Genetics of Development Flashcards by Malgorzata Gorajek

How many babies are affected by congenital anomalies?

1 in 20 babies

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Why are congenital animalities so dangerous?

Extremely lethal

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What is cyclopia?

Most severe form of holoprosencephaly

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Why is cyclopia so severe?

Due to a lack of connections on the midline and gaps in the brain.

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What is the mildest form of cyclopia?

Single midline incisor tooth

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What is cyclopia caused by?

Chromosomal abnormalities eg. Trisomy 13

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What are the Common congenital anomalies in live births?

Craniofacial Anomalies
Neural tube defects
Congenital Heart Defects
Congenital Kidney Disease
Multisystem Anomalies

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What kinds of Craniofacial Anomalies are there?

Cleft Lip/Palate

Craniosynostosis

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What are Craniosynostosis?

Bones in the head fuse prematurely.

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What is the cause of congenital anomalies, genetically?

Most are unknown but all discoverable.

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What is the VUS?

A variant of uncertain significance is a genetic change whose clinical impact is not understood.

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How long is a human pregnancy?

38-40 weeks.

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What is human pregnancy usually broken up into?

Embryonic and fetal stage

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When is the embryonic stage?

Up to 8 weeks

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When is the fetal stage?

8 weeks to term.

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When does oganogenesis occur?

During embryogenesis

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When do congenital anomalies occur?

First 8 weeks usually

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What are congenital anomalies caused by physical?

Abnormal development of the embryo/fetus

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What can be used to study genes regulating development?

Model organism

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What does it mean when genes regulating development are conserved?

This means they were kept from ancestors through evolution and are often shared between species.

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What is the Pax6 example of development gene conservation?

If you knockout pax6 the mouse is born with no eyes

If you remove the pax6 gene from a mouse and add it to a knockout fly it is born with eyes.

Pax6 gene similar between the two.

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What are the patterns of anomalies?

Isolated

Syndromes

Sequences

Associations

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What is an isolated pattern?

Single organ/structure affected

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What is a syndrome?

Multiple organs/structures affected, shared aetiology

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What is a sequence patten?

Multiple organs/structures affected, development is interconnected.

What is am association pattern?

Multiple organs/structures affected, too common to be just chance but no clear shared aetiology

What kind of patten is a cleft palate?

Isolated

What kinds of genetics cause a cleft palate?

TBX22

Where is TBX22 expressed?

Developing orofacial cavity.

What is Holt-Oram (“hand-heart”) syndrome?

Holt-Oram patients have defects in the upper limbs and the heart

How is Holt-Oram (“hand-heart”) syndrome inherited?

Autosomal dominant

What kinds of genes cause Holt-Oram (“hand-heart”) syndrome?

TBX5

Where is TBX5 expressed?

In the heart and the forelimbs (but not hindlimbs).

What is the Pierre-Robin sequence?

Defects in the lower jaw, palate, breathing difficulties and failure to thrive.

How is Pierre-Robin sequence inherited?

Not generally inherited – thought to be de novo mutations in multiple genes.

What is the initial defect in Pierre-Robin sequence?

Micrognathia

What is micrognathia?

A condition in which a child has a very small lower jaw.

How is Pierre-Robin sequence fatal?

Tongue is displaced which stops the palate closing and blocking airway.

What is VACTERL association?

* Vertebral defects * Anal atresia * Cardiac defects * Tracheo-Esophageal fistula * Renal abnormalities * Limb anomalies

What is VACTERL association caused by?

Cause unknown (not inherited).

What kinds of environmental causes are there for congenital anomalies?

Viruses Maternal illness Drugs Pollutants Diet

What kinds of genetic causes are there for congenital anomalies?

Chromosomal defects Single genes Multi-gene interactions

When is zika virus most dangerous?

During pregnancy.

What happens to the baby when the mother gets zika virus?

Microcephaly

What is microcephaly?

The head is very small and therefore so is the brain.

When are the biggest risk of getting zika virus?

First and second trimester.

How many pregnancies result in miscarriage?

10-15%

What percentage of miscarriages have chromosomal abnormality?

50%

What are chromosomal abnormalities caused by?

Non-disjunction events during meiosis

What is caused by non disjunction events during meiosis?

Whole or part of chromosome extra/missing therefore multiple genes affected.

What is the main risk for chromosomal activity?

Maternal age.

Why is maternal age the main risk factor for chromosomal abnormality?

Oocytes halt in metaphase II stage of meiosis for up to 40 years.

What is DiGeorge Syndrome?

Characteristic facial appearance Congenital heart defects Thymus and parathyroid hypoplasia

What is the genetic cause for DiGeorge syndrome?

Deletion of chromosome 22q11.2 ~30 genes deleted Haploinsufficiency for TBX1

What is the Ulnar-mammary syndrome?

Posterior limb deficiencies Delayed puberty in males Genital anomalies

What gene is Ulnar-mammary syndrome?

TBX3

What is the homeobox?

Contains the Genes of the Hox family. DNA binding region

What are hox genes?

Transcription factors that regulate the expression of other genes that specify body parts

Where is 22q11.2?

At the end of the chromosome.

What do Neural tube defects result in?

Elective TOP or still birth

What are Neural tube defects caused by?

Caused by abnormalities in the normal process of neurulation

What are the prevention measures of birth defects?

Folic acid (B vitamin) reduces the risk of neural tube defects by up to 35% 400 mg daily B vitamins (inositol)

What is cilia?

Complex microtubule-based structures that project from the cell surfacre

What are the 2 main types of cilia?

motile and primary

What is the function of cilia?

Movement Sensing Signalling

Where do mutations in motile cilia affect?

Organ placement Infertility Brain Respiration system heart

Where do mutations in non-motile cilia affect?

Eyes Nose Ears Energy Skeleton Reproduction Brian Kidney Liver

What can mutations in the cilia which affect movement cause?

Mutations in cilial genes found in patients with male infertility and severe persistent airway infections

What can mutations in the cilia which affect sensing cause?

Retinitis pigmentosa

What can mutations in the cilia which affect signalling cause?

Nephronophthisis and polycystic kidney disease

What is SHH gene?

Sonic Hedge Hog

What is the function of SHH?

Development in cell growth, specialization and normal shaping.