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a_Genetics > 11/12- Chromosomal Disorders > Flashcards

11/12- Chromosomal Disorders Flashcards

1
Q

What are the signs/symptoms of Trisomy 21 (Down syndrome)?

A
  • Generalized hypotonia
  • Microcephaly, brachycephaly
  • Small and round ears, upslanting palpebral fissures, epicanthal folds, midface hypoplasia, tongue protrusion
  • Intellectual Disability: IQ average is 40-60
  • Broad and short neck, redundant skin
  • Brachydactyly, single transverse palmar creases, 5th finger clinodactyly
  • Sandal gap deformity: big gap between 1st and 2nd toes
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2
Q

What is the recurrence risk for trisomy 21?

A

1%

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3
Q

What are the clinical features of Trisomy 21?

A
  • 40-50% congenital heart defect (AV canal)
  • Gastrointestinal anomalies: duodenal atresia, Hirschprung disease, celiac disease
  • Hematologic: acute megakaryoblastic leukemia (AML)
  • Gene responsible is on chr 21
  • Hypothyroidism
  • Increase incidence of Alzheimer disease
  • Amyloid plaque precursor (APP) protein is also on chr 21
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4
Q

What is a Robertsonian translocation?

  • Consequences
  • Most common types
  • Recurrence risk
A

Translocations occurring between acrocentric (one arm with satellite on other end) chromosomes:

  • 13, 14, 15, 21 and 22

Consequences:

  • Infertility, miscarriages
  • Trisomies

Most common:

  • 13q14q
  • 14q21q
  • 21q21q

Recurrence risk

  • 21q21 carrier parents: 100%
  • 13q14q carrier parents:
  • Mother: 5-7%
  • Father: 0-1%
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5
Q

What is seen here?

A

Robertsonian translocation (14;21)(q10,q10)

  • 46, XX + 21
  • Down syndrome pt
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6
Q

What is seen here?

A

Robertsonian carrier (15,21)(q10,q10)

  • 45, XX, rob(15,21)(q10,q10
  • Carrier DS translocation
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7
Q

What is the trisomy responsible for Edwards syndrome?

A

Trisomy 18

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8
Q

Describe Trisomy 18 (Edwards syndrome)

  • Incidence
  • Associations
  • Gender
  • Etiology
  • Recurrence
  • Prognosis
A
  • Incidence 1/8,000
  • Associated with advanced maternal age
  • 4x females
  • Etiology: majority de novo in meiotic nondisjunction
  • Recurrence in future pregnancies is 1% (or age related)
  • 50% die by 2 months, less than 10% survive more than 1 year
  • Those with longer lifespan tend to be due to mosaicism
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9
Q

What are signs/symptoms of Trisomy 18 (Edwards syndrome)?

A
  • Microcephaly
  • Micropthalmia
  • Low set and malformed ears
  • Micrognathia
  • Small mouth
  • Triangular face
  • Rocker bottom feet
  • Overlapping fingers
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10
Q

What are clinical features of Trisomy 18 (Edwards syndrome)?

A
  • Prenatal and postnatal growth deficiency
  • Heart disease: valvular disease, ventricular septal defect (VSD)
  • Overlapped fingers, rocker bottom feet
  • Cryptorchidism, renal anomalies
  • Severe intellectual disability
  • Brain anomalies, hypertonia, seizures
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11
Q

What is the trisomy responsible for Patau syndrome?

A

Trisomy 13

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12
Q

Describe Trisomy 13 (Patau syndrome)?

  • Incidence
  • Cause of abortions
  • Etiology
  • Recurrence risk
  • Prognosis
A
  • Incidence 1/20,000 livebirths
  • 100 fold greater in abortions (1% of total)

- Etiology:

  • 75% non-disjunction: advanced mat. age
  • 20% Robertsonian translocations (13q14q)
  • Recurrence risk 1% (non-disjunction)
  • Mean life expectancy is 4 months
  • 45% die in first month
  • 70% by 6 months
  • 86% by 1 year
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13
Q

What are the clinical features of Trisomy 13 (Patau syndrome)?

A

Primarily a midline defect

  • Clefting
  • Brain: seizures, holoprosencephaly, apneic episodes, severe intellectual disability
  • Microcephaly, scalp defects, malformed and low set ears, microphthalmia, iris and retinal colobomas, cleft lip and palate
  • Growth deficiency
  • Limb: postaxial polydactyly
  • Heart defects: VSD, ASD
  • Scalp defects
  • Iris coloboma
  • Malformed ears
  • Similar to Trisomy 18, but clefting is more distinct for this Patau
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14
Q

What is seen here?

A

Holoprosencephaly (feature of Trisomy 13)

  • Possibly related to ZIC2 (zinc finger protein of cerebellum)
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15
Q

What is seen here? What condition is this associated with?

A

Iris coloboma- Trisomy 13 (Patau’s)

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16
Q

T/F: Routine cytogenetic studies (G-binds) can detect deletions and duplications under 5-10 Mb?

A

False; they achieve 400-500 bands (5-10 Mb detection)

  • Need chromosomal microarray
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17
Q

What do chromosomal microarrays detect?

A

Arrays can detect cryptic microdeletions/microduplications

  • Deletions and duplications occur via recombination mechanisms
  • Often resulting from recombination between non-allelic low copy repeat (LCR) sequences
  • Reciprocal deletions and duplications occur with equal frequency
  • Deletion seen more frequently because it causes a more severe phenotype
18
Q

What are limits of detection: chromosomes vs. microarray

A
  • Limit of detection for G-banded chromosome analysis is about 4Mb
  • 4 Mb region of microarray data (on right) shows a 1 Mb deletion encompassing ~ 70 probes
19
Q

In what phase of cellular replication does non-allelic homologous recombination (NAHR) occur between LCRs?

A

Meisosis

20
Q

Provide examples for microdeletion and reciprocal microduplication causing conditions/diseases

A
21
Q

What is Williams Beuren Syndrome?

  • Genetic cause (deletion/duplication and chromosome)
  • Gene involved
  • Signs/symptoms
A
  • Microdeletion in 7q11.23 in 99% including the elastin (ELN) gene detected by CMA (not detectable by karyotype)
  • A distinctive “elfin” facial appearance
  • Mild intellectual disability with IQ’s up to 80
  • Typical behaviors: overfriendliness, attention deficit disorder
  • Hypercalcemia (15%) and/or hypercalciuria
  • Hypercalcemia symptoms: irritability, vomiting, constipation, and muscle cramps
  • Renal anomalies, nephrocalcinosis
22
Q

Cardiovascular disease in Williams Beuren syndrome is due to what gene? Describe mechanisms and consquences

A

ELN gene

  • Loss of the ELN gene (codes for the protein elastin) is associated with the connective-tissue abnormalities and cardiovascular disease
  • Supravalvular aortic stenosis and supravalvular pulmonary stenosis
  • Diffuse aortic hypoplasia
  • Coronary renal artery stenosis has been implicated in some cases of SIDS
  • Renal artery stenosis (hypertension In picture, top is normal and bottom is disordered
23
Q

Describe the mental capacities/aptitudes of kids with Williams Beuren Syndrome

A
  • Dissociation between drawing and language
  • Language use is very good (esp compared DS)
24
Q

What is genomic imprinting?

A
  • An epigenetic phenomenon in which the activity of a gene is reversibly modified depending on the sex of the parent that transmits it.
  • Leads to unequal gene expression from the maternal copy compared to the paternal copy.
  • Transcription of one allele at a locus is dependent on the parental origin of the allele.
  • Imprinting phenomena is a reversible form of gene inactivation (resets in meiosis).
25
Q

What are the genetic causes of Prader-Willi and Angelman syndrome?

A
  • Prader-Willi syndrome: deletions of 15q11-q13 in 70% of pts (paternal)
  • Angelman syndrome: deletions of 15q11-q13 in 70% of pts (maternal)
26
Q

Describe Prader-Will syndrome

  • Genetic responsible
  • Etiology
  • Signs/symptoms
  • Prognosis
A
  • Deletions of 15q11-q13 in 70% of patients (paternal deletion)
  • 25% have maternal uniparental disomy (UPD) (leads to paternal deficiency): both copies of chromosome come from mom
  • 5% mutations of deletions of imprinting center

Signs/symptoms

  • Severe hypotonia, poor feeding
  • Cryptorchidism
  • Increased weight gain by age 3 years, voracious appetite
  • Short stature, small hands and feet
27
Q

What is seen in adults with Prader-Willi syndrome?

A
  • Generalized obesity
  • Small hands and feet
  • Intellectual disability, obsessive compulsive behavior
  • Dysmorphic features: almond shaped eyes
28
Q

Describe Angelman syndrome

  • Genetic responsible
  • Etiology
  • Signs/symptoms
  • Prognosis
A
  • Microdeletions at 15q11-13 in 70-75% of the patients
  • 11% have mutations in the UBE3A gene: gene encoding the E6AP-3A ubiquitin protein ligase (imprinted gene)
  • 2-5% paternal uniparental disomy (UPD) (maternal deficiency)
  • 2-5% mutations of deletions of imprinting center
29
Q

What is seen here?

A

patUPD15 Angelman isodisomy

  • AOH = Absence of heterozygosity: observe the absence of AB (all AA or BB)
  • This shows that this child inherited only one chromosome from the father (monosomy rescue)
30
Q

What are signs/symptoms/features of Angelman syndrome?

A
  • Microcephaly with normal head circumference at birth, brachycephaly
  • Severe intellectual disability, IQ often below 40
  • Seizures, abnormal EEG’s
  • Midface retrusion, prognathism, wide spaced teeth, drooling, macrostomia
  • No speech, unprovoked bursts of laughter
  • Ataxia, wide base gait with upheld arms, poor coordination, tremors
31
Q

Look at this picture for the genetic causes of PWS

A
32
Q

Look at this picture for the genetic causes of AS

A
33
Q

What will be seen in the imprinted pedigree (as in AS)?

A

Skipped generations

  • Only causing phenotype when deletion is passed from mother; this is because gene is paternally imprinted (silenced when passed from father)
34
Q

What is the genetic cause of Tetralogy of Fallot?

A

22q11.2 deletion

(Aka DiGeorge syndrome/Velocardiofacial syndrome)

35
Q

What is another name for 22q11.2 deletion?

A

DiGeorge syndrome/Velocardiofacial syndrome

36
Q

What are the differences between DiGeorge syndrome (DGS) and Velocardiofacial syndrome (VCFS)?

A

DiGeorge syndrome

  • Presenting in infancy
  • Severe heart defects; often lethal
  • Severe infections (immunodeficiency)
  • Seizures; low Ca levels

Velocardiofacial syndrome

  • Childhood/adult
  • Heart defects: usually mild-moderate
  • Weak palate, cleft palate; nasal voice
  • Long face and fingers
37
Q

What is the prevalence of DGS/VCFS?

A

1/4000 (one of the most common genetic syndromes)

38
Q

What are other features of VCFS?

A
  • Heart disease: tetralogy of Fallot, interrupted aortic arch type B, truncus arteriosus, ventricular septal and atrial septal defects
  • Cleft palate (overt or submucous), velo-pharyngeal incompetence (VPI), bifid uvula.
  • Feeding difficulties
  • Dysmorphic -Small and cupped ears, prominent nose, long tapered fingers
  • Renal abnormalities (>30%)
  • Learning problems, mild Intellectual Disability (IQ ~ 80)
  • Hypocalcemia that improves with age
  • Psychiatric illnesses (>40 %): schizophrenia, bipolar disorder
39
Q

What are other features of DGS?

A
  • Defect of embryonic development in:
  • 3rd and 4th pharyngeal pouches
  • 4th branchial arch
  • Partial or complete thymus absence (immunodeficient)
  • Conotruncal heart anomalies: tetralogy of Fallot, truncus arteriosus, VSD (TBX1 = T-BOX gene related. TBX1 is a transcription factor mapped to the deleted region
  • Hypocalcemia (parathyroid hypoplasia)
  • Cellular immunodeficiency (thymus related)
  • Mild intellectual disability
  • Dysmorphic features: hypertelorism, low set ears, bifid uvula
40
Q

Mnemonic for the salient features of DiGeorge syndrome?

A

CATCH-22, with the 22 to remind one the chromosomal abnormality is found on the 22 chromosome

  • Cardiac abnormality (especially tetralogy of Fallot)
  • Abnormal facies
  • Thymic aplasia
  • Cleft palate
  • Hypocalcemia/Hypoparathyroidism

a_Genetics (18 decks)

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