Chromosomal Disorders Flashcards
What are the signs/symptoms of Trisomy 21 (Down syndrome)?
- 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
What is the recurrence risk for trisomy 21?
1%
What are the clinical features of Trisomy 21?
- 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
What is a Robertsonian translocation?
- Consequences
- Most common types
- Recurrence risk
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%
What is seen here?
Robertsonian translocation (14;21)(q10,q10)
- 46, XX + 21
- Down syndrome pt
What is seen here?
Robertsonian carrier (15,21)(q10,q10)
- 45, XX, rob(15,21)(q10,q10
- Carrier DS translocation
What is the trisomy responsible for Edwards syndrome?
Trisomy 18
Describe Trisomy 18 (Edwards syndrome)
- Incidence
- Associations
- Gender
- Etiology
- Recurrence
- Prognosis
- 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
What are signs/symptoms of Trisomy 18 (Edwards syndrome)?
- Microcephaly
- Micropthalmia
- Low set and malformed ears
- Micrognathia
- Small mouth
- Triangular face
- Rocker bottom feet
- Overlapping fingers
What are clinical features of Trisomy 18 (Edwards syndrome)?
- 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
What is the trisomy responsible for Patau syndrome?
Trisomy 13
Describe Trisomy 13 (Patau syndrome)?
- Incidence
- Cause of abortions
- Etiology
- Recurrence risk
- Prognosis
- 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
What are the clinical features of Trisomy 13 (Patau syndrome)?
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
What is seen here?
Holoprosencephaly (feature of Trisomy 13)
- Possibly related to ZIC2 (zinc finger protein of cerebellum)
What is seen here? What condition is this associated with?
Iris coloboma- Trisomy 13 (Patau’s)
T/F: Routine cytogenetic studies (G-binds) can detect deletions and duplications under 5-10 Mb?
False; they achieve 400-500 bands (5-10 Mb detection)
- Need chromosomal microarray
What do chromosomal microarrays detect?
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
What are limits of detection: chromosomes vs. microarray
- 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
In what phase of cellular replication does non-allelic homologous recombination (NAHR) occur between LCRs?
Meisosis
Provide examples for microdeletion and reciprocal microduplication causing conditions/diseases
What is Williams Beuren Syndrome?
- Genetic cause (deletion/duplication and chromosome)
- Gene involved
- Signs/symptoms
- 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
Cardiovascular disease in Williams Beuren syndrome is due to what gene? Describe mechanisms and consquences
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
Describe the mental capacities/aptitudes of kids with Williams Beuren Syndrome
- Dissociation between drawing and language
- Language use is very good (esp compared DS)
What is genomic imprinting?
- 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).
What are the genetic causes of Prader-Willi and Angelman syndrome?
- Prader-Willi syndrome: deletions of 15q11-q13 in 70% of pts (paternal)
- Angelman syndrome: deletions of 15q11-q13 in 70% of pts (maternal)
Describe Prader-Will syndrome
- Genetic responsible
- Etiology
- Signs/symptoms
- Prognosis
- 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
What is seen in adults with Prader-Willi syndrome?
- Generalized obesity
- Small hands and feet
- Intellectual disability, obsessive compulsive behavior
- Dysmorphic features: almond shaped eyes
Describe Angelman syndrome
- Genetic responsible
- Etiology
- Signs/symptoms
- Prognosis
- 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
What is seen here?
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)
What are signs/symptoms/features of Angelman syndrome?
- 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
Look at this picture for the genetic causes of PWS
Look at this picture for the genetic causes of AS
What will be seen in the imprinted pedigree (as in AS)?
Skipped generations
- Only causing phenotype when deletion is passed from mother; this is because gene is paternally imprinted (silenced when passed from father)
What is the genetic cause of Tetralogy of Fallot?
22q11.2 deletion
(Aka DiGeorge syndrome/Velocardiofacial syndrome)
What is another name for 22q11.2 deletion?
DiGeorge syndrome/Velocardiofacial syndrome
What are the differences between DiGeorge syndrome (DGS) and Velocardiofacial syndrome (VCFS)?
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
What is the prevalence of DGS/VCFS?
1/4000 (one of the most common genetic syndromes)
What are other features of VCFS?
- 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
What are other features of DGS?
- 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
Mnemonic for the salient features of DiGeorge syndrome?
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
