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).







