Genetics of ID, DD and ASD Flashcards
ID
-prevalence of 1 in 91
-limitation in intellectual function and adaptive behaviors that originates before age 18y
+can affect many social and practical skills
ASD
-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
DD
- 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
first line testing
- Fragile X DNA analysis
- chromosomal microarray analysis
uninformative FRAX, CMA
can now do clinical WES
etiologies of genetic DD
-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
Fragile X Syndrome
most common inherited form of ASD and ID with multigenerational implications
FRAX genetics
-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
FMR1 repeat ranges
- <45=normal
- 45-54=intermediate/”gray zone”
- 55-200=premutation
- > 200=full mutation, affected child
FRAX diagnosis and testing
- 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
FRAX premutation carrier risks
- 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
Female FRAX full mutation carriers
-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
classic FRAX
-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
FRAX and autism
1 in 20 individuals with ASD have this condition
FMR1 premutations
- 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
AGG interruptions
serve as anchors to help stabilize the CGG repeats and aid in preventing expansion
FXPOI
decreased ovarian reserve, infertility, early menopause in women
FXTAS
- late onset neurodegenerative condition
- results in progressive gait abnormality, tremors, personality changes
- affects 40-50% permutation males older than 50y
primary ASD
ASD without an apparent syndromic cause; accounts for nearly 70% of cases
uncomplicated ASD
ASD thats only obvious by behaviors and diagnosis, no features to suggest it; 70% of primary ASD
complex ASD
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
secondary ASD
- 30% of all ASD diagnoses
- can be related to genetic syndromes and environmental exposures
maternal 15q11.2 duplication
- increased risk for sudden, unexplained death
- 3% of chromosomal, secondary ASD diagnoses
16p deletion
- usually de novo
- accounts for 1% chromosomal ASD diagnosis
CNVs
-5-10% of chromosomal ASD diagnoses
isodicentric chromosome 15
chromosomal cause of ASD; think PWS, AS, and 15q duplication
Rett syndrome genetics
-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
SGDs and ASD
- 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
essential ASD
~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
new ASD genes and CNVs
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
Landau Kleffner
- non genetic disorder that causes regression with speech loss and ASD due to seizures
- treated by anticonvulsants
empiric primary ASD RRs
-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
Rett phenotype
-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
