Genetics of ID, DD and ASD

Question 1

ID

Answer 1

-prevalence of 1 in 91
-limitation in intellectual function and adaptive behaviors that originates before age 18y
+can affect many social and practical skills

Question 2

ASD

Answer 2

-incidence of 1 in 68
+may be related to changes in diagnostic criteria, increased awareness and increased surveillance
-complex disorder of brain development characterized by varying degrees of difficulty in social interaction, verbal and nonverbal communication and repetitive behaviors

Question 3

DD

Answer 3

• co-occurance can include ID and ASD, psychiatric conditions, CP
• reserved for diagnosing preschoolers
• psychiatric and educational diagnoses that are behaviorally defined symptom diagnoses, for which there are numerous etiologies

Question 4

first line testing

Answer 4

• Fragile X DNA analysis

- chromosomal microarray analysis

Question 5

uninformative FRAX, CMA

Answer 5

can now do clinical WES

Question 6

etiologies of genetic DD

Answer 6

-single gene disorders with Mendelian inheritance
-cytogenic and CNV alterations
-majority of cases still unknown-unidentified or candidate genes, multigenic, environment
+however, with WES 40% individuals learn diagnosis
+additional diagnoses, like epilepsy, psychiatric conditions, etc

Question 7

Fragile X Syndrome

Answer 7

most common inherited form of ASD and ID with multigenerational implications

Question 8

FRAX genetics

Answer 8

-incidence of 1 in 3600 males, 1 in 6000 females (~1% of population)
-pan ethnic
-XLR trinucleotide expansion in FMR1 (Xq27.3 intron/5’ UTR)
+can see other diagnoses than DD, ID, ASD in family
-causes a deficiency of FMRP due to abnormal methylation, which functions in neurons and testicular tissue in early development

Question 9

FMR1 repeat ranges

Answer 9

• <45=normal
• 45-54=intermediate/”gray zone”
• 55-200=premutation
• > 200=full mutation, affected child

Question 10

FRAX diagnosis and testing

Answer 10

• southern blotting with PCR to determine repeat and methylation status
• diagnostic and carrier testing can be done on blood
• prenatal diagnosis on chorionic villi and amniocytes

Question 11

FRAX premutation carrier risks

Answer 11

• due to an overproduction of FMR1 RNA in an effort to produce more FMRP; no cognitive effects
• primary ovarian insufficiency
• FXTAS
• neurodevelopmental and psychiatric effects

Question 12

Female FRAX full mutation carriers

Answer 12

-most have neurocognitive effects, often have less severe intellectual impairment
-50% have ID/DD, can also see ASD, LD, psych disorders
+poor eye contact, social anxiety, shyness, attention deficit
-long face with ears more prominent than males

Question 13

classic FRAX

Answer 13

-dysmorphism: long face, prominent ears, forehead and jaw, post-pubertal large testicles/macroorchidism
\+macrocephaly & tall stature in early childhood
-variable degree ID
\+rarely fail to meet criteria
-ASD
\+poor eye contact, hand flapping 
-ADD, anxiety, speech difficulty
-joint laxity and MVP

Question 14

FRAX and autism

Answer 14

1 in 20 individuals with ASD have this condition

Question 15

FMR1 premutations

Answer 15

• carrier rate: 1 in 151 females, 1 in 468 males
• maternal copies can expand during meiosis, paternal copies usually just pass to daughters
• contractions are usually less than 10 repeats or fewer

Question 16

AGG interruptions

Answer 16

serve as anchors to help stabilize the CGG repeats and aid in preventing expansion

Question 17

FXPOI

Answer 17

decreased ovarian reserve, infertility, early menopause in women

Question 18

FXTAS

Answer 18

• late onset neurodegenerative condition
• results in progressive gait abnormality, tremors, personality changes
• affects 40-50% permutation males older than 50y

Question 19

primary ASD

Answer 19

ASD without an apparent syndromic cause; accounts for nearly 70% of cases

Question 20

uncomplicated ASD

Answer 20

ASD thats only obvious by behaviors and diagnosis, no features to suggest it; 70% of primary ASD

Question 21

complex ASD

Answer 21

ASD associated with additional anomalies, such as macro or microcephaly or other dysmorphic features; 30% of primary ASD, 20% of all kids with ASDs

• poorer prognosis with ABA therapy
• 1:1 M:F ratio
• lower recurrence risk in siblings, more likely to be de novo changes

Question 22

secondary ASD

Answer 22

• 30% of all ASD diagnoses

- can be related to genetic syndromes and environmental exposures

Question 23

maternal 15q11.2 duplication

Answer 23

• increased risk for sudden, unexplained death

- 3% of chromosomal, secondary ASD diagnoses

Question 24

16p deletion

Answer 24

• usually de novo

- accounts for 1% chromosomal ASD diagnosis

Question 25

CNVs

Answer 25

-5-10% of chromosomal ASD diagnoses

Question 26

isodicentric chromosome 15

Answer 26

chromosomal cause of ASD; think PWS, AS, and 15q duplication

Question 27

Rett syndrome genetics

Answer 27

-accounts for 4% of females with ASDs; incidence of 1 in 10000
-caused by MECP2 mutation
+results in LOF of epigenetic regulation by protein in neurons and RNA splicing

Question 28

SGDs and ASD

Answer 28

• currently ~5% cases
• tuberous sclerosis and NF
• mitochondrial disorders
• PTEN syndromes
• CHARGE, Cornelia de Lange, SLOS, sotos, etc
• newly discovered disorders from WES and WGS

Question 29

essential ASD

Answer 29

~50% of all kids with an ASD

• absence of physical anomalies
• 4:1 male sex bias
• more likely when a family history of ASDs exists or if there are other behavioral issues

Question 30

new ASD genes and CNVs

Answer 30

most involved in synaptic formation or function, regulatory gene expression or play a role in chromatin formation and packing
-ex: CNTNAP2, NLGN3, NLGN4, SHANK3, SHANK2

Question 31

Landau Kleffner

Answer 31

• non genetic disorder that causes regression with speech loss and ASD due to seizures
• treated by anticonvulsants

Question 32

empiric primary ASD RRs

Answer 32

-5-10% when a couple has an affected child
+in complex 1% for same phenotype, 2% for lesser
-25-35% when two or more children affected
+unclear when one child is affected and another has less severe phenotype

Question 33

Rett phenotype

Answer 33

-nearly always lethal in males
+ cases of neonatal encephalopathy in affected males with unaffected carrier mothers
-causes acquired microcephaly, regression
+see plateau between 6-18mo
-loss of hand use with characteristic hand wringing
+sometimes hand implications not seen in milder mutations
-ASD, seizures, spasticity
-breathing disorder and sleep abnormalities
-absence of speech