Topic 2: developmental genetics

Question 1

What is developmental genetics?

Answer 1

The study of how genes and their encoded proteins regulate and participate in the growth and development of an organism.

Question 2

What is mitosis?

Answer 2

The process of duplicating genomic material and dividing it into equal portions to faithfully replicate the original genomic information. Occurs nearly everywhere in the body, especially during development, and is required for growth.

Question 3

What is meiosis?

Answer 3

The process where four haploid (unique) cells are created from parent cells. Occurs in germ cells only and creates new versions of genetic material through meiotic recombination.

Question 4

What is the purpose of making the polar body in oocytes?

Answer 4

To save energy for the next steps, ensuring enough energy for proper formation, which is crucial for early embryo development.

Question 5

What role do the position of the polar body and the orientation of the sperm play?

Answer 5

They play a role in early embryo development.

Question 6

How many polar bodies are made in sperm?

Answer 6

Four polar bodies are made.

Question 7

What are the stages of normal development from a fertilized egg up to when the embryo hatches?

Answer 7

Fertilized egg, day 0, with 2 pronuclei and polar bodies.

Two-cell embryo, day 1.

Four-cell embryo, day 2.

Eight-cell embryo, day 3.

16-cell embryo, day 3 - totipotent cells.

Morula (compaction), day 4.

Blastocyst formation, day 5.

Question 8

What are totipotent cells?
What are some medical applications?

Answer 8

Cells that can give rise to all tissues necessary for embryo survival. Medical applications include IVF, PGD, and scientific research.

Question 9

What is the significance of blastocyst formation?

Answer 9

Differentiation begins, and cells become pluripotent, meaning they can differentiate into many different cell types depending on their development path. Medical applications include transplantations and iPSC for scientific research.

Question 10

What is the medical importance of totipotent hematopoietic stem cells?

Answer 10

They can be transplanted into a deficient individual to restore specific types of hematopoietic cells. Genetic mutations in myeloid progenitor cells affect a wide range of cells.

Question 11

What happens on Day 6 of embryonic development?

Answer 11

Clear polarizations form, with cells forming an outer layer called trophoblasts.

Question 12

What happens on Day 7 of embryonic development?

Answer 12

Growth extends further into the endometrium to gather resources for further growth, supported by trophoblasts.

Question 13

What happens on Day 8 of embryonic development?

Answer 13

Expansion into the endometrium with trophoblast expansion and the beginning of the formation of the amniotic cavity.

Question 14

What is gastrulation?

Answer 14

A morphogenetic process leading to the development of 3 primary germ layers – ectoderm, mesoderm, and endoderm. It is an extremely critical phase of development.

Question 15

What does the ectoderm give rise to?

Answer 15

The nervous system and skin.

Question 16

What does the endoderm give rise to?

Answer 16

Many visceral organs and the lining of the gut.

Question 17

What does the mesoderm give rise to?

Answer 17

All connective tissues, bone, vasculature, lymphatic, and hematopoietic systems.

Question 18

What do the neural tube and crest give rise to?

Answer 18

Cells in the peripheral and enteric nervous system, muscle craniofacial bones and cartilage, melanocytes. They arise at the ectoderm-neural ectoderm boundary.

Question 19

Front: What is the embryonic period?

Answer 19

Back: The first 8 weeks of development where the organism does not resemble the adult, all major organ systems are established, and sensitivity to teratogens varies.

Question 20

Front: When are organisms less sensitive to teratogens during development?

Answer 20

Back: Up to week 2, with an all-or-nothing effect (will live or die).

Question 21

when are organisms more sensitive to teratogens?

Answer 21

early to later-embryonic period (2-8 weeks)

Question 22

Front: What is the fetal stage?

Answer 22

Back: Weeks 9-40, where the organism resembles a human, focusing on the maturation and further differentiation of organ components, and is susceptible to functional defects or minor physical abnormalities.

Question 23

Front: What is the importance of brain development in the context of early-onset diseases?

Answer 23

Back: Genes affecting brain development are considered for early-onset diseases, while genes controlling brain maintenance are considered for late-onset diseases.

Question 24

What percentage of infant deaths are due to birth defects?

Answer 24

More than 20% of infant deaths.

Question 25

Can genetic defects manifest later even if a baby is born 'normal'?

Answer 25

Yes, congenital diseases may manifest themselves later (minutes, hours, weeks, months, years).

Question 26

What is chromosome imbalance and which trisomies are most common?

Answer 26

Chromosome imbalance involves autosomal trisomies of chromosomes 21, 18, and 13.

Question 27

What are some examples of single gene mutations causing birth defects?

Answer 27

Achondroplasia and Waardenburg syndrome.

Question 28

What are multifactorial birth defects and examples?

Answer 28

Birth defects with no identifiable cause, considered multifactorial. Examples: cleft palate and congenital heart defects.

Question 29

What are the three major categories of birth defects?

Answer 29

Malformations, deformations, and disruptions.

Question 30

What are malformations and what causes them?

Answer 30

Result from intrinsic abnormal developmental processes, often due to a genetic cause. Example: Proteus syndrome.

Question 31

What is pleiotropy?

Answer 31

A birth defect resulting from a single causative gene affecting more than one organ system at different times during intrauterine life.

Question 32

What is a syndrome in the context of birth defects?

Answer 32

Multiple abnormalities occurring in parallel, such as Proteus syndrome (develop asymmetrical and disproportionate overgrowth of body parts (malformations in vascular system, skeleton, and connective tissue). Caused by somatic mosaicism for de novo activating mutations in AKT1)

Question 33

What is a sequence in the context of birth defects?

Answer 33

When a single organ system is affected, leading to other pleiotropic effects as secondary effects. Example: Greig cephalopolysyndactyly (loss of function in transcription factor GLI3)

Question 34

What are deformations in birth defects?

Answer 34

Caused by mechanical forces. Example: congenital arthrogryposis, thalidomide effects.

Question 35

What are disruptions in birth defects?

Answer 35

Destruction of irreplaceable normal fetal tissue, harder to treat, not inherited.

Question 36

What are neural tube defects and when do they form?

Answer 36

Defects due to improper closure of the neural tube by day 28 of development, most common and devastating among birth defects.

Question 37

What factors can influence the frequency of neural tube defects?

Answer 37

Social factors, season of birth, and time, with a marked decrease in recent years, with a small proportion with known specific causes (e.g. single gen defects)

Question 38

What is anencephaly?

Answer 38

Absence of the forebrain, overlying meninges, vault of the skull, and skin. Most infants with anencephaly are stillborn or die shortly after birth.

Question 39

What is spina bifida?

Answer 39

Failure of fusion of the arches of the vertebrae, typically in the lumbar region. Severity ranges from spina bifida occulta (defects in bony arch only) to spina bifida aperta (protrusion of meninges)

Question 40

What is the greatest factor causing neural tube defects?

Answer 40

Maternal folic acid deficiency, exacerbated by a genetic variant of the enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR).

Question 41

How can neural tube defects be prevented?

Answer 41

Dietary supplementation with folic acid (400 to 800 µg per day) one month before conception and continuing for two months after conception, and prenatal screening.

Question 42

What is prenatal screening for neural tube defects?

Answer 42

Detecting excessive levels of alpha-fetoprotein (AFP) and other fetal substances in the amniotic fluid, and ultrasonographic scanning.

Question 43

What is pattern formation and why is polarization important?

Answer 43

Proper polarization is needed to determine positions and axes for budding out. Important genes include SHH (sonic hedgehog) and GLI3R. Malformations occur when this process is perturbed.

Question 44

What are the different axes in development?

Answer 44

Dorsal-ventral, cranial-caudal, and left-right.

Question 45

How is the dorsal-ventral axis determined in development?

Answer 45

Sperm entry point determines the boundary between trophoblast and inner cell mass.

Question 46

How is the cranial-caudal axis determined in development?

Answer 46

Determined by the position of the second polar body.

Question 47

How is the anterior-posterior axis determined?

Answer 47

Determined by SHH and GLI3. SHH inhibits the conversion of transcription factor GLI3 to GLI3R in the posterior region of the limb bud.

Question 48

What happens when there are mutations in GLI3?

Answer 48

GLI3 mutations cause two pleiotropic developmental syndromes: polydactyly and polydactyly with severe cutaneous syndactyly.

Question 49

What are morphogen gradients?

Answer 49

Secreted chemicals that signal to allow cells in a tissue to determine their position. ## Footnote Example: Zone of polarizing activity (ZPA).

Question 50

What are some effects of SHH mutations?

Answer 50

SHH missense mutation in a mother and her daughter causes different manifestations. The daughter has severe abnormalities, while the mother has a single central upper incisor.

Question 51

What is situs inversus and which gene is associated with it?

Answer 51

An abnormality in the X-linked gene ZIC3, involved in left-right axis determination, associated with cardiac anomalies.

Question 52

What are HOX genes and their significance?

Answer 52

HOX genes encode transcription factors with a conserved DNA-binding motif called the homeodomain. The segment encoding the homeodomain is called a homeobox.

Question 53

What are the effects of a gain-of-function mutation in HOXD13?

Answer 53

Creates an abnormal protein with a dominant negative effect, causing synpolydactyly.

Question 54

What is Congenital Vertical Talus and which HOX gene is associated with it?

Answer 54

A condition called ‘rocker bottom foot’ associated with HOXD10.

Question 55

What is Hand-foot-genital syndrome and which HOX gene is associated with it?

Answer 55

A syndrome causing shortening of thumbs and toes, genital and urinary tract anomalies, associated with HOXA13.

Question 56

Why is programmed cell movement critical in development?

Answer 56

Critical for development, especially in the central nervous system.

Question 57

What is Miller-Dieker syndrome and its cause?

Answer 57

Caused by a deletion involving one copy of the LIS1 gene on chromosome 17, leading to disorganized cortical neuron migration and severe brain abnormalities (progressive waves of migration of cortical neurons do not occur in an organized fashion because of reduced speeds of migration. Result is a thickened, hypercellular cerebral cortex with undefined cellular layers and poorly developed gyri).

Question 58

What is Lissencephaly and its characteristics?

Answer 58

A severe abnormality of brain development causing a 'smooth brain' with profound intellectual disability, associated with Miller-Dieker syndrome.

Question 59

What are the categories of chromosomal and genomic abnormalities?

Answer 59

Nondisjunction, recurrent chromosomal syndromes, idiopathic chromosomal abnormalities, unbalanced familial chromosomal abnormalities, chromosomal and genomic events revealing regions of genomic imprinting.

Question 60

What are the mechanisms of chromosomal abnormalities?

Answer 60

Aneuploidy, Uniparental Disomy, Microdeletion and duplication syndromes, Idiopathic chromosome abnormalities, Disorders associated with genomic imprinting, Neurodevelopmental disorders.

Question 61

What is aneuploidy?

Answer 61

Errors in chromosome segregation leading to trisomy or monosomy. Only three well-defined nonmosaic autosomal chromosome disorders compatible with postnatal survival: trisomy 21 (Down syndrome), trisomy 18, and trisomy 13.

Question 62

What determines the developmental abnormalities in trisomies?

Answer 62

The extra gene dosage. Current research is beginning to localize specific genes responsible for the abnormal phenotypes.

Question 63

What is Down Syndrome (trisomy 21)?

Answer 63

The most common genetic defect of moderate intellectual disability. Diagnosed by dysmorphic features and intellectual disability. Caused by an extra copy of chromosome 21 due to meiotic nondisjunction.

Question 64

What are the features of Down Syndrome?

Answer 64

Hypotonia, short stature, brachycephaly, short neck with loose skin, single transverse palmar crease, and clinodactyly. Intellectual disability varies among patients.

Question 65

How does meiotic nondisjunction lead to Down Syndrome?

Answer 65

This occurs in 95% of down's syndrom. Usually occurs during maternal meiosis (90% of cases) in meiosis I. Results in an extra copy of chromosome 21.

Question 66

What is mosaic Down Syndrome?

Answer 66

Approximately 2% of patients. The phenotype may be milder with wide variability due to variable proportion of trisomy 21 cells during early development.

Question 67

What is Robertsonian translocation in Down Syndrome?

Answer 67

Approximately 4% of patients have 46 chromosomes with a Robertsonian translocation between chromosome 21q and another chromosome's long arm. Involves fusion of whole long arms of acrocentric chromosomes.

Question 68

What is uniparental disomy?

Answer 68

A disomic cell line containing two chromosomes or portions thereof, inherited from only one parent. Can lead to recessive traits and imprinting related traits.

Question 69

What are microdeletion and duplication syndromes?

Answer 69

Syndromes characterized by developmental delay, intellectual disability, and dysmorphic features due to recurrent subchromosomal or regional abnormalities. where the phenotype is due deletion or duplication of only a single gene within the region. ## Footnote Example: 22q11.2 deletion associated with DiGeorge syndrome, velocardiofacial syndrome, and conotruncal anomaly face syndrome.

Question 70

What is the significance of the TBX1 gene in 22q11.2 deletion syndrome?

Answer 70

Thought to play a role in up to 5% of all congenital heart defects and is a frequent cause of left-sided outflow tract abnormalities.

Question 71

What is Cri du chat syndrome?

Answer 71

Terminal or interstitial deletion of part of the short arm of chromosome 5. Characterized by a distinctive cry resembling a mewing cat, microcephaly, hypertelorism, epicanthal folds, low-set ears, and micrognathia.

Question 72

What is genomic imprinting?

Answer 72

For some disorders, the expression of the disease phenotype depends on whether the mutant allele or abnormal chromosome has been inherited from the father or the mother. Results from parent-of-origin effects.

Question 73

what are the different ways Trismy 21 (down's syndrome can occur)?

Answer 73

1. meiotic nondysjunction (often mother's side during meiosis 1) 2. mosicism (a nondysjucntion event occuring in mitosis, so not related to the parents) 3. robertsonian translocation 4. 21q21q translocation 5. partial trisomy (very rare) where only part of the long arm in chromosome 21 is presetn in triplicate

Question 74

what is an isodisomy and a heterodisomy?

Answer 74

they are different situations in uniparental disomy: iso: the two chromosomes are derived from identical sister chromatids hetero: if both homologues from one parent are present

Question 75

where in the genome are microdeletion and duplication syndromes often found?

Answer 75

breakpoints localize to low-copy repeated sequences in the genome termed segmental duplications

Question 76

what is CATCH22 and what type of genetic defect is it?

Answer 76

Cardiac abnormality (commonly interrupted aortic arch, truncus arteriosus and tetralogy of Fallot), Abnormal facies, Thymic aplasia, Cleft palate, Hypocalcemia/Hypoparathyroidism associated with a 22q11.2 microdeletion