Paediatric Genetics

Question 1

What are the features of Down syndrome?

Answer 1

Trisomy 21
Learning disability
Congenital heart disease
Hypothyroidism
Immunity (possibility of lymphopenia)
Early onset Alzheimer disease

Question 2

What form of Down’s testing poses no harm to the foetus?

Answer 2

Non-invasive prenatal testing using next-generation sequencing of free fetal DNA in maternal blood

Question 3

What other trisomies are there?

Answer 3

13 and 18

Question 4

What does congenital mean?

Answer 4

Present at birth

Can be caused by genetics, environment or both

Question 5

What are Multiple Congenital Anomaly Syndromes?

Answer 5

Two or more unrelated major structural malformations that cannot be explained by an underlying syndrome or sequence

Single gene disorders 30%
10% chromosomal
5% teratogens
55% unknown

Question 6

How common are congenital abnormalities?

Answer 6

3% all births
20% children’s hospital admissions
30% infant deaths

Question 7

What is a syndrome?

Answer 7

Pattern of clinical features occurring together

Cause may or may not be known

Question 8

How common are Multiple Congenital Anomaly Syndromes?

Answer 8

Individually rare

Common as a group

Question 9

What are the principles of diagnosing syndromes?

Answer 9

Clinical experience

Gestalt vs. recognition of pattern of features

Use of databases
-22 000 genes - how many genetic disorders?

Rapidly increasing utility of genomic analysis is revolutionizing diagnosis

Question 10

How is a rare intellectual disability and/or malformation syndrome diagnosed?

Answer 10

History
Description
Recognition of patterns

Testing

• Standard- biochemical, chromosome structure
• Microarray now standard
• Targetted testing
• Moving to trio-based exome/genome

Question 11

What signs of genetic condition may manifest in the head?

Answer 11

Shape
Size: macrocephaly, microcephaly
Ear position - Low set, posteriorly rotated indicates lack of maturity

Question 12

What signs of genetic condition may manifest in the eyes?

Answer 12

Hypertelorism
-Inner canthal distance ICD and inter-pupillary distance IPD increased

Telecanthus/epicanthic folds
-ICD and IPD increased

EYES

Question 13

What signs of genetic condition may manifest in the hands?

Answer 13

Finger length
Digital abnormalities
Palmar creases

Examples Marfan syndrome, Down syndrome

Question 14

What is the hand anomalies in Marfan’s Syndrome?

Answer 14

Long, thing fingers

MF/THL usually >44%

Question 15

What are the words used describe long and short fingers?

Answer 15

Arachnodactyly

Brachydactyly

Question 16

What is polysyndactyly and what is a cause?

Answer 16

Conjoined and extra fingers or toes

Hox D13

Question 17

What is acrocephalopolysyndatyly and what is a cause?

Answer 17

Premature closing of cranial sutures commonly along with syndactuly (fusion of fingers or toes)
Greig/GLI3

Tall forehead
Polydactyly (multiple)
Syndactyly (joined)

Question 18

What are sequences?

Answer 18

One abnormality leads to another, can have multiple causes

Question 19

What is the Pierre-Robin sequence?

Answer 19

Small chin to cleft palate

Question 20

What is the foetal akinesia sequence?

Answer 20

Reduced foetal movement
Reduced breathing
Contractures
Clefting
Lung hypoplasia

Question 21

What is deformation and disruption?

Answer 21

Pattern of development normal to start with but becomes abnormal

Deformation: Organ parts are there
Disruption: Parts of organ/body part absent

Question 22

What is an association?

Answer 22

Two features or more features occur together more often than expected by chance
Mechanism unclear

Question 23

What is VATER?

Answer 23

V vertebral/VSD
A anorectal atresia
T tracheo-
E (o)esophageal fistula
R radial anomalies

Vaters syndrome

Question 24

What are features of Turner syndrome?

Answer 24

45 X

Lymphoedema (Puffy feet, nuchal translucency/cystic hygroma)

Increased carrying angle, low hairline, wide sp nipples, sandal gap

Short stature, occ. v mild learning diffy

Coarctation of aorta, hypothyroidism, UTI, osteoporosis & hypertension

Primary amenorrhoea & infertility

Hormonal therapy mitigates some features

Question 25

How might you genetically investigate a learning disability?

Answer 25

Microarray

Fragile X - for learning disability

Targetted tests driven by phenotype (cheaper)

Trio based Exome vs. trio-base genome analysis

• Funding remains an issue
• Trio-based exome in Scotland and genome in England!

Question 26

What are the signs of 22q11 deletion?

Answer 26

CATCH 22

C - Cleft palate
A - Abnormal facies
T - Thymic hypoplasia/immune deficiency
C - Calcium
H - Heart problems

Question 27

We all have variation in our genome so how can we test thousands of genes and find the cause of the intellectual disability?

Answer 27

Trio-based testing compares parents with child to filter out silent variations

• Exons are targeted
• Only relevant parts of genome targeted

Question 28

What is the importance of phenotyping?

Answer 28

The key to assessment of clinical relevance is the phenotype
That’s why accurate description of clinical features is important
A diagnosis helps the family see the future
And can help with future pregnancy planning, clinical care and treatment