4 Chromosomal Disorders

Question 1

What is aneuploidy?

Answer 1

Aneuploidy is any chromosome number that is not an exact multiple of haploid number (23)

Question 2

What are the most common forms of aneuploidy in humans?

Answer 2

Trisomy (presence of extra chromosome), Monosomy (the presence of a single chromosome)

Question 3

What is the leading genetic cause of intellectual disability?

Answer 3

Aneuploidy

Question 4

The genotype 45, X and coarctation of the aorta is what syndrome?

Answer 4

Turners Syndrome

Question 5

What are the most tolerated autosomal aneuploidies?

Answer 5

Trisomy 18, 13, 21 (Down sydnrome)

Question 6

Which trisomies are semilethal?

Answer 6

Trisomy 18 and 13 are semilethal with low survival rates beyond a few months

Question 7

Complete monosomies of autosomes are …

Answer 7

lethal

Question 8

When does frequency of trisomies increase?

Answer 8

Advanced maternal age, 35 yo or greater at delivery warrant prenatal diagnosis

Question 9

What is the most common trisomy?

Answer 9

trisomy 16 but it is never observed in liveborns

Question 10

Why are aneuploidies 21, 18, 13, Y and X tolerated?

Answer 10

It may have to do with the size of the chromosome, these are the smallest chromosomes

Question 11

What is the parental origin of aneuploidy for 21, 18, 13, and XXX?

Answer 11

Maternal nondisjunction

Question 12

What is the parental origin of aneuploidy for XXY?

Answer 12

Maternal and paternal non-disjunction is equal

Question 13

What is the parental origin of aneuploidy 45, X (Turner syndrome)?

Answer 13

Mainly paternal non-disjunction

Question 14

Trisomy 21 (Down Syndrome)

Answer 14

Dysmorphology (upslanting palpebral fissures, overfolded helices, single palmar transverse creases, short/bent 5th fingers), 40-50% congenital heart disease, hearing loss due to otitis media, strabismus and refractive errors, hypothyrodism, moderate intellectual disability

Question 15

Chromosomes in Down Syndrome

Answer 15

95% of trisomy 21 due to nondisjunction (75% in maternal meiosis I, 25% in maternal meiosis II), 4% Robertsonian translocation between 21 and another acrocentric chromosome (14, 22), 1% mosaic trisomy 21

Question 16

Robertsonian translocation

Answer 16

translocation between two acrocentric chromosomes by fusion at or near the centromere, with loss of the short arms (karyotype 46, XY, t (14;21) - down syndrome due to Robertsonian translocation - part of 21 is translocated to 14)

Question 17

What do you do when a patient has a structurally abnormal chromosome?

Answer 17

Study parental chromosomes, karyotype parents if there is structurally abnormal chromosomes (could have been inherited from parent (~1/3 cases)

Question 18

Trisomy 18 (Edwards Syndrome)

Answer 18

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 and left foot with missing digits. Cardiac defect and renal anomaly. Severe ID

Question 19

Trisomy 13 (Patau Syndrome)

Answer 19

Holoprosencephaly with premaxillary agenesis (atypical median cleft lip/palate); micropthalmia, flexed fingers, polydactly, cryptorchidism, abnormal scrotum, cardiact defect and cystic kidneys. Normal birthweight but microcephaly, holoprosencephaly, closed hand, short prominent sternum, omphalocele, micropenis, “rocker-bottom” feet, ventricular septal defect

Question 20

What is the recurrence risk for carier t(21, 21)?

Answer 20

100%

Question 21

What is 5p- syndrome?

Answer 21

Deletied part of chromosome 5, Cri du chat syndrome (cat like cry in infancy is due to hypotonia and laryngeal abnormality), growth restriction, microcephaly, round face with widely spaced eyes, single palmar creases, moderate to severe intellectual disability

Question 22

What techniques do you want to use for microdeletion syndromes?

Answer 22

FISH and Microarray allow for greater detail

Question 23

What is 22q11.2 deletion syndrome?

Answer 23

Due to deletion of 22q11, mild facial dysmorphology, slow growth, cleft palate, cardiac defects, thymus and parathyroid abnormalities, broad face, minor ear anomalies, palatal abnormalities, long narrow, tubular nose, round tip, tetralogy of fallow, ventricular septal defect, growth and learning deficiency

Question 24

What is the mechanism of 22q11.2 deletion?

Answer 24

Non-alleclic homologous recombination (NAHR)

Question 25

What is WAGR syndrome?

Answer 25

Multiple malformation syndrome, Wilms tumor of the kidney (40%), Identification of WT1 gene at 11p13, Aniridia (deletion of PAX6 gene at 11p13, genital anomalies - del of WT1 at 11p13, Retardation of growth and development

Question 26

What is a contiguous gene deletion syndrome?

Answer 26

is a clinical phenotype caused by a chromosomal abnormality, such as adeletion or duplication that removes several genes lying in close proximity to one another on the chromosome.

Question 27

What are the clinical phenotypes associated with Williams Syndrome?

Answer 27

Depressed nasal bridge, eye puffiness, blue eyes (stellate pattern), long philtrum, wide mouth, delayed development, cocktail personality, supravalvar aortic stenosis (75%), hypercalcemia (33%) - associated with elastin gene

Question 28

What sex chromosome disorder is associated with a distinctive phenotype?

Answer 28

Klinefelter syndrome (47, XXY), usually seen later in life

Question 29

What are the characteristics of Klinefelter syndrome (47, XXY)?

Answer 29

1/1,000 males, small firm testicles, relatively long legs, gynecomastia (breast CA risk = women), hypogenitalism and azospermia (no sperm), multiple variants (48 XXXY - mental retardation and dysmorphology)

Question 30

47, XYY and 47,XXX are…

Answer 30

not syndromes, no phenotype and there is generally normal fertility, offspring usually chromosomally normal, genetic counseling emphasizes lack of predictability of antisocial behavior of 47, XYY

Question 31

What is Turner Syndrome?

Answer 31

Defined as a disorder in females in which there is absence of a normal second sex chromosome, phenotypicall female, due to absence of all or part of an X chromosome

Question 32

What are the characteristics of Turner Syndrome?

Answer 32

Commonly diagnose in Newborns - edema of hands and feet, web neck, Adolescence- lack of puberty and short stature. Suspect in any girl with short stature. Short stature due in part to haploinsufficiency (1 of 2 copies not present) of SHOX gene. 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 33

What is a 46, XY Female/

Answer 33

SRY gene is deleted. In embryogenesis, the SRY gene on the Y chromosme directs the indifferent gonad to develop into a testis. Females need a 2nd X for ovarian maintenance, thus patients have streak gonads and are infertile.