Developmental Disabilities

Question 1

Developmental disabilities broadly

Answer 1

Affect ~15% of all children (1/6). Can be environmental, genetic or both
Key is that they all start during developmental period
Common examples: ID, ASD, cerebral palsy, specific language impairment, attention deficit disorder, learning disability

Question 2

Intellectual disability

Used to be mental retardation

Answer 2

Characterized by significant limitations in both intellectual functioning and in adaptive behaviour, which covers many everyday social and practical skills. The disability originates before the age of 18
-1/91 children has ID

Question 3

Autism spectrum disorder

Answer 3

Complex disorder of brain development characterized, in varying degrees, by difficulties in social interaction, verbal and nonverbal communication and repetitive behaviours
-1/68 children

Question 4

Developmental disabilities

Answer 4

ID, ASD, CP, etc: symptom constellations with numerous underlying causes

Often co occur:

• ~50% with ASD have ID/ low IQ
• ~40% with ID diagnosed with psychiatric disorder
• ~40% with CP have ID

Psychiatric and educational diagnoses that are behaviourally-defined symptom diagnoses for which there are numerous etiologies

A behavioural diagnosis (autism or ID) tell you “what” you are seeing, an etiologic diagnosis (genetics) tells you “why”

Question 5

Developmental delay

Answer 5

Used for preschool children to determine eligibility for services

Not generally used after the age of 5

Question 6

Etiology matters

Answer 6

Genetic counselling - to address reproductive concerns, to alleviate guilt

Anticipation of medical needs
Insight into behaviour and learning styles
Syndrome specific support organizations
Targeted research and intervention

Genetic causes and syndromes are individually rare but collectively common
- >1000 genetic conditions associated with developmental disabilities

Question 7

Genetic etiologies of DDisabilities

Answer 7

Diagnostic yield of genome wide arrays: ID: 15-20%, Autism: 10-15%, epilepsy ~9%, schizophrenia ~5%

Up to 40-50% genetic etiology

Question 8

Top 10 recurrent CNVs

Answer 8

22q11. 2del (1/167 cases)
16p11. 2del (ASD,DD/ID,macrocep, 1/241)
1q21. 1del
15q13. 2-q13.3del
22q11. 2dup
7q11. 23del
16p11. 2dup
15q11. 2-q13 dup
15q11. 2-q13del
1q21. 1 dup (1/584)

Question 9

Emerging perspectives

Answer 9

1) same genetic underpinnings seen in a range of developmental and psychiatric diagnoses (ID, ASD, schizophrenia, etc) even within the same family
2) genomic evidence has led to reconsideration of categorical diagnostic models of developmental and psychiatric disabilities
3) evolving perspectives on developmental brain dysfunction have important implications for pedigree interpretation, genetic counselling, and prognosis.

Question 10

Fragile X syndrome

Answer 10

Most common known inherited cause of ID, ASD.
1/3600 males, 1/6000 females
X linked trinucleotide expansion disorder
FMR1 testing recommended for all males and females with DD/ID/ASD of unknown etiology
- located at Xq27.3
-variable section of CGG repeats in the 5’ UTR
-PCR followed by southern blot with methylation status

Question 11

FMR1 repeats

Answer 11

6-45 normal range
(Unaffected)
45-54 intermediate
55-200 premutation (produces MORE mRNA) (FXPOI, FXTAS, Neurodevelopmental, psychiatric and other symptoms) “mRNA toxicity”
>200 full mutation (much less mRNA produced and no protein, hypermethylation) (Fragile X)

Question 12

Fragile X syndrome

Answer 12

FMR1 gene discovered in 1991
Expanded FMR1 gene becomes methylated, fails to produce Fragile X mental retardation protein
FMRP expressed in brain and essential for neuronal functioning throughout life
Primary cause of FXS is lack of FMRP

Question 13

Females with FMR1 full mutations

Answer 13

Minority without developmental symptoms
Often less severe intellectual impairment than in males
Mild to moderate ID, ASD, learning disabilities, psychiatric disorders
Long face, prominent ears ( more subtle than males)
Poor eye contact, attention problems, shyness and social anxiety

Question 14

Fragile X syndrome and ASD

Answer 14

Majority of males and many females with FXS have symptoms consistent with an ASD
Conversely, ~1/20 children with ASD has FXS as the underlying cause
Fragile X is the most common know single gene cause of autism

Question 15

FMR1 premutations

Answer 15

Prevalence: 1/151 females, 1/468 males
Maternal premutations can expand to full mutations in sons and daughters , happens during oogenesis
Paternal premutations pass on to daughters, usually with minimal expansion
Contractions: usually small (10 repeats or fewer)
Premutation disorders/ symptoms due to mRNA toxicity

Question 16

Factors influencing FMR1 expansion

Answer 16

Gender: premutations in females can expand to full mutations in sons and daughters, premutations in males relatively stable and only passed on to daughters

CGG repeat number: in females, larger premutations have greater chance to expand to full mutations in one generation. Premutations less likely to expand when inherited from males

AGG interruptions: AGG interruptions serve as anchors to stabilize the CGG repeat sequence, make it less likely to expand

Nolin et al, 2003: repeats of 55-59 have ~3.7% chance of expanding to a full mutation, repeats of >100 have a 94-100% chance of expanding

Question 17

Fragile X associated disorders

Answer 17

Due to mRNA toxicity
FXPOI : decreased ovarian reserve, with infertility and early menopause in women
FXTAS: progressive ataxia, tremors, personality changes; 40-50% of premutation males >50 have symptoms, 8-17% of premutation females develop FXTAS symptoms in late adulthood, often less severe

Males and females with full mutations are NOT at risk for FX POI/TAS

Question 18

FMR1 mosaicism

Answer 18

• Mosaicism: 2 or more different CGG repeat sizes or methylation patterns
• Repeat size mosaicism (most common): may have different full mutation sizes or a mix of full and premutations
• methylation mosaicism: FMR1 may not be methylated in all cells, some FMRP may be produced
• if mosaicism results in production of significant amounts of FMRP, fragile X syndrome symptoms may be milder
• individuals with FXS and full/premutation mosaicism may be at risk for FXPOI/TAS

Question 19

Indications for FMR1 testing

Answer 19

• Dx testing of males or females with ID/ASD/ DD of unknown etiology
• carrier testing for individuals with family history of Fragile X or ID/DD/ASD of unknown etiology
• prenatal diagnosis when mother has known FMR1 mutation
• Diagnostic testing for women with symptoms of FXPOI, unexplained infertility or early menopause
• Diagnostic testing for males, females with adult onset ataxia, tremors of unknown etiology

Question 20

Reproductive options

Answer 20

PGD using linkage analysis or gene mutations
Donor egg/ artificial insemination
Sperm selection
Adoption 
Prenatal testing: amniocentesis, CVS 
NIPT NOT available for FMR1 mutations