congenital anomalies (25%)
Who should be offered genetic testing?
• Initial work up:
Metabolic evaluation might include a
– 3 generation family history
blood features
count, ammonia,
– Examination with special attentioncomplete
to dysmorphic
serum amino acids, urine organic acids
– Consider pediatric or genetic referral
and mucopolysaccharide testing.
• First tier genetic testing:
Specialist advice might be needed
– Chromosomal Microarray (CMA) to look for Copy Number Variants
– Fragile X gene analysis
– If evidence of regression, consider metabolic* workup
• Second tier genetic testing if first tier uninformative:
– Genetic testing for specific single gene conditions
– Possibly brain imaging
What sorts of chromosomal microarray
results might I receive?
• Normal
– Excludes a micro-deletion/micro-duplication (CNV) within the limits of
resolution of the test (typically very high)
• Cannot completely rule out a CNV in all areas of the genome
• Cannot exclude a syndrome caused by a mutation within a single gene
• Cannot detect balanced chromosome differences
• Pathogenic micro-deletion or micro-duplication (CNV)
– CNV previously described and associated with a known phenotype, autism or
other
• Variation of unclear clinical significance (VUS)
– Not every CNV in the genome is pathogenic
– A variant that has not been described in the literature is challenging to
interpret and benefits from knowledge of parental status
– Parental samples should be obtained and analysed
– Next steps*before a referral to the Genetics clinic is initiated
CNV – Copy Number Variant
VUS identified in
child  Test
parents
Both parents
have normal
CMA results
• Finding in child is
new, de novo
• Likely pathogenic
One parent
has same CMA
result as child
• Finding in the
child is normal
familial variant
• Not pathogenic
• Finding in the child is pathogenic,
but parent displays reduced
penetrance (not everyone with
the CNV will have symptoms),
variable expressivity (individuals
with this CNV have varied
presentation)
• A second predisposing factor is
needed to cause problems
What do these results mean for the recurrence
risk of autism spectrum disorder (ASD)?
• If no genetic cause is identified
– Empirical studies suggest sibling recurrence risk (RR) is 10-18%
• If the sex of the next child is male his risk will be on the higher end
– If two siblings in one family are affected RR is 25-35%
• If a de novo pathogenic mutation/CNV is found
– RR is 1% to account for rare gonadal mosaicism
• When a ASD ‘risk variant’ with incomplete penetrance and/or
variable expressivity is identified on CMA
– If de novo, RR of the CNV itself is <1%, but the empirical RR for ASD is
more difficult to predict. Empirical risks similar to simplex families
– If inherited from a normal parent, RR is very difficult to decide as CNV
may not be the sole cause for the child’s ASD, however the CNV
increases the ASD risk by indeterminate amount
CMA – Chromosomal Microarray
CNV – Copy Number Variant
How do I order the genetic test?
• Genetic testing is generally performed on a blood sample
• Specifics will depend on your region
– Details can be found at www.geneticseducation.ca
How will genetic testing help you and your
patient?
• A specific diagnosis allows:
– Better understanding of etiology, natural history and
prognosis
– Informed treatment decisions
– Specific anticipatory guidelines
– Accurate recurrence risk information
• de novo pathogenic CNV versus ASD risk variant
• Single gene disorder: disorder-specific risk depending on mode of
inheritance and whether de novo or not
– Prenatal diagnosis
CNV – Copy Number Variant
Are there harms or limitations of genetic
testing?
• Potential harms
– Insurance discrimination
• Genetic testing may affect an individual’s ability to obtain life, disability, critical
illness, long-term care and/or extended health insurance if the test reveals a
predisposition to other medical issues, e.g. increased cancer risk
– CNVs may be identified that are unrelated to the health/developmental
problems in the child, but could possibly cause other health problems in the
future
– CMA is unable to detect single gene disorders (e.g. Fragile X) or balanced
chromosome rearrangements, such as a translocation
– Normal result does not rule out the possibility of a genetic cause for an
individual’s health and/or developmental concerns
– Non-paternity could be disclosed
CMA – Chromosomal Microarray
CNV – Copy Number Variant
67
Carl
A&W
Cathy
A&W
Cameron
A&W
42
44
Benjamin
A&W
10
56
64
10
Barb
Menopause
at age 38
34
Beverly
A&W
Adam
Developmental
delay
Alice
A&W
Coral
A&W
26
Brenda
A&W
Brett
A&W
4
14
36
55
2
• First tier genetic testing
• CMA = Negative
• Fragile X testing =
Positive
• Refer to genetics (if not
already done)
• Consider carrier testing
for family members- can
have health and
reproductive
implications
Aidan
• Floppy
• Balance & coordination difficulties
• Difficulty establishing sleep pattern
• Hypersensitive to noise
• Language delay
Key points
• If autism is suspected
– refer for definitive diagnosis
• When autism or ASD is confirmed
– Initial investigations (family history, examination, referral)
– Refer to pediatrics or arrange first tier testing
– Refer to genetics for dysmorphology examination and further testing
• Pearls:
– The child with autism who has, in addition, overgrowth, a seizure disorder,
muscle weakness or ataxia, cognitive regression, pigmentary abnormalities, or
multiple congenital anomalies is the one most likely to be diagnosed with a
single gene disorder
– If the genetic cause of autism (spectrum) is diagnosed, family testing may be
extremely important to establish risks for other relatives
References
• Carter M, Scherer SW. Autism spectrum disorder in the
genetics clinic: a review. Clin Genet 2013; 83(5): 399-407
• Schaefer GB, Mendelsohn NJ. Clinical genetics evaluation in
identifying the etiology of autism spectrum disorders: 2013
guideline revisions. Genet Med 2013; 15: 399-407.
• Flore LA, Milunsky JM. Updates in the genetic evaluation of
the child with global developmental delay or intellectual
disability. Semin Ped Neurol 2012; 19: 173-180.