Clinical cytogenetics

Question 1

3 well defined non mosaic autosomal trisomies

Answer 1

Trisomy 21-Downs syndrome
Trisomy 18, Trisomy 13.
Somewhat tolerated by body so we will see live born infants . . . No other chromosome trisomies would tolerate life

Question 2

Autosomal disorders

Answer 2

Can be either TRISOMIES OR MONOSOMIES

Question 3

Down syndrome

Answer 3

most common chrome disorder and cause for moderate mental retardation.*Atrioventricular septal defect. Simian crease, clinodactyly, congential Heart disease,duodenal atresia, and tracheoesophageal fistula, premature dementia w/ features of alzheimers. Hypotonia, short,brachycephaly,flat occiput, flat nasal bridge with low set ears,Burshfield spots around iris, epicanthal folds

Question 4

Chromosomes in Down syndrome: True Trisomy 21

Answer 4

95% due to meiotic nondisjunction
4% Robertsonian translocation 21q and chromosome 14 or 22. no relation to maternal age, high risk of recurrence in families.
21q21q translocation-> isochormosome: can’t have normal children, 1% recurrence risk, greater for mothers over 30

Question 5

Mosaic down syndrome

Answer 5

rare

Question 6

Partial trisomy

Answer 6

very rare; only part of q arm of chromosome 21 in triplicate. A down syndrome patient with no cytogenetically visible chromosome abnormalities.

Question 7

Trisomy 18-Edward Syndrome-phenotype

Answer 7

*Fist clench of 2nd and 5th digits overlapping 3 and 4th, ears low set and malformed, head with prominent occiput, jaw recedes, Rocker-bottom feet, hypo plastic nails, mental retardation, severe malfomation of heart

Question 8

Trisomy 18

Answer 8

Increased maternal age. exists in translocation and mosaic form. 95% of conceptuses are spontaneously aborted.Usually do not survive more than a few months.

Question 9

Trisomy 13-Patau Syndrome phenotype

Answer 9

Cleft lip and palate, occular abns, microcephaly and wide open suture, congential heart and urogenital defects, severe central nervous system, rocker-bottom feet, clenched fist, simian crease, mental retardation, microphthalmia, iris coloboma, post axial polydactyly, sloping forehead and malformed ears

Question 10

Trisomy 13

Answer 10

increased maternal age, usually nondisjunction, recurrence <2%.

Question 11

Full monosomies cannot be tolerated, but

Answer 11

there are some partial monosomies,

Question 12

Autosomal deletion syndromes

Answer 12

cytogenetically visible autosomal deletions occur with an incidence of 1/7000.
Ex. Cri du Chat

Question 13

Cri Du Chat Syndrome

Answer 13

Large deletion in chromosome 5p. del5p15.3. 1% of institutionalized mentally retarded. 10-15% are offspring of translocation carriers.
Haploinsufficiency of genes within band 5p15.2

Question 14

Cri Du Chat phenotype

Answer 14

Microcephaly, hypertelorism-wide bridge of nose, wide spaced eyes; severe mental retardation, epicanthal folds, low set ears, micrognathia, heart defects

Question 15

Microdeletion syndromes

Answer 15

Segmental aneusomy->small deletions. Contiguous gene syndrome:haploinsufficiency of multiple contiguous genes.
Ex.Charcot-Marie-Tooth, DiGeorge syndrome
Cannot be seen under normal microscope-use high resol like FISH.

Question 16

DiGeorge Syndrome or Velocardiofacial Syndrome

Answer 16

AD Microdeletion in chromosome 22q11.2.

common,mediated by homologous recombination b/w low copy repeated seqs.

Question 17

DiGeorge Syndrome or Velocardiofacial Syndrome-Phenotype

CATCH-22

Answer 17

Heart defects-5% of all congenital heart defects.
40% of patients with tetralogy of Fallot and Pulmonary atresia.
60% with tetralogy of Fallot and absent pulmonary valve.
Craniofacial anomalies, mental retardation
Cardiac
Abnormal facies
Thymic hypoplasia
Cleft palate
Hypocalcemia

Question 18

Tetralogy of Fallot:

Answer 18

1. Ventricular septal defect b/w right and left ventricles
2. narrowing of pulmonary outflow tract
3. Overriding aorta that is shifted over the right ventricle and ventricular septal defect, instead of coming out only from the left ventricle
4. Thickened wall of the right ventricle (right ventricular hypertrophy)

Question 19

Sex chromosomes,X and Y play role in primary(gonadal) sex

Answer 19

X and Y pair during meiosis I -> pseudoautosomal region. Y encodes for less than 50 genes

Question 20

Embryology of the reproductive system

Answer 20

6th wk both sexes form primitive gonads.
Default developmental pathway -> ovarian
TDF-testis determining factor-> medullary tissue forms testis with seminiferous tubules and Leydig cells.
Female ext genitalia form regardless of ovary present

Question 21

Y Chromosome

Answer 21

TDF/SRY-sex determining region on Y
SRY strongly implicated in male sex determination, near pseudoautosomal boundary.
AZF-Azoospermia factors->AZF a,b,c. Deletion can lead to azoospermia->idiopathic infertility

Question 22

X chromosome inactivation

Answer 22

Barr body-> inactive X chromosome, extra X’s also inactivated to form barr bodies.
*Both male and female have ONLY ONE active X chromosome.

Question 23

X chromosome inactivation center

Answer 23

Xq13 and encodes for XIST gene-inactive X specific transcripts

Question 24

XIST

Answer 24

produces key regulatory non coding RNA that is only expressed on the inactive chromosome and transcriptionally silent on the active X
XIST RNA/Barr body complex

Question 25

Non random X chromosome inactivation

Answer 25

Normally see random inactivation. | unbalanced structure causes abn chrome to be inactive. Most X autosome translocations are non randomly inactivated

Question 26

X-linked mental retardation

Answer 26

high freq of mutations/microdeletions that cause X-linked mental retardation. common

Question 27

Monosomy X (Turner Syndrome)

Answer 27

less freq in live born, common in spontaneous abortions. Rare structural abns: isochrone of q of X chrome. Mosaicism is more common for sex chromes than autosomes

Question 28

Klinefelter Syndrome

Answer 28

50% errors in paternal meiosis. Barr bodies 15% mosaic karyotypes

Question 29

Klinefelter Syndrome phenotype

Answer 29

Tall, thin males, long legs, hypogonadism appear at puberty, underdeveloped secondary sex characteristics, infertile, some psych probs

Question 30

47, XYY Syndrome

Answer 30

tall, attention deficit, hyperactivity, impulsiveness, normal intelligence, fertile, no increase in aggression or psychopathology. Paternal meiotic nondisjuntion Not assoc with clinical phenotypes

Question 31

Trisomy X (47, XXX)

Answer 31

above avg stature, no abn phenotype, fertile but increased risk of abn offspring, abn behavior, IQ below normal, (48, XXXX)-restricted physical and mental dev (49,XXXXX)-severe developmental retardation with multiple physical defects

Question 32

Turner Syndrome (45, X and variants)

Answer 32

50% 45,X | 25% mosaic karyotypes, isochromosome X

Question 33

Turner Syndrome Phenotype

Answer 33

Short stature, webbed neck, Broad chest w/widely spaced nipples, coarctation of aorta, cystic hygroma, Low post. hairline, gonadal dysgenesis, renal and cardio anomalies, infantile edema of dorsum of foot Above to avg. intelligence, worse social cognition skills if X from mother

Question 34

Hermaphroditism

Answer 34

presence of both ovarian and testicular tissue.

Question 35

Gonadal Maldevelopment: Camptomelic dysplasia

Answer 35

mutation in SOX9 gene which is involved in testes formation

Question 36

Gonadal Maldevelopment: Sex Reversed 46,XY

Answer 36

``` subclass SRY not deleted-> testis formation at a critical point. Duplication of Xp21->excess of DAX1 suppresses SRY and leads to ovarian development ```

Question 37

Denys-Drash Syndrome

Answer 37

female or ambiguous external genitalia, mutation in WT1 gene disrupts normal testicular development. 9p deletion syndrome->DMRT1 gene deletion which is involved with gonad development

Question 38

Female Pseudohermaphroditism

Answer 38

gonadal tissue of only one sex. 46, XX with ambiguous external genitalia usually caused by congenital adrenal hyperplasia. -AR disorder arising from defects in enzymes for cortisol biosynth. Ovarian dev normal, excess androgens cause masculinization-clitoral enlargement and labial fusion. *21-hydroxylase deficiency***

Question 39

Congenital Adrenal Hyperplasia

Answer 39

AR, cortisol and aldosterone deficiency, androgen overproduction- can affect both sexes.

Question 40

Congenital Adrenal Hyperplasia: Female phenotype

Answer 40

Female phenotype:enlarged clot with urethral opening at base-ambiguous. Normal internal structures of repro tract W/age->deep voice, appearance of facial hair, failure to menstruate at puberty.

Question 41

Congenital Adrenal Hyperplasia: Male phenotype

Answer 41

testes small at puberty, may cause adrenal crises in neonates due to salt wasting. vomitting, dehydration, changes in electrolyte profile, cardiac arrythmia. death if untreated

Question 42

Male Pseudohermaphroditism

Answer 42

Deficiency of 5-reductase steroid! Androgen insensitivity syndrome (AIS), lack of androgen receptors in target cells. Normal female external genitalia, blind vagina, no uterus/uterine tubes. AIS-X-linked inheritance