18.03.44 Chromosome 21

Question 1

What is the incidence of Down syndrome?

Answer 1

The chromosome abnormality with the highest incidence at birth is trisomy 21 - 1 in 750 births

Question 2

What are the possible genetic origins of Down syndrome.

Answer 2

Nondisjunction (95%)
Robertsonian (5%)
Reciprocal translocation (0.1%)

Question 3

What is the most common nondisjunction event that can lead to Down syndrome?

Answer 3

Nondisjunction at maternal meiosis 1 accounts for ~70% of NDJ events leading to trisomy 21

20% at meiosis II
5% paternal MI and MII
5% Mitosis

Question 4

What is the recurrence risk for T21 that has resulted from a non-disjunction event?

Answer 4

1%

Question 5

What proprotion of T21 Robertsonian cases arise de novo? What is the most common form?

Answer 5

75%

82% are isochromosome i(21;21)

Question 6

What are the recurrence risks for T21 associated with inhertied heterologous Robertsonian translocations?

Answer 6

10-15% if maternal

<1% if paternal

Question 7

What is the recurrence risk associated with the inherited homologous Robertsonian translocation t(21;21)

Answer 7

100%

Question 8

What proportion of trisomy 21 cases are mosaic?

Answer 8

2%, usually as a result of anaphase lag in trisomic conceptus or nondisjunction in a normal conceptus

Question 9

What are the characteristic features of Down syndrome?

Answer 9

Frequent single known cause of intellectual disability IQ 25-70. Phenotype is variable
Characteristic facial features: brachycephaly/microcephaly, epicanthic folds, flattened nose, low set ears, protruding tongue
Short stature
Broad short hands with single palmar crease
clinodactyly
sandle-gap
infantile hypotonia
infertility in males
cardiac abnormalities (50%) (ASD, 40%, VSD 30%)
Transient leukaemia (10%) at birth
Eye disease (60%)
Hearing loss (70%)
Hypothyroidism (15%)
Early-onset Alzheimers

Question 10

Where on chromosome 21 is the DSCR located?

Answer 10

21q22.13-q22.3
however suggestive there are multiple susceptibility loci rather than one particular critical region
DYRKA1 gene is thought to play a crucial role in brain development and a strong candidate for LD
ADAMTS1 - candidate for normal growth, fertility, organ morphology and function.

Question 11

What are the features of monosomy 21?

Answer 11

<9 cases reported
Few survive to term. Die soon after delivery. Cryptic mosaicism in these case can’t be excluded.
Only reported autosomy monosomy reported in early miscarriages and perinatally.
Features highly variable, may include: IUGR, severe multiple malformations, complex cardiac abnormalities, skeletal abnormalities, microcephaly, hypotonia eye anomalies.

Question 12

Describe the types of phenotypes associated with the ring 21 karyotypes: 47,XN,+r(20), 46,XN,r(21), mosaic ring(20)

Answer 12

+r(21) partial trisomy and DS features expected
r(21) replacing a normal chr 21 leads to partial monosomy with a variable phenotype; developmental delay with congenital malformations to normal (particularly those that are inherited). Can lead to infertility or subfertility.
Mosaic: ring can be lost of forms double rings. may lead to ‘ring-syndrome’.
Compensatoy isodisomy of ring 21 or 21qdel has been observed.

Question 13

Describe the features of DYRK1A-related syndrome.

Answer 13

DYRK1A (21q22.13) disruption is associated with distinct syndrome including developmental delay, ID< microcephaly, speech delay, feeding difficulties. Deletions can be larger and include adjacent genes.
Should be considered as a differential diagnosis to Angelman syndrome.

Question 14

Describe the features of Braddock-Carey syndrome.

Answer 14

Contiguous deletion encompassing RUNX1 (21q22.11-q22.13).
Main features are thrombocytopaenia adn Pierre-Robin sequence, agenesis of corpus callosum, developmental delay and dysmorphism.
HI of SON has been proposed as candidate for the ID seen in this syndrome. SON point mutations also associated with cardiac disease and dysmorphism.