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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
Q

____% those with 22q deletion syndrome have feeding issue.

A

36%

Constipation, dysphagia, nasopharyngeal reflux

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26
Q

Immunodeficiency (Thymic hypoplasia) in individuals with 22q deletion syndrome

A

Thymus- gland that makes T-cells to fight infection/disease

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27
Q

Psychiatric illness and cognitive function in 22q deletion syndrome

A

66%- nonverbal learning disability

Delays in motor milestones

20%-ASD

ADD and anxiety common

25% adults have schizophrenia

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28
Q

Most common illness associated with developmental disabilities and ID.

INHERITED

A

22q11.2 Deletion Syndrome

INHERITED FRAGILE X

OTHERWISE DOWN SYNDROME

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29
Q

Incidence of 22q11.2 deletion syndrome 1/___

A

1/4,000- 1/6,400

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30
Q

What are the causes of 22q11.2 Deletion syndrome?

A

Deletion of q11.2 region of 22nd chromosome.

> 90% de novo

Autosomal dominant if affected

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31
Q

Prader-Willi Syndrome, Smith-Magenis Syndrome, Phelan-McDermid Syndrome, and 22q11.2 Deletion syndrome are examples of what?

A

Duplication and deletion syndromes

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32
Q

Loss of paternal allele at 15q11.2-q13 (Deletion, microdeletion, UPD, methylation defect) results in what?

A

Prader-Willi Syndrome

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33
Q

Symptoms of Prader-Willi Syndrome

A

FTT, severe hypotonia, excessive eating, ID/DD, short stature, behavioral issues

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34
Q

17q11.2 deletion (RAI1gene) results in what?

A

Smith-Magenis syndrome

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35
Q

Symptoms of Smith-Magenis syndrome

A

Characteristic facial features, feeding issues, FTT, sleep disturbance, self-injurious behaviors, ID/DD, SI issues)

36
Q

22q13.3 deletion (close to 22q11) results in

A

Phelan-McDermid syndrome

37
Q

Symptoms of Phelan-McDermid syndrome

A

GDD, moderate to profound ID, speech delay – by age 4 lose speech, but can regain although remains impaired; receptive>expressive

38
Q

____ is any change in the reference DNA sequence.

A

Variant

39
Q

Why is the word variant used in place of mutation?

A

Mutation suggests the change is inherently associated with a disease.

40
Q

If a Variant is pathogenetic it is ______

If a variant is polymorphic it is _______

A

Disease causing

Benign

41
Q

When is single gene testing useful?

A

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
Q

When is Panel gene testing useful?

A

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
Q

Rett syndrome

-Symptoms

-Prevalence

-Genes

A

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
Q

Neurofibromatosis Type 1, Tuberous Sclerosis Complex, and Metabolic disorders such as untreated phenylketonuria and Smith-Lemli Opitz syndrome are _____ disorders.

A

Mendelian

45
Q

Symptoms of Neurofibromatosis Type 1

A

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
Q

Symptoms of Tuberous Sclerosis Complex (TSC)

A

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
Q

Symptoms of untreated phenylketonuria (PKU)

A

Seizures, DD, ID

Now lifelong diet

48
Q

Symptoms of Smith-Lemli Opitz syndrome

A

Growth retardation, microcephaly, moderate to severe ID, congenital birth defects

Very rare. CHOLESTREROL DEFECT
Too low plasma cholesterol

49
Q

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?

A

Target Variant Testing

50
Q

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

A

Trinucleotides

Severity and age of onset

Example: “There is a round table here”
“There is a round round round table here”

51
Q

What is an example of repeat expansion disorder?

A

Fragile X

52
Q

What is the most commonly INHERITED disorder in MALES?

A

Fragile X

53
Q

Symptoms of Fragile X syndrome

A

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
Q

Why do more males than females have fragile X?

A

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
Q

Normal, premutation, and Full mutation of CGG (FMR1-Gene)

A

Normal <55

Premutation 55<n<200 (males tremor ataxia, parkinson’s congitive decline; females risk FXTAS and premature ovarian failure) “Carriers”

Full mutation n>200

56
Q

FMR1-Primary ovarian insufficiency (FXPOI) in individuals with ovaries who have >55 - <200 CGG repeats

A

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
Q

FMR1-Associated Tremor Ataxia (FXTAS) in individuals with >55 - <200 CGG repeats

A

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
Q

As fragile X gene is passed on, expansion gets…

A

Larger

59
Q

Is Down Syndrome inherited?

A

No Fragile X is

60
Q

Exome Sequencing

A

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
Q

Genetic Test Results: Negative

A

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
Q

Genetic Test Results: Positive or Pathogenic variant

A

Disease causing change identified.

61
Q

Genetic Test Results: Unexpected/Incidental/Secondary

A

ACMG Secondary Findings Genes
Many of these are associated with cancer and cardiac risk
Degree of biological relationships (i.e. consanguinity)
Non-paternity

61
Q

Genetic Test Results: Uncertain

A

change identified but not enough evidence to suggest disease-causing or benign

62
Q

Four testing options

A
  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
Q

What type of genetic testing needs maternal and paternal samples, ACMG secondary findings, and is more likely to have an uncertain result?

A

Exome

64
Q

Disorders caused by multiple genes and addictive behavioral and environmental factors are called what?

A

Multifactorial

65
Q

Coronary Artery Disease, Autism, Cleft lip/palate, Congential heart defect, and Epilepsy are examples of what?

A

Multifactorial Diseases.

Controllable (diet, smoking, stress, obesity, diabetes, etc) + uncontrollable (family history, age, bio sex) factors

66
Q

Teratogenic and Enviornmental Factors

A

Pre-conception risks

Prenatal risks
Obstetric complications
Viral infection
Teratogens
Alcohol
Medication/drugs
Maternal stress

Postnatal risks
Lead poisoning

67
Q

What professional performs clinical examinations, diagnostic work-ups, genetic counseling & testing.

A

Medical Geneticist (MD)

68
Q

What professional provides Provide laboratory-based diagnostic work-ups and interpretation (biochemical, cytogenetic, molecular)

A

Laboratory Geneticist (PhD)

69
Q

What professional provides risk assessment, genetic counseling and testing services?

A

Genetic Counselors (MS)

70
Q

What professional provides nursing interventions, counseling, and testing services?

A

Nurses (RN, NP)

71
Q

________ is the process of helping people understand and adapt to medical, psychological and familial implications of genetic contributions to disease.

A

Genetic counseling

72
Q

What are the steps to a genetic counseling session?

A
  1. Information Gathering
  2. Establish/verify diagnosis
  3. Risk assessment
  4. Result disclosure/disease discussion
  5. Psychological counseling
73
Q

How can you better establish rapport with family, educate them, and provide them with medical care/offer preventative care QUICKLY and EFFICIENTLY?

A

Pedigree

74
Q

How many generations should a pedigree be?

What questions should you ask?

A

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
Q

Risk classifications

A
  1. Average (general pop screen recommendations)
  2. Moderate/Familial (personalized detection/prevention recommendations)
  3. High/Genetic (personalized disease-specific recommendations)
76
Q

Circles, Squares and Diamonds are

A

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
Q

In 2004 the US surgeon general’s family history initiative was launched declaring what day family history day?

A

Thanksgiving

78
Q

Purpose of Genetic Evaluation in the work-up of an individual with ID or GDD

A

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
Q

What are the limits of genetic services ?

A
  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
Q

May 21st, 2008

A

GINA! - confidentiality and disclosure of genetic info

81
Q

GINA: Group and Individual Health insurers CANNOT

A

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
Q

GINA: Employers CANNOT

A

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
Q

What does GINA NOT do?

A

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
Q

Who does GINA NOT apply to?

A

Employers with less than 15 employees

US military, Veterans Administration, Indian Health Service, or Federal Employees Health Benefits program (FEHB)

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