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Autism7717 > Genetic and Biological Causes of ID 9/18 > Flashcards

Genetic and Biological Causes of ID 9/18 Flashcards

1
Q

Etiology of ID

A

60% Unknown

Chromosomal - structure or number (Down Syndrome) - Anueploidies and deletions/duplications. Rett Syndrome-single gene.

Multifactorial

Premature (4%) Enviornmental (10%)

Teratogenic - meds during pregnancy, lead poisoning

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2
Q

What is the FIRST whole genome technology?

A

Cytogenetics

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3
Q

The number and appearance of chromosomes within a cell (all of them 1-22, 21 and 22 mixed up then sex)

A

Karyotype

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4
Q

FISH

A

Fluorescence in situ hybridization

detect and locate specific DNA sequence on chromosome
“Extra information”

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5
Q

Visualization of paired chromosomes

A

Karyotype

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6
Q

Clinical Prenatal Uses of Karyotyping

A

Amniocentesis and Chorionic Villi Sampling

Can do Karyotyping in womb

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7
Q

Clinical Postnatal Uses of Karyotyping

A

Diagnosis

Aneuploid conditions, analysis of deletions, duplications, translocations, inversions.

Diagnosis reason for pregnancy loss and infertility

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8
Q

Facial Features of Down Syndrome

A

Brachycephaly, epicanthal folds, flat face and occiput, upward slanting palpebral fissures

Short neck

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9
Q

Hypotonia in Down Syndrome

A

Feeding issues and motor delays

Achieves milestones, but later than expected

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10
Q

Congenital defects in down syndrome: name them

A

VSD to AVSD

Hirschsprung Disease
Duodenal atresia

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11
Q

Hirschsprung disease in down syndrome

A

nerve cells missing in large intestine causing bowel obstruction.

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12
Q

Duodenal Atresia in down syndrome

A

stenosis/blockage between stomach, duodenum, and intestine

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13
Q

Other medical issues in down syndrome

A

Hypothyroidism, celiac disease, sleep apnea, depression, leukemia, ASD/OCD, single transverse palmar crease, short fifth finger with clinodactyly, wide space between first and second toe

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14
Q

Neurological functioning in down syndrome

A

Most in moderate range of ID

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15
Q

____% of those with Down Syndrome have trisomy 21.

How is this characterized?

A

95%

Mostly maternal non-disjunction

Increases risk with advanced maternal age (peak 20s and later)

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16
Q

___% of those with down syndrome have Roberstonian translocation.

What is this?

A

3%

21st gets stuck on 14.

Normal, Balanced Carrier, Trisomy 14 (3x 14, 2x 21, pair are attached), Monosomy 14 (1x 14, 2x 21), Monosomy 21 (2x 14, 1x21), or Trisomy 21 (3x 21, 2x14, pair are attached)

Only normal, balanced, and trisomy 21 are viable.

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17
Q

____ mosaic down syndrome.

A

1-2% Early in fertilization. Body starts correcting, but some cells retain it.

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18
Q

What chromosomal aneuploidies WILL cause ID?

A

Klinefelter syndrome- 47, XXY

Trisomy 18, Trisomy 13

Unbalanced translocations (partial trisomy, partial monosomies, impact hard to predict)

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19
Q

What chromosomal aneuploidies DON’T usually cause ID?

A

Turner syndrome (45,X)

Triple X Syndrome (47, XXX)

XYY Syndrome

Balanced translocations

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20
Q

Comparative genomic hybridization, Bacterial Artificial Chromosomes (BAC), Oligonucleotide, and Single Nucleotide polymorphism (SNP) are examples of what?

A

Arrays

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21
Q

What are uses for arrays?

A

see small extra or missing pieces you might miss when karyotyping.

Subtle copy number variations (CNVs)

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22
Q

What is considered first line testing?

A

SNP array

first line for those with multiple anomalies, non-syndromic DD, or ASD

most comprehensive

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23
Q

Heart defects are in ____% of those with 22q deletion syndrome.

What is the most common?

A

75%

Conotruncal

Others: TOF, interrupted aortic arch, VSD, truncus arteriosus, ASD

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24
Q

Palate abnormalities affect ____% of those with 22q deletion syndrome.

A

~70%

Velopharyngeal incompetence, submucosal cleft, cleft palate, bifid uvula

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25
____% those with 22q deletion syndrome have feeding issue.
36% Constipation, dysphagia, nasopharyngeal reflux
26
Immunodeficiency (Thymic hypoplasia) in individuals with 22q deletion syndrome
Thymus- gland that makes T-cells to fight infection/disease
27
Psychiatric illness and cognitive function in 22q deletion syndrome
66%- nonverbal learning disability Delays in motor milestones 20%-ASD ADD and anxiety common 25% adults have schizophrenia
28
Most common illness associated with developmental disabilities and ID. INHERITED
22q11.2 Deletion Syndrome INHERITED FRAGILE X OTHERWISE DOWN SYNDROME
29
Incidence of 22q11.2 deletion syndrome 1/___
1/4,000- 1/6,400
30
What are the causes of 22q11.2 Deletion syndrome?
Deletion of q11.2 region of 22nd chromosome. >90% de novo Autosomal dominant if affected
31
Prader-Willi Syndrome, Smith-Magenis Syndrome, Phelan-McDermid Syndrome, and 22q11.2 Deletion syndrome are examples of what?
Duplication and deletion syndromes
32
Loss of paternal allele at 15q11.2-q13 (Deletion, microdeletion, UPD, methylation defect) results in what?
Prader-Willi Syndrome
33
Symptoms of Prader-Willi Syndrome
FTT, severe hypotonia, excessive eating, ID/DD, short stature, behavioral issues
34
17q11.2 deletion (RAI1gene) results in what?
Smith-Magenis syndrome
35
Symptoms of Smith-Magenis syndrome
Characteristic facial features, feeding issues, FTT, sleep disturbance, self-injurious behaviors, ID/DD, SI issues)
36
22q13.3 deletion (close to 22q11) results in
Phelan-McDermid syndrome
37
Symptoms of Phelan-McDermid syndrome
GDD, moderate to profound ID, speech delay – by age 4 lose speech, but can regain although remains impaired; receptive>expressive
38
____ is any change in the reference DNA sequence.
Variant
39
Why is the word variant used in place of mutation?
Mutation suggests the change is inherently associated with a disease.
40
If a Variant is pathogenetic it is ______ If a variant is polymorphic it is _______
Disease causing Benign
41
When is single gene testing useful?
Sequence 1 gene Useful for patients with a presentation consistent with a specific condition that is associated with various variants within a single gene Example: Cystic fibrosis test
42
When is Panel gene testing useful?
Sequencing of a cohort of genes associated with a broader clinical presentation, 5-100 genes. Common in many genetic conditions now (Hereditary cancer, aortopathies, renal disorders)
43
Rett syndrome -Symptoms -Prevalence -Genes
Normal development 6-18 months, regression followed by recovery or stabilization. 1/8,500 females Genes; MECP2, FOXG1 50% chance passing it on (most don't have children of their own)
44
Neurofibromatosis Type 1, Tuberous Sclerosis Complex, and Metabolic disorders such as untreated phenylketonuria and Smith-Lemli Opitz syndrome are _____ disorders.
Mendelian
45
Symptoms of Neurofibromatosis Type 1
Cafe au lait lesions (darker pigment lesions) freckling in odd places, optic gliomas, lisch nodules, skeeltal findings, normal cog to mild ID. neurofibromas (benign brain tumors), variability in families
46
Symptoms of Tuberous Sclerosis Complex (TSC)
LIGHT pigement/skin lesions Skin lesions (hypomelanotic macules, facial angiofibromas, shagreen patches, cephalic plaques, ungual fibromas); brain lesions (cortical dysplasias, subependymal nodules, subependymal giant cell astrocytomas); seizures, ID/DD, renal (cysts, renal cell cancer, angiolipomas); lymphangioleiomyomatosis
47
Symptoms of untreated phenylketonuria (PKU)
Seizures, DD, ID Now lifelong diet
48
Symptoms of Smith-Lemli Opitz syndrome
Growth retardation, microcephaly, moderate to severe ID, congenital birth defects Very rare. CHOLESTREROL DEFECT Too low plasma cholesterol
49
What type of genetic testing is genotyping for specific variant, useful for patients with known family variant, and useful for patients with clinical presentation consistent with condition caused by known single variant?
Target Variant Testing
50
Repeat expansion is a genetic condition with repeats of _____ in the gene. The size of the expansion is correlated to ___ and ____ of onset of disorder
Trinucleotides Severity and age of onset Example: "There is a round table here" "There is a round round round table here"
51
What is an example of repeat expansion disorder?
Fragile X
52
What is the most commonly INHERITED disorder in MALES?
Fragile X
53
Symptoms of Fragile X syndrome
IQ 30-50 ASD/hyperactive/ADHD, social anxiety hand flapping, aggression DD/ID. Moderate learning disability to severe ID. Dysmorphia: long face, forehead prominent, large ears, prominent jaw, Macro-oorchidism. Connective tissue issues, ear infections, flat feet, double jointed fingers and flexible joints. Some features more common post puberty like long face.
54
Why do more males than females have fragile X?
XY- if they have the repeats, nothing they can do XX- if one has expansions, our bodies can self correct and shut off the other X preferentially
55
Normal, premutation, and Full mutation of CGG (FMR1-Gene)
Normal <55 Premutation 55200
56
FMR1-Primary ovarian insufficiency (FXPOI) in individuals with ovaries who have >55 - <200 CGG repeats
21% lifetime risk for primary ovarian insufficiency (menopause) 3% of individuals will have irregular menstrual cycles (teens) ~30% will stop having periods by age 29 1% will cease menstruation before 18 years of age 80-100 CGG repeats: Highest risk for ovarian dysfunction
57
FMR1-Associated Tremor Ataxia (FXTAS) in individuals with >55 - <200 CGG repeats
Tremors (shakiness of hands) Gait imbalance (ataxia) Parkinsonism Memory deficits (Alzheimer- like) Executive cognitive function deficits Risks: 16.5 % risk over age 50 years in individuals assigned female at birth 45.5% risk over age 50 years in individuals assigned male at birth
58
As fragile X gene is passed on, expansion gets...
Larger
59
Is Down Syndrome inherited?
No Fragile X is
60
Exome Sequencing
Patients with complex clinical presentation that doesn't suggest genetic etiology. Based on Clincal presentation 1% genome, NGS sequencing of coding regions (exons) of genome. See exomes more in kids (30%) than adults (15%) because many children don't make it to adulthood
61
Genetic Test Results: Negative
no disease causing variants identified Example: The red hat vs. The red bat. Normal variation. We don't know what the sentence should be. Lab data must prove if it effects gene function
61
Genetic Test Results: Positive or Pathogenic variant
Disease causing change identified.
61
Genetic Test Results: Unexpected/Incidental/Secondary
ACMG Secondary Findings Genes Many of these are associated with cancer and cardiac risk Degree of biological relationships (i.e. consanguinity) Non-paternity
61
Genetic Test Results: Uncertain
change identified but not enough evidence to suggest disease-causing or benign
62
Four testing options
1. Single Gene - specific gene/variant 2. Panel/Exome - many genes, multiple hereditary cancer syndromes 3. Exome - sequencing all coding regions, interpretation on phenotype 4. None
63
What type of genetic testing needs maternal and paternal samples, ACMG secondary findings, and is more likely to have an uncertain result?
Exome
64
Disorders caused by multiple genes and addictive behavioral and environmental factors are called what?
Multifactorial
65
Coronary Artery Disease, Autism, Cleft lip/palate, Congential heart defect, and Epilepsy are examples of what?
Multifactorial Diseases. Controllable (diet, smoking, stress, obesity, diabetes, etc) + uncontrollable (family history, age, bio sex) factors
66
Teratogenic and Enviornmental Factors
Pre-conception risks Prenatal risks Obstetric complications Viral infection Teratogens Alcohol Medication/drugs Maternal stress Postnatal risks Lead poisoning
67
What professional performs clinical examinations, diagnostic work-ups, genetic counseling & testing.
Medical Geneticist (MD)
68
What professional provides Provide laboratory-based diagnostic work-ups and interpretation (biochemical, cytogenetic, molecular)
Laboratory Geneticist (PhD)
69
What professional provides risk assessment, genetic counseling and testing services?
Genetic Counselors (MS)
70
What professional provides nursing interventions, counseling, and testing services?
Nurses (RN, NP)
71
________ is the process of helping people understand and adapt to medical, psychological and familial implications of genetic contributions to disease.
Genetic counseling
72
What are the steps to a genetic counseling session?
1. Information Gathering 2. Establish/verify diagnosis 3. Risk assessment 4. Result disclosure/disease discussion 5. Psychological counseling
73
How can you better establish rapport with family, educate them, and provide them with medical care/offer preventative care QUICKLY and EFFICIENTLY?
Pedigree
74
How many generations should a pedigree be? What questions should you ask?
3 generations Current age Age at any diagnosis, Age at and cause of death Any corrective surgeries Associated congenital abnormalities Primary or secondary condition Environmental exposures (i.e.., sun, smoking) Presence of other features associated with syndromes Ethnicity/race
75
Risk classifications
1. Average (general pop screen recommendations) 2. Moderate/Familial (personalized detection/prevention recommendations) 3. High/Genetic (personalized disease-specific recommendations)
76
Circles, Squares and Diamonds are
GENDER (not sex) square male circle female diamond nonbinary triangle miscarriage Double line- more than normal bio relationship Adopted OUT solid line Adopted IN dotted line
77
In 2004 the US surgeon general's family history initiative was launched declaring what day family history day?
Thanksgiving
78
Purpose of Genetic Evaluation in the work-up of an individual with ID or GDD
Clarification of etiology Prognosis or clinical outcome Delineate recurrence risk Treatment and management Avoidance of unnecessary or redundant testing Psychological Adaptation Coping with risk Adapt to illness Support of family Research options Enhances co-management and patient outcome
79
What are the limits of genetic services ?
1. Testing- need pathogenic variant in family member for informativeness (also might be a different or uninherited gene). 2. Pathogenic variant might not lead to disease 3. Tests may not detect 100% of variants 4. Don't know all genes 5. Difficult to predict recurrence risk or causes is multifactorial 6. Coverage of services (insurance covers consultation but need to meet testing criteria or authorization for testing)
80
May 21st, 2008
GINA! - confidentiality and disclosure of genetic info
81
GINA: Group and Individual Health insurers CANNOT
use a person’s genetic information in setting eligibility or premium or contribution amounts. request or require a person to undergo a genetic test.
82
GINA: Employers CANNOT
Refuse to hire, or discharge Discriminate against with respect to compensation, terms, conditions, or privileges of employment Limit, segregate, or classify any employee to deprive them of employment opportunities request, require, or purchase genetic information on an employee or their family member (even if info is job-related)
83
What does GINA NOT do?
Protect info about CURRENT health status Protect info about disease simply because it is genetic when disease already diagnosed and manifest apply to life, disability, or long term care insurers.
84
Who does GINA NOT apply to?
Employers with less than 15 employees US military, Veterans Administration, Indian Health Service, or Federal Employees Health Benefits program (FEHB)

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