8: Chromosome Disorders

Question 1

Aneuploidy

Answer 1

Any chromosome number not an exact multiple of the haploid number (23)

Common forms:
Trisomy- extra chromosome
Monosomy- single chromosome

Leading genetic cause of intellectual disability

Question 2

Spontaneous Abortions (frequency of cause)

Answer 2

40% normal

60% abnormal:
30% Trisomy (most common trisomy 16)
10% 45,X 
10% Triploid
5% Tetraploid
5% Other

Question 3

Autosomal aneuploidies (frequency)

Answer 3

Down syndrome (trisomy 21)- 1/800
Trisomy 18 (Edwards)- 1/5-7000
Trisomy 13 (Patau's)- 1/10-20000

18 and 13 are semi lethal
Complete monosomies of autosomes lethal

Frequency of all 3 trisomies increase with advanced maternal age (35+)

Question 4

Parental Origin of Aneuuplody

Answer 4

XXX roughly same as autosomal trisomies (mostly from mother, meiosis I)

XXY maternal and paternal non-disjunction equal

45,X: mainly paternal non-disjunction

Question 5

Trisomy 21 (Down Syndrome) (symptoms)

Answer 5

1/800 live births: >95% non familial
*Not higher recurrence risk

Upslanting palpebral fissures, over folded helices, single palmar transverse creases, short bent 5th fingers
40-50% congenital heart disease (need echocardiogram)
Hearing loss due to otitis media
Strabismus and refractive errors (need eye doctor)
Hypothyroidism
Moderate Intellectual Disability

Question 6

Down Syndrome (chromosomes)

Answer 6

95% trisomy 21 from nondisjunction
-75% maternal meiosis I
-25% maternal meiosis II
Karyotype: 47, XY, +21

4% Robertsonian translocation between 21 and Acrocentric (little p arm) chromosome (14,22)
Karyotype: 46, XY, t(14,21)

1% mosaic trisomy 21

Question 7

Down Syndrome (Robertsonian Translocation)

46, XY, t(14;21)

Answer 7

Translocation between two acrocentric chromosomes by fusing near centromere, with loss of short arms

See 46 chromosomes, there are 3 21’s but 1 of them is attached to 14.

Can be inherited:
Normal father may have 45 chromosomes (technically 46 but translocation)
Karyotype 45, XY, t(14;21)- phenotypically normal

Question 8

When You Have a Structurally Abnormal Chromosome? (What to do)

Answer 8

Study parental chromosomes

Question 9

Girl with Down Syndrome

46, XX, t(21;21)

Answer 9

3 21 copies, but one of them is doubled up.

Check parents:
Mother: 45, XX, t(21;21)- phenotypically normal

If mother has kids, 100% risk of future children with Down syndrome

Question 10

Trisomy 18 (Edwards Syndrome) (symptoms)

Answer 10

Characteristic facial features:
Low frontal hairline, short palpebral fissures, blunt nasal tip with small nostrils, small chin, fawn-like ears, high nasal bridge.

Short sternum, overlapping fingers with clenched fists, genital anomaly, digit abnormalities, cardiac defect, renal anomaly, severe intellectual disability.

*Semi lethal

Question 11

Trisomy 13 (Palau syndrome) (symptoms)

Answer 11

Holoprosencephaly (not separation of ventricles in brain- ultrasound) with premaxillary agenesis (atypical median cleft lip/palate); microphthalmia (small eyes), flexed fingers, polydactyly (extra fingers), cryptorchidism, abnormal scrotum, cardiac defect and cystic kidneys

Normal birthweight
“Rocker-bottom” feet with prominent calcanei, ventricular septal defect, cystic dysplastic kidneys

Question 12

Trisomies Recurrence Risk

Answer 12

1% until maternal age above 40 years (offer amino/CVS)

Don’t need to karyotype parents if karyotype shows nondisjunction trisomy 21.

Robertsonian translocation: check parents karyotype.
Recurrence risk for carrier t(21;21) is 100%

Question 13

5p- Syndrome

Answer 13

Part of P arm on 5 missing

Cri du chat syndrome (cat-like cry in infancy due to hypotonia and laryngeal abnormality)

Growth restriction, microcephaly, round face with widely spaced eyes, single palmar creases.
Moderate to severe ID.

Question 14

Microdeletion Syndromes

Answer 14

Deletion on chromosome dependent on band resolution of the karyotype

Use FISH and Microarray

22q11 deletion syndrome (DiGeorge/Velocardiofacial)

Contiguous gene deletion syndromes

Variable phenotypes

Question 15

Recurrent

Answer 15

22q11 deletion syndrome

Same size of deletion

Question 16

Non-recurrent

Answer 16

5p- (Cri du Chat)

Not always same size deletions

Question 17

22q11.2 deletion syndrome

Answer 17

Originally independent syndromes (DiGeorge or Velocardiofacial syndrome) 
Deletion on 22q11
Mild facial dysmorphology, slow growth
Cleft palate 
Pharyngeal pouch anomalies

Question 18

DiGeorge syndrome (22q11)

Answer 18

Thymus and parathyroid abnormalities (neonatal hypocalcemia)
Cardiac defects (interrupted aortic arch, tetralogy of Fallot)
Broad face, minor ear anomalies

Question 19

Velocardiofacial- VCF (22q11)

Answer 19

Palatal abnormalities
Face: long narrow, tubular nose, round tip
Heart: ventricular septal defect, tetralogy of Fallot
Growth and learning deficiency
***Autosomal dominant

Question 20

22q11.2 deletion (mechanism)

Answer 20

Non-allelic homologous recombination (NAHR)

Long repeats similar and so can get mispairing and non-allelic homologous recombination=> get two sizes of deletions

Contiguous: all the beads on the string get deleted.

More analysis does not help.

Question 21

22q11.2 FISH

Answer 21

Probe for 22q11.2 and control probe 22q13 (end up seeing deletion)

Can see results in interphase too!

Question 22

WAGR Syndrome

Answer 22

Multiple malformation syndrome:
Wilms tumor of the kidney (40%)
Identification of WT1 gene at 11p13
Aniridia (blindness)- deletion of PAX6 gene at 11p13
Genital anomalies (small phallus, undescended R testis)- deletion of WT1
Retardation of growth and development

Question 23

Williams Syndrome

Answer 23

Contiguous gene deletion syndrome

Depressed nasal bridge, eye puffiness, blue eyes (stellate the pattern), long philtrum, wide mouth, delayed development
Cocktail personality
Supravalvar aortic stenosis (75%)
Hypercalcemia (33%)

Heart anomaly-> test them

Deletion can be of many sizes (on 7q)-including elastin

Autosomal dominant

Question 24

Sex Chromosome Disorders

Answer 24

XXX (1/1000 females)
XXY (1/1000 males)
XYY (1/1000 males)

Phenotype not detected at birth

Klinefelter syndrome (47, XXY) is only distinctive phenotype later in life.

10 point IQ deficit
Employed and married
Good outcome if low-stress home

Question 25

Klinefelter syndrome (47, XXY)

Answer 25

1/1000 males
Small firm testicles; long legs
Gynecomastia: breast cancer risk=women
Hypogenitalism and azospermia

Multiple X variants (48XXXY-mental retardation and dysmorphology)

Male with multiple X chromosomes

Question 26

47, XYY and 47, XXX

Answer 26

No syndromes: no phenotype and normal fertility

Diagnosed by amniocentesis

Offspring usually chromosomally normal

Genetic counseling emphasizes lack of predictability of antisocial behavior for XYY

Question 27

Turner Syndrome (overview)

Answer 27

Disorder in females where there is absence of normal second sex chromosome
1/5000
Karyotypes: 
50% 45,X
25% mosaic (may include Y)
Various X deletions
Rings, isochromosomes

Question 28

Turner Syndrome (general)

Answer 28

Newborns: edema of hands and feet, web neck
Adolescents: lack of puberty and short
Short because halpoinsufficiency (1 of 2 copies not present) of SHOX gene
80% dude to a sense of father’s X or Y
No increase in recurrence risk to parents

Treatment with growth hormone

Question 29

45, X Turner Syndrome

Answer 29

Term AGA female with excess posterior nuchal skin folds, dorsal edema of the feet with small nails and weak femoral pulses.

Found to have coarctation of the aorta

Question 30

46, XY Female Turner Syndrome

Answer 30

FISH probe for SRY gene (SRY gene deleted)
SRY for male development of testis
Females need 2nd X for ovarian maintenance, thus streak gonads

Meiosis: pseudoautosomal regions on short arms of X and Y pair and recombination.
Abnormal crossover: SRY transferred to X chromosome.

46, XX male: SRY moved to X chromosome
46, XY female: SRY not on Y chromosome