Genetic disorders Patho

Question 1

Contents of the Human Genome

Answer 1

Question 2

How does DNA get damaged

Answer 2

Question 3

Estimated rates of DNA damage per human cell per day

Answer 3

Question 4

How does DNA damage lead to cancer and ageing

Answer 4

Question 5

WHich mutations are passed on the offspring

Answer 5

Permanent change in the nucleotide sequence or arrangement of DNA

1. Mutations involving germ cells (e.g., ovum) can be transmitted to offspring
2. Mutations involving somatic cells are not transmitted to offspring

Question 6

WHat is a point mutation

Answer 6

Change in a single nucleotide base in a nucleotide sequence.

Silent, nonsence and missense.

Question 7

What is a silent mutation

Answer 7

DNA codes are altered for the same amino acid withotu changing the phenotypic effect

Question 8

Missense mutation

Answer 8

Point mutation in which a single nucleotide change results in a codon that codes for different amino acids (eg, sicke cell trait/disease); accounts for 50% of disease-causing mutations

Question 9

Nonsense mutation

Answer 9

Altered DNA codes for a stop codon that causes prmature termination of protein synthesis; accounts for 10% of isease producing mutations.

Question 10

Sickle cell trait and sickle cell disease patho

Answer 10

• Missense mutation occurs when adenine replaces thymidine, causing valine to replace glutamic acid in the sixth position of the B globin chain.
• As a result, red blood cells spontaneously sickle in the peripheral blood if the maount of sickle haemoglobin is greater than 60%.

Question 11

What is a framehsift mutation

Answer 11

• Insertion or deletion of of one or more nucleotides bases shiftsthe reading frame of the DNA strand
• If the number of bases that is added or deleted is not a multiple of three, a frameshift results in premature termination of protein synthesis downstream from the mutation.
• This type of mutation accounts for 25% of disease causing mutations.
• Tay sachs disease is an example

Question 12

Tay-Sachs disease- patho

Answer 12

• Framehsift mutation - 4base insertion results in an altered DNA code leading to decreased synthesis of hexosaminidase
• It is a rare neurodegenerative inherited condition that mainly affects babies and young children. It stops the nerces working properly and is usually fatal. It used to be most common in those with Ashenazi jewish decent (Most jewish people in uk) but many cases now occur in other ethnic backgrounds.

Question 13

Non-framehsift mutation

Answer 13

If the number of base pairs that is either deleted or inserted is a multiple of three, it is not a frameshift mutation and the translated protein has either gained or lost amino acids

Eg cf

Question 14

Cystic fibrosis - the mutation

Answer 14

• Non-frameshift mutation
• Example: In cystic fibrosis, a three-nucleotide deletion that normally codes for phenylalanine produces a protein (i.e., cystic fibrosis transmembrane regulator [CFTR]) that is missing phenylalanine …… The defective CFTR is degraded in the Golgi apparatus

Question 15

Trinucleotide Repeat Disorder

Answer 15

• Trinnucleotide repeat disorder is an example of DNA replication error. It is an uncommon cause of a disease-causing mutation
• There is an amplification of a sequence of 3 nucleotides, which prevents the normal expression of the gene
• Most trinucleotide repeats (TRs) contain guanine (G) and/ or cytosine (C)
• Examples of TR disorders and their triplet repeats include fragile X syndrome (FXS) with a CGG repeat; myotonic dystrophy (MD) with a CTG repeat; Friedrich ataxia (FA) with a GAA repeat; and Huntington disease (HD) with a CAG repeat

Question 16

Fragile X syndrome

Answer 16

• Physical - large prominent ears, long face, large head, prominent forehead and jaw, hyperflexible joints, lrge testis
• ID OR LD - avg, IQ 40-50, decline with age in childhood, specific cognitive profile, most common presentation speech delay.
• Motor coordination/ Praxis Deficits
• Behaviour problems - LIMITIGN anxiety (65%), attent (57%), sensory hypersensitivity (51%), hyperactivty (43%), agression (38%) and perseveration (32%)
• ASD: 43-67%
• Medical - seizures (12%), strabismus (18%), frequent otitis media (55%) , GE reflux (10%), sleep apnea (7%), loose stools (12%)
• ▪ Tendency for expanding (amplifying) TRs is highly dependent on the sex of the parent transmitting the disease. For example, expansion of TRs in FXS primarily occurs in oogenesis, whereas in Huntington disease, it occurs in spermatogenesis

▪ Number of TRs determines the severity of the disease. For example, in FXS, unaffected individuals have 5 to 54 CGG repeats, individuals with premutations have 55 to 200 CGG repeats (normal to mild disease), and those with full mutations have more than 200 repeats (more severe disease)

Question 17

Effects of an Amplification that occurs in noncoding areas of the gene (intron)

Answer 17

Amplification that occurs in noncoding areas of the gene (intron) produce a loss-of function type of mutation manifested as a decrease in protein synthesis

▪ Examples of diseases that fit under this category include FXS, myotonic dystrophy, and Friedrich ataxia. Because protein synthesis is decreased in the these disorders, multiple organ systems are adversely affected

Question 18

Mendelian Disorders - Single-gene mutations that produce large effects

Answer 18

▪ The majority of mendelian disorders are familial (80%–85% of cases); however, the remainder are new mutations

▪ Patterns of single-gene mutations chiefly depend on whether a dominant or recessive phenotype is present in a chromosome pair

a. Dominant phenotype is expressed when only one chromosome of a pair carries the mutant allele (gene).
b. Recessive phenotype is expressed only when both chromosomes of a pair carry mutant alleles.

▪ Chromosomal location of the gene locus of the mutation may be on an autosome (chromosomes 1 to 22) or on a sex chromosome (chromosomes X and Y)

The vast majority of sex chromosome disorders are X-linked

▪ The four basic single-gene mutation disorders are autosomal recessive (most common type), autosomal dominant, X-linked recessive (XR), and X-linked dominant (XD)

Question 19

Protein defects asociated with selected mendelian disorders

Answer 19

Question 20

Sex chromosomes and their structure

Answer 20

Question 21

Pattern of autosomal recessiv einheritance

Answer 21

A, Pattern of autosomal recessive inheritance. Note that both parents (*) are heterozygous for the disease. B, Pedigree illustrating the typical pattern in autosomal recessive disease inheritance. The affected individual is shown in solid red, and carriers outlined in red, with the normal gene being indicated by a and the disease gene by A. Autosomal recessive inheritance typically results in the disease being seen in siblings, regardless of their gender, but usually not in previous generations. Only about a quarter of the offspring of carrier parents are affected, and sibling expression is therefore only likely in larger families, although another 50% are carriers. In very rare disorders, consanguinity is likely to be evident in the family.

Question 22

Pedigree of autosomal recesisve disorder

Answer 22

Question 23

Autosomal recessive disorders

Answer 23

Individuals with autosomal recessive disorders must be homozygous (aa) for the mutant recessive gene (a) to express the disorder

▪ Homozygotes (aa) are symptomatic early in life

▪ Heterozygous individuals (Aa) are usually asymptomatic carriers. Dominant gene (A) overrides the mutant recessive gene (a)

▪ Both parents must be heterozygous (Aa) to transmit the disorder to their children

(Link 6-4 A, B; Fig. 6-3 B). Example of an autosomal recessive disorder: Aa × Aa →

AA, Aa, Aa, aa (25% without disorder [AA]; 50% asymptomatic carriers [Aa]; 25% with

disorder [aa])

▪ New mutations are uncommon

▪ Complete penetrance is common (i.e., homozygotes express the disease)- Penetrance refers to the proportion of individuals with the mutation who exhibit clinical symptoms

Question 24

Cystic fibrosis rate

Answer 24

Question 25

Inborn errors of metabolism

Answer 25

Inborn errors of metabolism

▪ Most metabolic disorders are due to an enzyme deficiency.

▪ Substrate and intermediates proximal to the enzyme block increase.

▪ Intermediates and the end-product distal to the enzyme block decrease (Link 6-5).

Example:

▪ Phenylketonuria, where there is a phenylalanine hydroxylase deficiency, phenylalanine increases and tyrosine decreases

▪ Lysosomal storage diseases: Enzyme deficiencies lead to accumulation of undigested substrates (e.g., glycosaminoglycans [GAGs], sphingolipids, glycogen) in lysosomes

▪ Other autosomal recessive disorders include hemochromatosis (MC), 21-hydroxylase

deficiency, Wilson disease, and thalassemia

Question 26

Overview of glycogenoses and inborn errors metabolism

Answer 26

In the glycogenoses, there may be an increase in glycogen synthesis (e.g., von Gierkedisease) or inhibition of glycogenolysis (glycogen breakdown; e.g., debranching enzyme deficiency). There may be an increase in normal glycogen in tissue (e.g., von Gierke disease) or structurally abnormal glycogen in tissue (e.g., debranching enzyme deficiencies). Glycogen deposition in tissue produces organ dysfunction (e.g., restrictive heart disease in Pompe disease and hepatorenomegaly in von Gierke disease). In some glycogenoses, there is fasting hypoglycemia due to a decrease in gluconeogenesis (e.g., glucose-6-phosphatase deficiency in von Gierke disease) or a decrease in liver glycogenolysis (e.g., liver phosphorylase deficiency).

Question 27

Phenylketnuria (autosomal recessive)

Answer 27

Lack of phenylalanine hydroxylase blocks the transformation of phenylalanine into tyrosine. Unmetabolized phenylalanine is shunted into the pathway that leads to the formation of phenylketones (phenylpyruvic acid). A decrease in tyrosine leads to a decrease in melanin, proteins, and dopamine.

Question 28

Pathological mechanisms in inborn errors of metabolism

Answer 28

Pathologic mechanisms in inborn errors of metabolism. The defective enzyme or transporter within a metabolic pathway leads to a build-up of substances upstream and a loss of product downstream with clinical consequences being related to any potential toxicity of the excess material or alternative product, and effect of the lack of the intended product.

Question 29

Selected inborn error of metabolism - alkaptonuria.

The deficient enzyme, accumulated sibstrae and comment s

Answer 29

• Deficient enzyme = Homogentisate oxidase. So increased homogentisate and then decreased maleylacetoacetate.
• Accumlated substrate = homogentisate; binds to collagen.
• Black urine undergoes oxidation when exposed to light; black pigementation nose, ears, cheeks, black cartilage in joints and intervertebral disc producing degenerative arthritis.

: there is a deficiency of homogentisate (homogentisic acid) oxidase (solid ellipse) with proximal accumulation of homogentisic acid, which turns black in urine on oxidation. It also deposits in cartilage (e.g., intervertebral disks and joints), producing degenerative arthritis. NADPH, Reduced nicotinamide adenine dinucleotide phosphate.

Question 31

Selected inborn error of metabolism - Galactosemia

Deficient enzyme, accumulated substare and comments

Answer 31

• Deficient in GALT: increase Galactose 1-P, Decrease Glucose 1-P, decrecease Glucose 6-P, Decrease Glucose (fasting state)
• Accumulated substrates - Glalactose 1-phosphate (toxic to liver/CNS), galactose in urine, galactitol
• Mental impairment, cirrhosis, fasting hyperglycaemia, cataracts
• Avoid dairy porducts.

A, Galactosemia. There is an increase in galactose and galactitol (alcohol sugar) proximal to the block and a decrease in glucose 1-phosphate (G1P) distal to the block (hypoglycemia in fasting state).

B, Galactosemia cataract. The accumulation of galactose in the lens leads to the production of galactitol. This sugar alcohol exerts increased osmotic pressure within the lens because it diffuses very slowly.

The induced swelling is not solely responsible for subsequent cataract formation; however, evidence supports its role in cataract formation rather than G1P because a galactokinase deficiency in which G1P is absent will still yield cataracts. ADP, Adenosine diphosphate; ATP, adenosine triphosphate; GALT, galactose-1-phosphate uridyltransferase; P, phosphate; UDP, uridine diphosphate.

Question 32

Selected inborn errors of metabolism: Deficient enzyme. accumulate dusbstarte and comments…

Hereditary fructose intolerance

Answer 32

• Deficient in Aldolase B: so Increase fructose 1-P then decrease G3P+ decrease DHAP and then decrease glucose (fasting state)
• Accumulates - Fructose 1-phosphate (toxic substrate)
• Cirrhosis, hypoglycaemia, hypophosphataemia
• Avoid fructose (eg, honey_ and sucrose.

HFI is caused by a deficiency of aldolase B. This causes an increase in fructose 1-phosphate (toxic substance) and fructose (proximal) and a decrease in DHAP and glyceraldehyde (distal), which, in normal circumstances, is converted to glyceraldehyde 3-phosphate, a three-carbon intermediate in glycolysis and gluconeogenesis. In hereditary fructose intolerance, hypoglycemiaoccurs in the fasting state. ADP, Adenosine diphosphate; ATP, adenosine triphosphate; DHAP, dihydroxyacetone phosphate; P, phosphate.

Question 33

Selected inborn errors of metabolism: Deficient enzyme. accumulate dusbstarte and comments…

Homocystinuria

Answer 33

• Deficient in cystathionine synthase -> increase homocyteine -> decrease cystathionine
• Accumulate dusbstrate - homeocysteine and methionine
• mentla impairment, vessel thrombosis, lens dislocation, aechnodactyly.

Question 34

Selected inborn errors of metabolism: Deficient enzyme. accumulate dusbstarte and comments…

Maple syrup urine disease

Answer 34

• Deficient in: Branced chain a-keto acid dehydrogenase. Leads to increased isoleucine which decreases AcCoA+ decreases succinyl CoA. Also leads to increase leucine-> Decreases AcCoA + decreases Acac. Finally decreases valine so decrease succinyl CoA.
• Aummulated substarte - lucine, valine, isoleucine and their ketoacids
• Mental impairment, seixures, feeding problems, sweet smelling urine

Question 35

Selected inborn errors of metabolism: Deficient enzyme. accumulate dusbstarte and comments…

Phenylketonuria

Answer 35

• Deficient in phenylalanine hyroxylase which leads to increased phgenyalanine and decreased tyrosine
• Accumulate sphenylalanine and neurotoxic by porducts
• Mental impairment, microcephaly, mousy odor, decrease pigmentation
• Mus tbe exposed to phenylananince (milk) before phenylalanine increased
• Restrict phenylalaninel avoid sweetners
• Add tyrosine to diet
• Pregnant women with PKU must be on phenylanaine-free diet or newborns will have mental impairment at birth/

Phenyloketonuria- there is a deficiency of phenylalanine hydroxylase (interrupted ellipse) with a buildup of products proximal to the enzyme block (e.g., phenylalanine, phenyllactate, phenylacetate) and a decrease in substrates distal to the block (e.g., tyrosine, which is a precursor of melanin).

Question 36

Selected inborn errors of metabolism: Deficient enzyme. accumulate dusbstarte and comments…

Malignant phenylketonuria

Answer 36

• Deficient in dihydropterin reductase
• Accumulated substarte - phenylalanine, nurotoxic by porducts
• Similar to PKU
• Inability to emtabolie tryptophan or tyrosine so decrease synthesis of NTs
• Neurologic problems occur despite adequate dietary therapy
• Restrict phenyalanine in the diet Administer L-dopa and 5-hydorxytryptophan to replace NTs.
• Administer BH4.

Question 37

Selected inborn errors of metabolism: Deficient enzyme. accumulate dusbstarte and comments…

McArdle Disease

Answer 37

• Deficient in Muscle phosphorylase -> icnrease glycogena and decrease glucose
• Glycogen accumulates
• Glycogenlysis with muscle fatigue and propensity fo rhabdomyolysis with myoglobinuria
• No lactic acid increase with exercise due to lack of glucose in muscle and a correspond lack in anaerobic glycolysis

Question 38

Selected inborn errors of metabolism: Deficient enzyme. accumulate dusbstarte and comments…

Pompe Disease

Answer 38

• Deficient in a-1,4-glucosidase (lysosomal enzyme)
• Glycogen accumulates
• Glycogenosis, cardiomegaly with early death from heart failure (restrictive cardiomyopathy)

Question 39

Selected inborn errors of metabolism: Deficient enzyme. accumulate dusbstarte and comments…

Von Gierke Disease

Answer 39

• Deficient in Glucose-6-phosphatase (gluconeogenic enzyme). Leads to increase G6P and decrease glucose
• Accumulates glucose-6-phosphate
• Glycogenosis, enlarged liver and kidneys,f asting hypoglycaemia.

Question 40

Patho of lysosomal storage disease

Answer 40

A, Pathogenesis of lysosomal storage disease.

Left, Normal lysosomes digest the material included within the lytic bodies. Right, Lack of degradation enzymes leads to the accumulation of metabolic residues inside the lysosomes. B, Sphingolipid metabolism. See Table 6-3 for discussion of selected sphingolipidoses. C, Hurler syndrome. Note the coarse facial features and short neck. D, Cherry red spot (arrow) in Tay-Sachs disease is due to glycolipid deposits in the retinal ganglion cells, giving a whitish appearance to the retina. Because the parafoveal area has many ganglion cells and the fovea has none, the fovea has its normal orange-red colour, whereas the retina peripheral to the fovea is white. This produces a “cherry red spot” in the macula. Recall that the fovea is a tiny pit located in the macula of the retina that provides the clearest vision. E, Tay-Sachs disease. Left, On light microscopy the neural system cells appear to be swollen and vacuolated because their cytoplasm contains an increased number of lipid-rich lysosomes. Right, On electron microscopy the cells are seen to contain myelin figures composed of concentric membranes.

Question 41

Selected lysosomal storage disease - Gaucher disease (adult type)

Answer 41

• Deficient in Glucocerebrosidase
• Accumulated substarte = Glucocerebroside
• Most common lysosomal storage disease, seen in easten european jews
• In type 1 = hepatospelnomegaly, fibrillar- appearing macrophages foudn in liver, spleen, bone marrow. Pancytopenia results form marrow invovlement an dhyperspelnism from enlarged spleen. No CNS involvement.
• Replacement therapy with recombinant enzyme is effective

Question 42

Lysosomal sotrage disease- Hurler syndrome

Answer 42

• Deficient in - alpha 1-iduronidase
• Accumulates: dermatan and heparan sulfate
• Normal at birth but patients develop severe mental impairment and hepatosplenomegaly by 6-24 months
• CHarcterstics include coarse facial features, short neck, corneal clouding, coronary artery disease and vacuoles in ciruclating lymphocytes
• The XR form (Hunter syndrome) is milder

Question 43

Lysosomal storage disease- Niemann-Pick Disease

Answer 43

• Deficient in the enyme sphingomyelinase
• Accumulated substarte - Sphingomyelin
• Seen in eastern European jews
• Signs + symptoms begin at birth
• Type A is very severe and involves CNS (psychomotor dysfunction, short lifespan)
• Type B does not have CNS involvement patients survive in to adulthood. Phagocytic cells are invovled in the liverm spleen, lymph nodes, and bone marrow. Phagocytes have foamy appearence and cherry red macula present in 30-50% cases

Question 44

Lysosomal storage disease - Tay-sachs disease

Answer 44

• Deficient in the enxyme hexosaminidase
• Accumulates the substrate GM2, ganglioside
• Seen in Eastern european jews
• Normal at birth but manifest signs and symptoms by 6m of age
• Motor (muscle weakness) and mental deterioration, whorled configurations in neurons, cheery red macula.

Question 45

describe autosomal dominant disorders

Answer 45

One dominant mutant gene (A) is required to express the disorder

▪ Heterozygotes (Aa) express the disorder

▪ Most homozygotes (AA) are spontaneously aborted

▪ Most of the living individuals with autosomal dominant disorders are heterozygotes (Aa)

▪ Example of an autosomal dominant disorder: Aa × aa → Aa, Aa, aa, aa (50% have the disorder [Aa]; 50% do not have the disorder [aa])

Question 46

Pedigree with complete penetrance in autsomal dominant disorder

Answer 46

Question 47

Example of a disease where it has delayed manifestation

Answer 47

• Adult polycystic kidney disease (cysts not present at birth) and familial polyposis (polyps not present at birth)

Question 48

What is penetrance in genetic disorders

Answer 48

• Penetrance = proportion of individiuals with the mutation who exhibit clinical symptoms
• Complete pentrance = all individuals with the mutant gene express the disorder (eg, familial polyposis)
• Incomplete penetrance = individuls with the mutant gene are phenotypically normal. However they can transmit the disorder to their offspring (eg, Marfan syndrome)

Question 49

WHat is Variable Expressivity and

Answer 49

Variable expressivity = all idnividuals with the mutant gene express the disorder but at different levels of severity

Eg - in neurofibromatosis, some patients may have a few cafe au lait spots (coffe- coloured flat lesions) or numerous neurofibromas (pedunculated, pigmented lesions)

Question 50

Autosomal dominant disorders and hat essentially confirms them

Answer 50

▪ A male-to-male transmission essentially confirms an autosomal dominant inheritance

1. Autosomal dominant protein defects: Enzyme deficiencies are relatively uncommon in autosomal dominant disorders
2. Other autosomal dominant disorders include
   - von Willebrand disease (vWD; MC autosomal dominant disorder),
   - Huntington disease,
   - osteogenesis imperfecta,
   - achondroplasia,
   - tuberous sclerosis,
   - hereditary spherocytosis, myotonic dystrophy, and familial hypercholesterolemia

Question 51

Inheritance pattern characteristics of XR disorders:

Answer 51

Males must have the mutant recessive gene on the X chromosome to express the disorder

1) Y chromosome disorders are more likely to involve defects in spermatogenesis
2) X chromosome in a male is active, whereas in females, random inactivation of one

of their two X chromosomes leaves ≈50% of their X chromosomes active while the

other X chromosome is an inactive Barr body located on the cell’s nuclear

membrane

▪ Affected males (XY) transmit the mutant gene to all of their daughters

1) Males are hemizygous for the X-linked mutant gene. Y chromosome is not

homologous to the X chromosome; hence the term hemizygous

2) Daughters (XX) are usually asymptomatic carriers. Heterozygous females (XX)

usually are asymptomatic because of the paired normal allele, unlike affected

males (XY), who do not have a paired homologous allele

Question 52

Random X chromsome inacitvation early in female development

Answer 52

Question 53

Typical X-linked recessive inheritance

Answer 53

Question 54

Asymptomatic vs symptomatic female carriers in XR linked disease

Answer 54

▪ Asymptomatic female carriers (X mutant gene) transmit the disorder to 50% of their male offspring and 50% of their female offspring, who are asymptomatic carriers (see Fig. 6-12 A).

▪ In rare cases, female carriers are symptomatic

1) Female carriers can be symptomatic if maternally derived X chromosomes without the

mutant gene are preferentially inactivated. Therefore, only paternally derived X

chromosomes with the mutant gene remain

2) Offspring of a symptomatic male and asymptomatic female carrier can have a

symptomatic female child (XX).

a) Example: XX × XY → XX, XX, XY, XY
b) However, because of random inactivation of one of the X chromosomes, the disease is usually not as severe as in a male

▪ Sex-linked recessive protein defects: Enzymes are the most common type of proteins affected in sex-linked recessive disorders

Question 55

Fragile X syndrome (FXS)

Answer 55

• FXS is an X-linked triple repeat disorder (CGG)
• Carrier rate for affected males is 1/1550 (some authors say 1/2500–4000) and 1/800 for affected female
• Most common Mendelian disorder causing mental impairment

Patho:

• Genetic defect is at the distal end of the long arm of the X chromosome (band Xq27.3).
• At this site, CGG amplification produces a constriction that gives the appearance of a fragile portion of the X chromosome; hence the term fragile X
• Familial mental impairment-1 (FMR1) gene is located at this site
• Loss of function of this gene, which is most abundantly expressed in the brain and testis, is responsible for mental impairment in FXS as well as other findings

–

▪ Males with a premutation (60-200 repeats) are usually asymptomatic or mildly affected and can transmit the premutation to their daughters

▪ Males with the full mutation (>200 CGG repeats) have manifestations of FXS

▪ Mothers of nearly all males with FXS have premutation (60-200 repeats) or FXS (>200 repeats)

▪ Females with a premutation (60-200 repeats) are usually asymptomatic, or they have a mild degree of mental impairment and/or premature ovarian failure (25% of cases)

▪ Half of the females with the full mutation on a single X chromosome are asymptomatic because of random inactivation of more than half of the affected X chromosomes. The other 50% of females have FXS, although the degree of mental impairment is much less than in males with FXS.

Question 56

Clinical findings of fragile X sydnrome

Answer 56

1) Affected males have mental impairment with an IQ range of 20 to 70.
2) Females with FXS and less affected males have IQs that approach 80.
3) Facial changes include long face, large mandible, everted ears, and high-arched palate
4) Macro-orchidism (enlarged testes) at puberty is almost universal. Normal testicular volume at puberty is 17 mL, whereas in individuals with FXS, the volume is >25 mL
5) Other findings include mitral valve prolapse (MVP), pectus excavatum, scoliosis, and hyperextensible joints.

Question 57

Diagnosis of Fragile X sydnrome

Answer 57

1) DNA analysis (polymerase chain reaction) to identify TRs is the best test
2) Fragile X chromosome study (false negative rate of 20%)

Question 58

Lesch-Nyhan SYndrome

Answer 58

▪ XR disorder with a deficiency of hypoxanthine-guanine phosphoribosyl-transferase (HGPRT)

▪ HGPRT is normally involved in salvaging the purines hypoxanthine and guanine

▪ Clinical findings include mental impairment, hyperuricemia, and self-mutilation

Question 59

XR disorder examples

Answer 59

• Lesch-Nyhan SYndrome
• Androgen insensitivity syndrome (AIS)
• Chronic granulomatous disease (CGD)
• Bruton agammaglobulinemia (BAG)
• Glucose-6-phosphate dehydrogenase (G6PD) deficiency

Question 60

X-linked dominant (XD) disorders - general characteristics

Answer 60

▪ An XD disorder is the same as an XR disorder except the dominant mutant gene causes disease in males and females

▪ Female carriers are symptomatic

▪ Distinguished from autosomal dominant disorders by the fact that there is no male-to-male transmission

▪ Impossible in X-linked inheritance, as males transmit the Y chromosome to their sons

Question 61

Vitamin D-reisstant rickets

Answer 61

• X linked dominant
• Defect in renal and gastrointestinal reabsorption of phosphate (hypophosphatemia)
• Defective bone mineralization (i.e., osteomalacia), because phosphate is required to drive calcium into bone

Question 62

Normal chromsome amoutn and te lyon hypothesis and chromosomal disorders

Answer 62

▪ Most human cells are diploid (46 chromosomes)

a. Autosomes: 22 pairs
b. Sex chromosomes (XX in females and XY in males): 1 pair

▪ Gametes, the products of meiosis, are haploid (23 chromosomes)

▪ Lyon hypothesis

a. In females, one of the two X chromosomes (X paternal, X maternal) is randomly
inactivated. Inactivation occurs on day 16 of embryonic development.
b. Inactivated X chromosome is called a Barr body. It is attached to the nuclear

membrane of cells and can be counted in squamous cells obtained by scraping the

buccal mucosa

c. Normal females have one Barr body per cell, and normal males have none.
d. Inactivation accounts for parental derivation of the X chromosomes in females
1) ≈50% of X chromosomes are paternal and ≈50% are maternal
2) Number of Barr bodies = number of X chromosomes − 1

Question 63

X chromosome inactivation

Answer 63

Question 64

Chromosomal alterations

Answer 64

1. Definition: Numeric or structural abnormalities of autosomes or sex chromosomes

2. Nondisjunction (Fig. 6-16)

a. Definition: Unequal separation of chromosomes in meiosis
b. Results in 22 or 24 chromosomes in the egg or sperm
c. Examples: Turner syndrome (22 + 23 = 45 chromosomes); Down syndrome (24 + 23 = 47 chromosomes; trisomy)

3. Mosaicism

a. Definition: Nondisjunction of chromosomes during mitosis in the early embryonic period (Fig. 6-17)
b. Two chromosomally different cell lines are derived from a single fertilized egg.
c. Mosaicism most often involves sex chromosomes (e.g., Turner syndrome).

4. Translocation

a. Definition: Transfer of chromosome parts between nonhomologous chromosomes
b. In a balanced translocation the translocated fragment is functional.

A robertsonian translocation is a balanced translocation between two acrocentric chromosomes (centromere is near the end of the chromosome; e.g., chromosomes 14 and 21).

5. Deletion. Definition: Loss of a portion of a chromosome

• Cri du chat syndrome. Definition: Loss of the short arm of chromosome 5. Clinical findings include mental impairment, cat-like cry, and ventricular septal defect (VSD).

Question 65

Nondisjunction vs normal meiosis

Answer 65

Question 66

Mosaicism

Answer 66

Mosaicism: a mutation occurs in one cell of the

developing embryo. All descendants of that cell have the

same mutation, resulting in mosaicism. If the first mutated

cell is part of the germline, mosaicism results.

Question 67

Disorders involving autosomes

Answer 67

• Dows syndromes
• General appearance
• Congenital heart defects
• GI tract abnormalities
• Hematologic abnormalities
• CNS abnormalities
• Immune abnormalities -Patients are also at an increased risk of developing hypothyroidism, lung infections, and diabetes mellitus (DM).
• Fertility abnormalities - Males unable, Females decreased fertility and an increased incidence of miscarriage.
• Other abnormlaities include umbilical hernia, a gap between first and second toes (Fig. 6-19 D), short fifth finger (Fig. 6-19 E), Brushfield spots in the eyes (Fig. 6-19 F; white or yellow-coloured s

Question 68

Downs syndrome - def, causes, RFs, median age death

Answer 68

• Def = chromosomal disorder characterised by distinct facial features, multiple malformations and moderate to severe mental impairment
• Causes = Nondisjunction (95%cases, trisomy 21), Robertsonian translocation (4% of cases, 46 chromsoomes) mosaicism (1% cases)
• RFs = Increased maternal age (meiotic nonD of chromosome 21 that occurs in oogenese, usually M1, is 1 in 25 liver births in those over 45. Approx 75% of conceptions with T21 die in embryonic or foetal life). Also female with Down syndrome has 50% risk of having children with downs syndrome
• Median age of death = 47years.

Question 69

Clinical findings of downs syndrome

Answer 69

• Mental impairement
• Downs syndrome is most common chromosomal abnormality associated with mental impairment
• Patients may ave midl impairment (IQ 50-75, usuallu mosaics), or severe impairment (IQ 20-35)

Question 70

Screening of Downs syndrome

Answer 70

(1) Maternal screening with the triple test
(a) Decrease in serum α-fetoprotein (AFP), decrease in urine unconjugated estriol (uE3), and increase in serum human chorionic gonadotropin (hCG)
(b) Triple test has a sensitivity of ≈70% and must be followed by invasive diagnostic tests.
(2) Invasive diagnostic testing (sensitivity ≈100%) includes amniocentesis with chorionic villous sampling and percutaneous umbilical blood sampling.
(3) Cytogenetic and DNA studies are used to confirm the diagnosis.

Question 71

General appearance disorders involving autosomes

Answer 71

(a) Muscle hypotonia is present at birth. Down syndrome is the most common cause of the “floppy baby” syndrome.
(b) Upslanting of the palpebral fissures, epicanthic folds, a flat facial profile, and macroglossia with a protuberant tongue (Fig. 6-19 B)
(c) Simian crease (Fig. 6-19 C)

Question 72

Congenitla heart defects -a disorder involving autosomes

Answer 72

(a) Heart defects are present in 40% to 60% of patients.
(b) Heart defects are the major factor affecting survival in early childhood.
(c) Heart defects include endocardial cushion defect (ECD, atrioventricular defect; 43%), VSD (32%), atrial septal defect (10%), tetralogy of Fallot (6%), and isolated patent ductus arteriosus (PDA; 4%).

Question 73

GIT abnormalities -d isorders involving autosomes

Answer 73

(a) Tracheoesophageal (TE) fistula. Proximal oesophagus ends blindly and the distal oesophagus arises from the trachea (see Fig. 18-10).
(b) Duodenal atresia. Atresia (incomplete formation of a lumen) of the small bowel distal to where the common bile duct empties into the duodenum; vomiting of bile-stained fluid at birth (see Fig. 18-22 C)
(c) Hirschsprung disease. An aganglionic segment in the large bowel, which causes problems with stooling at birth (see Fig. 18-22 D, F)

Question 74

Haematologic abnormlaity disorders involving autosomes

Answer 74

(a) Increased risk for developing leukaemia
(b) Acute lymphoblastic leukaemia (ALL) and acute megakaryocytic leukaemia are the most common types of leukaemia (see Chapter 13).
(c) Leukaemia is usually preceded by transient myeloproliferative diseases (MPDs).

Question 75

CNS abnormality disorders involving autosomes

Answer 75

(a) Most patients develop the neuropathologic signs of Alzheimer disease by 35 to 40 years of age.
(b) Chromosome 21 codes for amyloid precursor protein, which is the progenitor for Aβ protein. When phosphorylated, this protein induces apoptosis of neurons (see Chapter 26).
(c) Alzheimer disease is the major factor affecting survival in older individuals.

Question 76

Trisomy 18 - Edwards Syndrome: Def, clinical findings

Answer 76

• Def = chromosomal disorder cused by the presence of all, or part of, an extra 18th chromosome
• Second most common trisomy (incidence 1/9000) birtha
• Clinical findins:
  
  • Mental impairment, clenched fist with overlapping fingers
  • Rocker-bottom feet, VSD, early death

Question 77

Patua syndrome - de,f clinical findings

Answer 77

• Def= Trisomy 13 chromosome disorder
• EPi = incidence of 1 in 15000 births
• Clinical:
  
  • Mental impairment, midline defects (cleft lip and palate), clenched hand with overlapping fingers, polydactyly
  • VSD, Cystic kidneys, early death

Question 78

Disorders involving sex chromosomes:

Answer 78

• Turner syndrome - in females with complete or partial absence of a second normal X chromosome resulting in short sature, primary ovarian failure and other phenotypic defects.
• Klinefelters syndrome - 47 XXY chromosome pattern

Question 79

Turners syndrome - def, epidemiology and types

Answer 79

• Chromosomal condition where females have complete or partial absence of a second normal X chromosome resulting in short stature, primayr ovarian falure and other phenotypic defects
• Epidemiology: Most common sex chromsome abn. in females, 15% spontaneous abortions due to Turners, normal intelligene
  
  • Karyotype abnormalitues:
    
    • 45, X karyotopic, mostly due to paternal nondisjunction. No barr bodies in x types
    • Structural abnormalities (eg, isochromsoomes- (chromsoome produced by transverse spliiting of centromere so both arms from same side centromere are of eual length and posses identical genes) deletion)
    • Mosaicism (most common type of Turners); 45X/46XX karyotype, 45X/46XY (risk of gonadoblastoma of ovary). Using sensitive DNA tecniques, mosaicism accounts for up to 75% of cases of Turners as most 45XO are non viable.

Question 80

Clinical features of Turners Syndrome

Answer 80

• Physical exam:
  
  • Short stature (>95%) = GH/IGF-1 noemal, short stature due to deletion of second SHOX gene on X chromosome which is critical for reg of growth and remains active on both X chromosomes so a deletion of one of the two SHOX genes causes the short stature.
  • Carrying angle of the arms is increased (cubitus valgus)
  • SHort fourth metacarpal or metatarsal bone produces the knuckle (index finger)-knuckle-dimple, knuckle sign
  • Shield chest ahs widely spaced nupples and underdeveloped breasts
  • Pubic hair development normal
• Ly,phedema may occur in the hands, feet and neck in infancy. Webbed neck in Turner syndrome is caused by dilated lymphatic channels (cystic hydroma) and persists into adult life.
• CV abnormalities:
  
  • COngenital heart disease in 20-50%
  • Hypoplastic left heart is major cause of mortality in early infancy
  • Preductal coarctation commonly occurs and often presents with left sided heart failure
  • Bicuspid aortic valves are another commonc ardiac abnormality.
• Genitourinary abnormalities:
  
  • Both ovaries replaced by fibrous stroma (streak gonads). Increased risk for develping oviarian dysgerminoma
  • Ovaries devoid of oocytes by 2years of age. Some women wih mosaicism are fertile
  • Primary amenorrhea occurs with delayed sexual maturation: Turner syndrome is most common cause of this. Estradiol and progesterone decreases whilsts FSH and LH increases
  • Incidence of horshoe kidneys increased
• Hypothyroidisim due to hashimotos thyroidisims, occurs in 10-30% OF CASES.

Question 81

Def, and eipidemiology (of causes) of Klinefelters syndrome

Answer 81

• Def = male dominant disease characterised by presence of 47XXY chromosome pattern
• Most common genetic cause of male hypogonadism
• Causes:
  
  • Nondisjunction is most common (90%) causes and produces 47 chromsoomes with XXY karyotype. Maternal and paternal nondisjunction in meiosis I occurs in roughly equal proportions. One Barr body forms through random inactivation of one of the two X chromosomes.
  • Mosaicism is the remaining cause of the syndrome, with most common karyotupe 46XY/47XXX
• Testicular abnoralities and female secondary sex characteristics do not develop until puberty.

Question 82

Patho of Klinefelter syndrome

Answer 82

Testicular vol at puberty decreases (<17ml) due to atrophy

• Histologc exam reveals fibrosis of seminferous tubules with absence of spermatogenesis (azoospermial, infertility)), loss of Sertoli cells and presence of Leydig cells
• Loss of Sertoli cells leads to decrese in inhibin and a corresponding increase in FSH (loss of negative feedback with inhibin). increase in FSH increases the synthesis of aromaase in the Leydig cells
• Leydfig cells are prominent beacuse of atrophy of other portions of the testis.Increased synthesis of aromatase very likely converts a little of the testosterone synthesized by the Leydig cells into estradiol; however, this does not fully explain why patients with Klinefelter syndrome have hypogonadism and feminization.

(2) Primary reason for hypogonadism and feminization is that testosterone does not have a normal interaction with androgen receptors.

• X chromosome carries genes that encode for androgen receptors, testis function, brain development, and growth
• Testosterone mediates its function through the androgen receptors.
• Gene on the X chromosome that is responsible for androgen receptor synthesis contains CAG TRs
• Functional response of testosterone is dependent on the number of CAG repeats in the androgen receptor
  
  • Testosterone interacts better with androgen receptors that have the smallest number of CAG repeats
  • In Klinefelter syndrome, the X chromosome with the smallest number of CAG repeats is preferentially inactivated, leaving behind androgen receptors that have the longest CAG repeats.
  • Testosterone does not interact with androgen receptors with the longest CAG repeats, which, along with increased conversion into estradiol by aromatase, causes hypogonadism and leaves estradiol unopposed by any androgen effects resulting in feminization.

Question 83

Clinical and lab findings of Kleinfelters syndrome

Answer 83

• Signs of male hypogonadism/feminization begin at puberty.
  
  • Persistent gynecomastia (breast development in a male) is a characteristic feature in late puberty.
  • Facial, body, and pubic hair are diminished.
  • Hair distribution in the pubic region resembles that of a female (lack of extension of hair from the genitalia to the umbilicus).
  • Penis is small (micropenis) because of decreased foetal production of testosterone in utero.
  • Testicular volume is decreased from testicular atrophy
• Eunuchoid body habitus with disproportionately long legs.
• Intelligence in Klinefelter syndrome
  
  • Mean IQ is lower than normal.
  • Minor developmental and learning disabilities are present in most cases.
  • Variants with more than two X chromosomes (e.g., XXXY, XXXXY) have even lower IQ.
• Cardiovascular abnormalities in Klinefelter syndrome. Mitral valve penetrance (MVP; sometimes severe) is present in 50% of adults.
• Endocrine abnormalities in Klinefelter syndrome. Increased incidence of type 2 DM and metabolic syndrome (insulin resistance; see Chapter 23).
• Findings: Decreased serum testeosterone + increased serum LH, increased serum FSH/Estradiol, decreased serum inhibin, azoospermia (non sperm)
• Increased risk for developign autoimmune disease (eg, SLE, RA, sjogren syndrome), breast cancer and osteoporisis

Question 84

XYY Syndrome

Answer 84

a. Definition: Sex chromosome aneuploidy where males tend to be taller than average and have a 10- to 15-point

lower IQ

b. Epidemiology
(1) Caused by a paternal nondisjunction
(2) Occurs in 1 in 2000 live births
(3) Associated with aggressive (sometimes criminal) behavior. In the prison population, its incidence in the male population may be as high as 1 in 30 compared with 1 in 1000 in the general male population.
(4) Normal gonadal function

Question 85

Multifactoria (complex) inheritance

Answer 85

1. Definition: Result of complex interactions between a number of genetic and environmental factors
2. Epidemiology: Incidence of multifactorial inheritance is ≈50 in 1000 live births.

• Open neural tube (ONT) defects. Associated with decreased maternal folic acid levels.
• Type 2 DM. Associated with obesity, which down-regulates insulin receptor synthesis.
• Other examples of multifactorial inheritance include gout, cleft lip/palate, congenital heart defects, pyloric stenosis, and coronary artery disease.

Question 86

Mitochondrial DNA (mtdna) Disorders

Answer 86

Definition: A group of disorders caused by mutations in mtDNA that display characteristic modes of inheritance that have a large degree of phenotypic variability

Epidemiology

• Mitochondrial DNA codes for enzymes that are involved in mitochondrial oxidative phosphorylation (OP) reactions.
• Inheritance pattern
  
  • Affected females transmit the mutant gene to all their children Ova contain mitochondria with the mutant gene.
  • Affected males do not transmit the mutant gene to any of their children. Sperm lose their mitochondria during fertilization.
  • Examples: Leber hereditary optic neuropathy and myoclonic epilepsy

Question 87

Genomic imprinting

Answer 87

1. Definition: Allelic expression is parent-of-origin specific for some alleles.

2. Inheritance pattern

a. Examples include Prader-Willi (PW) syndrome and Angelman syndrome.
b. Epidemiology; pathogenesis (Fig. 6-25 A)

Question 88

Genetics of Angelman and Prader-Willi (PW) syndromes.

Answer 88

• Normal changes in the maternal chromosome 15 occur during gametogenesis.
  
  • Expression of PW genes (series of genes) is imprinted. Imprinted means that the gene has been inactivated by methylation.
  • Angelman gene (UBE3A) is active. Active means that the gene has not been methylated.
• Normal changes in the paternal chromosome 15 occur during gametogenesis.
  
  • PW genes are active
  • Angelman gene expression is imprinted (inactivated) by methylation
• Microdeletion of the entire gene site on paternal chromosome 15 (C15) causes PW syndrome.
  
  • Complete loss of expression of the PW genes
  • On the maternal chromosome, the PW genes are imprinted and the Angelman gene is active.
• Microdeletion of the entire gene site on maternal chromosome 15 causes Angelman syndrome.
  
  • Complete loss of Angelman gene expression
  • On the paternal chromosome 15, the Angelman gene is imprinted and the PW genes are active.

Clinical findings in Angelman syndrome: mental impairment, jerky, wide-based gait with hand flapping (resembles a marionette), and outbursts of inappropriate laughter (“happy puppet” syndrome).

Clinical findings in PW syndrome: neonatal hypotonia and genital hypoplasia at birth, short stature (due to GH deficiency), and hyperphagia (insatiable appetite) leading to obesity.

• Satiety defect is due to increased levels of gherlin, a polypeptide hormone produced by the stomach and arcuate nucleus in the hypothalamus that increases food intake (see Chapter 8).

Question 90

Prader- Willi syndrome

Answer 90

• Expression of PW genes is imprinted in gametogenesis so the gene has been inactivated by methylation.
• Leading to neonatal hypotonia and genital hypoplasia at birth, short stature (due to GH deficiency), and hyperphagia (insatiable appetite) leading to obesity.

• Satiety defect is due to increased levels of gherlin, a polypeptide hormone produced by the stomach and arcuat nucleus in the hypothalamus that increases food intake (see Chapter 8).

Question 91

Angelman Syndrome

Answer 91

• Patho; Angelman gene UBE3A is active in gametogenesisi so it has not been methylated
• . Clinical findings in Angelman syndrome include (Fig. 6-25 B) mental impairment, jerky, wide-based gait with hand flapping (resembles a marionette), and outbursts of inappropriate laughter (“happy puppet” syndrome).

Question 92

Normal Sex Differentiation

Answer 92

Y chromsoome - contains 50genes and single Y gene determined male sex

• SRY (sex determinign geen) gene encodes testis-determining factor (gonads->testis).
• Mullerian inhibitory substance (syntehsised in sertoli cells of testes) causes paramesonephric ducts to undergo apoptosis
• Fetal testosterone - develops mesnoephric duct structures (epididymus, seminal vesicles, vas(ductus) deferens)
• 5a-Reductase - in peripheral tissues, converts testosterone -> dihydrotestosterone
• Fetal DHT: Makes genitalia phenotypically male (from female) in male embryo, labia fuses to become scrotum, clitoris -> elongates to penis. Also develops prostate gland.

No Y chromosome:

• Gonadal tissues differentiate to ovary (as early as 8th wk gestation) and continues
• Fallopian tubes, uterus, upper vagina develop from paramesonephric ducts (mullerian ducts) while mesonephric duct structures undergo apoptosis.
• Contact of uterovaginl primordium (sinus tubercle) with urogenital sinus idnuces formation of sino-vaginal bulbs that fuse to form vaginal plate, which canalises to form lumen of vagina.

Question 93

Cytogenetic fluorescence in situ hybridization (FISH) studies.

Answer 93

A, Male (46 XY).

B, FISH analysis of a male using fluorescent probes directed against SRY gene (spectrum red) and against the X centromere (spectrum green). C, Female (46 XX).

D, Photomicrograph showing the X chromatin body (Barr body, arrow) in the nucleus of buccal mucosal cells from a female (XX).

Question 94

True hermaphrodite

Answer 94

1. Definition: Fetus has a testis on one side and an ovary on the other side or a fusion of ovarian and testicular tissue (ovotestes).
2. Karyotype is 46,XX in 50% of cases, whereas the remaining 50% are mosaics with a 46,XX/46,XY karyotype.

Question 95

C. Pseudohermaphrodite

Answer 95

1. Definition: Phenotype (external appearance) and genotype (true genetic sex) do not match.
2. Male pseudohermaphroditism
   a. Definition: Male pseudohermaphrodite is genotypically a male (XY with testes); however, phenotypically, the

external genitalia is ambiguous (male and female looking) or completely female.

b. Examples include AIS (see section V.D.) and deficiency of 5α-reductase.
3. Female pseudohermaphroditism
a. Definition: Female pseudohermaphrodite is genotypically a female (XX with ovaries), but phenotypically she has

ambiguous genitalia or the genitalia is virilized.

b. Ovaries and internal genitalia are normal.
c. Most common cause of female pseudohermaphoditism is adrenogenital syndrome due to 21- or 11-hydroxylase

deficiency (see Chapter 23).

Question 96

D. Androgen insensitivity syndrome (AIS; testicular feminization) : Def, epidemiology

Answer 96

1. Definition: Type of male pseudohermaphroditism due to a loss-of-function mutation in the androgen receptor gene

2. Epidemiology

a. XR disorder
b. Most common cause of male pseudohermaphroditism
c. Pathogenesis
(1) Loss-of-function mutation in the androgen receptor gene on the long arm of the X chromosome (Xq11-13). Loss of receptor function means that even though male hormone synthesis is normal, the effects of the hormone in tissue do not occur, resulting in prenatal undervirilization of external genitalia and loss of pubertal changes one would expect in a male (e.g., voice changes, male distribution of hair, acne).
(2) Complete loss of the androgen receptor or an alteration in the substrate (testosterone) binding affinity to the receptor

Question 97

Androgen insensitivity syndrome (AIS; testicular feminization)

CLINICAL FINDINGS

Answer 97

• At birth, testicles are in inguinal canal or abdominal cavity.
• Paramesonephric duct (PMD) structures are absent (fallopian tubes, uterus, cervix, upper vagina), because MIS is present and initiates apoptosis of those structures in utero.
• Male accessory structures (epididymis, seminal vesicles, vas deferens, prostate gland) are absent.
• External genitalia remain female in appearance.
  
  • No DHT effect on the external genitalia
  • Vagina ends as a blind pouch. Lower two-thirds of the vagina is not of paramesonephric duct origin (see previous discussion); therefore, it is present and the vagina ends as a blind pouch.
• If not identified in the newborn period, patients present with primary amenorrhea (lack of menses) in their teenage years.
• Gynecomastia (swelling of breast tissue) is usually present as a postpubertalfinding.
• If testes not surgically removed, there is an increased risk for developing a gonadoblastoma.
• Laboratory test findings
  
  • Karyotype is essential in order to differentiate an undermasculinized male from a virilized female.
  • Serum testosterone/DHT levels are those of a normal male.
  • Slight increase in serum LH
  • Slight increase in serum estradiol
    
    • Since estrogen activity is unopposed and estrogen receptors are present, the patient has female phenotypic findings.
    • Term unopposed means that testosterone function is neutralized by the absence or nonfunctionality of the androgen receptors.
  • Mutation analysis of the androgen receptor gene detects up to 95% of the mutations.
• Majority are reared as a female.

Question 98

Congenital Anomalies:

Answer 98

• Defects recognised only at birth (born with)
• Epi = 3-5% newborns, mst common cause death in <1yr
• Major causes:
  
  • Genetic abnormalities - chromosome abn. and single -gene mutations
  • Maternal abnormalities
    
    • DM (increased risk neural tube defects+ chd, hyperglycaemia causes fetal macrosomia, because hyperinsulinemia in the fetus increases muscle mass and stores of fat in the adipose. Hyperinsulinemia is present in the fetus, because increased glucose from the mother enters the fetus and the fetal pancreas responds by increasing insulin synthesis.)
    • SLE - newborn may develop congenital heart block if mothers has anti-Ro Abs that cros spalcenta
    • Hypothyroidism - may develop cretinisim with severe mental impairment as thyroud hormone necessary for nromal development of brain
  • Maternal intake of drugs + chemcials
  • COngenital infections:
    
    • TORCH syndrome - toxoplasmosis, other agents, rubella, cytomegalovirus (CMV), herpes simple virus)
    • Newborns with congenital infection have increase in cord blood IgM (only synthesised if infection, as normally doesnt until after birth, CMV most common congeital infection).
    • Vertical transmission (mother to baby after birth) via transplacental, birth canal or breastfeeding
  • Ionising radiation - malforamtions in embyronic period so micrencephaly, skull defects, blidnness, ONT defects like spina bifida
  • Multifactoria inheritance - including ONT defects, CHD, clef lip/palate

Question 99

Foetal alsochol syndrome

Answer 99

Question 100

Phocomelia

Answer 100

Question 101

Cleft palate

Answer 101

Absence of palate

Question 102

COngenitsal Infections associated with congenital defects

Answer 102

Question 103

Normal prenatal development stages

Answer 103

Question 104

Teratogens acting on pregnant women that may adversely affect structure and function of fetus and newborn

Answer 104

Question 106

Types of Errors in Morphogenesis

Answer 106

• Malformation - disturbance in morphogenesis (development) of an organ. Mianly in embryogenesis (first 9wks) and most 3-9th weeks. Most suscpetible embryonig period for developing malformation is 4&5th weeks when organs being formed from germ layers
• Deforatmion - congenitla anomaly caused by extrinsic factors that physically imping on fetal development in utero. Between 9&10th week after fetal organs developed. Most often ass. with restricted movement of fetus in uterin cavity *uterine restraint). Maternal factors like malformed uterus or large leiomyomaa in uterine wall that bulde into uterine cavities or placental factors like oligohydraminos (reduced amniotic fluid) or twinc prgenancies.
• Disruption - Type of deformation that results from destruction of irreplaceable normal fetal tissue. Deformation may be due to vascular insufficiency (e.g., thrombosis of vessels in the placenta), trauma, or teratogens.Disruption may be due to amniotic bands . Rupture of the amnion (lines the fetal sac) is associated with the formation of fibrous bands that encircle parts of the fetus leading to partial amputation of a limb or constriction rings around digits.
• Agenesis -: Complete absence of an organ due to absence of the anlage (primordial tissue), Example: renal agenesis
• Aplasia - Defective development or congenital absence of an organ or tissue. The anlage (primordial tissue) present, but it never develops into an organ.Eg, In lung aplasia, the tissue only contains rudimentary ducts and connective tissue.
• Hypoplasia - Primordial tissue develops incompletely, but the tissue is histologically normal.Examples: microcephaly (small brain), hypoplastic left heart
• Atresia= Incomplete formation of a lumen. Example: small bowel atresia

Question 107

Congenital infections on images

Answer 107

Question 108

Answer 108

Potter facies, characterized by low-set ears and a small hooked nose, is seen in association with renal agenesis and pulmonary hypoplasia

Question 109

Answer 109

Question 110

Embryonic period and where things go wrong

Answer 110

Question 111

1. At a certain locus, a person has two alleles, A and a.
   a. What alleles will be present in this person’s gametes?
   b. When do A and a segregate
   (1) if there is no crossing over between the locus and the centromere of the chromosome?
   (2) if there is a single crossover between the locus and the centromere?

Answer 111

a) A or a.

b)

1. At meiosis I
2. At meiosis II

Question 112

Allele segregation

Answer 112

Question 113

Segregation, independent assoirtment and principle of dominance

Answer 113

Question 114

2. What is the main cause of numerical chromosome abnormalities in humans

Answer 114

Meiotic nondisjunction

Question 115

3. A chromosome entering meiosis is composed of two sister chromatids, each of which is a single DNA molecule.
   a. In our species, at the end of meiosis I, how many chromosomes are there per cell? How many chromatids?
   b. At the end of meiosis II, how many chromosomes are there per cell? How many chromatids?
   c. When is the diploid chromosome number restored? When is the two-chromatid structure of a typical metaphase chromosome restored?

Answer 115

(a) 23; 46.
(b) 23; 23.
(c) At fertilization; at S phase of the next cell cycle

Question 116

Answer 116

Chromosome 1, ≈9 genes/Mb; chromosome 13, ≈3-4 genes/Mb; chromosome 18, ≈4 genes/Mb; chromosome 19, ≈19 genes/Mb; chromosome 21, ≈5 genes/Mb; chromosome 22, ≈10 genes/Mb

Because of the higher density of genes, one would expect that a chromosome abnormality of chromosome 19 would have a greater impact on phenotype

than an abnormality of chromosome 18

Similarly, chromosome 22 defects are expected to be more deleterious than those of chromosome 21

Question 117

5. The following amino acid sequence represents part of a protein. The normal sequence and four mutant forms are shown. By consulting Table 1, determine the double stranded sequence of the corresponding section of the normal gene. Which strand is the strand that RNA polymerase “reads”?

●

What would the sequence of the resulting mRNA be?

What kind of mutation is each mutant protein most likely to represent?

Answer 117

There are several possible sequences because of the degeneracy of the genetic code.

One possible sequence of the double-stranded DNA is

(PIC)

RNA polymerase “reads” the bottom (3′ to 5′) strand. The sequence of the resulting

mRNA would be 5′ AAA AGA CAU CAU UAU CUA 3′.

The mutants represent the following kinds of mutations:

Mutant 1: single-nucleotide substitution in fifth codon; for example, UAU → UGU.

Mutant 2: frameshift mutation, deletion in first nucleotide of third codon.

Mutant 3: frameshift mutation, insertion of G between first and second codons.

Mutant 4: in-frame deletion of three codons (nine nucleotides), beginning at the third base

Question 118

6. The following items are related to each other in a hierarchical fashion: chromosome,

base pair, nucleosome, kilobase pair, intron, gene, exon, chromatin, codon, nucleotide,

promoter. What are these relationships?

Answer 118

The sequence of the haploid human genome consists of nearly 3 billion nucleotides,

organized into 24 types of human chromosome. Chromosomes contain chromatin,

consisting of nucleosomes. Chromosomes contain G bands that contain several thousand kilobase pairs of DNA (or several million base pairs) and hundreds of genes, each containing (usually) both introns and exons.

The exons are a series of codons, each of which is three base pairs in length.

Each gene contains a promoter at its 5′ end that directs transcription of the gene under appropriate conditions.

Question 119

7. Describe how mutation in each of the following might be expected to alter or interfere with normal gene function and thus cause human disease:
   * Promoter

▪ Initiator codon

▪ Splice sites at intron-exon junctions

▪ One base pair deletion in the coding sequence

▪ Stop codon

Answer 119

A mutation in a promoter could interfere with or eliminate transcription of the gene.

Mutation of the initiator codon would prevent normal translation. Mutations at splice

sites can interfere with the normal process of RNA splicing, leading to abnormal

mRNAs. A 1-bp deletion in the coding sequence would lead to a frameshift mutation,

thus changing the frame in which the genetic code is read; this would alter the encoded

amino acids and change the sequence of the protein.

A mutation in the stop codon would allow translation to continue beyond its normal

stopping point, thus adding new, incorrect amino acids to the end of the encoded

protein.

Question 120

8. Contrast the mechanisms and consequences of RNA splicing and somatic rearrangement.

Answer 120

RNA splicing generates a mature RNA from the primary RNA transcript by combining segments of exonic RNA and eliminating RNA from introns. RNA splicing is a critical step in normal gene expression in all tissues of the body and operates at the level of RNA. Thus the genomic DNA is unchanged. In contrast, in somatic rearrangement, segments of genomic DNA are rearranged to eliminate certain sequences and generate mature genes during lymphocyte precursor cell development as part of the normal process of generating immunoglobulin and T-cell receptor diversity. Somatic rearrangement is a highly specialized process, specific only to these genes and specific cell types.

Question 121

9. Contrast the mechanisms and consequences of genomic imprinting and X chromosome inactivation.

Answer 121

Genomic imprinting involves epigenetic silencing of an allele (or alleles at a number of closely located genes) based solely on parental origin due to epigenetic marks inherited through the germline.

X inactivation involves epigenetic silencing of alleles along much of an entire chromosome based not on parental origin, but rather on a random choice of one or the other X chromosome at the time of initiation of the process in early embryonic development.

Question 122

10. Polymorphism can arise from a variety of mechanisms, with different consequences.

Describe and contrast the types of polymorphism that can have the following effects:

a. A change in dosage of a gene or genes
b. A change in the sequence of multiple amino acids in the product of a protein-coding gene
c. A change in the final structure of an RNA produced from a gene
d. A change in the order of genes in a region of a chromosome
e. No obvious effect

Answer 122

(a) CNV: A copy number variation (CNV) is when the number of copies of a particular gene varies from one individual to the next
(b) Indel: An insertion/deletion polymorphism, commonly abbreviated “indel,” is a type of genetic variation in which a specific nucleotide sequence is present (insertion) or absent (deletion)
(c) A mutation in a splice site.
(d) An inversion.
(e) A SNP (or in/del) in a noncoding region or intron, or a SNP that leads to a synonymous substitution.

Question 123

11. Aniridia is an eye disorder characterized by the complete or partial absence of the iris and is always present when a mutation occurs in the responsible gene. In one population, 41 children diagnosed with aniridia were born to parents of normal vision among 4.5 million births during a period of 40 years.

Assuming that these cases were due to new mutations, what is the estimated mutation rate at the aniridia locus?

On what assumptions is this estimate based, and why might this estimate be either too high or too low?

Answer 123

Assuming 20 years is one generation, 41 mutations/9 million alleles/2 generations = ≈2.3 × 10−6 mutations/generation at the aniridia locus.

The estimate is based on assumptions that ascertained cases result from new mutation, that the disease is fully penetrant, that all new mutants are liveborn (and ascertained), and that there is only a single locus at which mutations can lead to aniridia

If there are multiple loci, the estimated rate is too high. If some mutations are not ascertained (because of lack of penetrance or death in utero), the estimated rate might be too low

Question 124

12. Which of the following types of polymorphism would be most effective for distinguishing two individuals from the general population:

▪ a SNP

▪ a simple indel

▪ a microsatellite?

Explain your reasoning.

Answer 124

A microsatellite polymorphism, because microsatellite polymorphisms typically have more alleles, which provides greater capacity to distinguish genomes.

A single SNP or indel would only have two alleles.

Question 125

13. Compare the likely impact of each of the following on the overall rate of mutation detected in any given genome:

▪ age of the parents,

▪ hot spots of mutation,

▪ intrachromosomal homologous recombination,

▪ genetic variation in the parental genomes.

Answer 125

Different types of mutations are sensitive to maternal or paternal age. Both single-bp mutations and CNVs show an increase in frequency with increasing age of the father. In contrast, meiotic nondisjunction for many chromosomes (including chromosome 21) shows an increase with increasing age of the mother.

The rate of mutation (per bp) varies greatly in different locations around the genome; hot spots of mutation show much higher rates, although the basis for this is poorly understood.

Intrachromosomal homologous recombination can lead to copy number variation in gene families or to deletion/duplications for regions flanked by homologous sequences (e.g., segmental duplications). Overall, the rate of mutation can be influenced also by genetic variation, both at a population level and in specific parental genomes. In any individual genome, this may influence where one falls in the ranges observed in typical genomes

Question 126

14. You send a blood sample from a dysmorphic infant to the chromosome laboratory for
    analysis. The laboratory’s report states that the child’s karyotype is 46,XY,del(18)(q12).
    a. What does this karyotype mean?
    b. The laboratory asks for blood samples from the clinically normal parents for analysis. Why?
    c. The laboratory reports the mother’s karyotype as 46,XX and the father’s karyotype as 46,XY,t(7;18)(q35;q12). What does the latter karyotype mean?
    d. In light of this new information, what does the child’s karyotype mean now? What regions are monosomic? trisomic? Estimate the number of genes present in the trisomic or monosomic regions.

Answer 126

(a) Forty-six chromosomes, male; one of the chromosome 18s has a shorter long arm

than is normal.

(b) To determine whether the abnormality is de novo or inherited from a balanced carrier parent.
(c) Forty-six chromosomes, male, only one normal 7 and one normal 18, plus a reciprocal translocation between chromosomes 7 and 18. This is a balanced karyotype.
(d) The del(18q) chromosome is the der(18) translocation chromosome, 18pter → 18q12::7q35 → 7qter. The boy’s karyotype is unbalanced; he is monosomic for the distal long arm of 18 and trisomic for the distal long arm of 7. Given the number of genes on chromosomes 7 and 18, one would predict that the boy is monosomic for approximately 100 genes on chromosome 18 and trisomic for approximately 100 genes on chromosome 7

Question 127

15. For each of the following, state whether chromosome or genome analysis is indicated

or not. For which family members, if any? For what kind of chromosome abnormality

might the family in each case be at risk?

a. A pregnant 29-year-old woman and her 41-year-old husband, with no history of genetic defects
b. A pregnant 41-year-old woman and her 29-year-old husband, with no history of genetic defects
c. A couple whose only child has Down syndrome
d. A couple whose only child has cystic fibrosis
e. A couple who has two boys with severe intellectual disability

Answer 127

(a) Not indicated.
(b) Foetal karyotyping indicated; at risk for trisomy 21, in particular.
(c) Karyotype indicated for the child to determine whether it is trisomy 21 or translocation Down syndrome. If it is translocation, parental karyotypes are indicated.
(d) Not indicated, unless other clinical findings might suggest a contiguous gene syndrome
(e) Karyotype indicated for the boys to rule out deletion or other chromosomal abnormality. If clinical findings indicate possibility of fragile X syndrome, a specific DNA diagnostic test would be indicated.

Question 128

16. Explain the nature of the chromosome abnormality and the method of detection

indicated by the following nomenclature.

a. inv(X)(q21q26)
b. 46,XX,del(1)(1qter → p36.2:)
c. 46,XX.ish del(15)(q11.2q11.2)(SNRPN−,D15S10−)
d. 46,XX,del(15)(q11q13).ishdel(15)(q11.2q11.2)(SNRPN−,D15S10−)
e. 46,XX.arrcgh1p36.3(RP11-319A11,RP11-58A11,RP11-92O17) ×1
f. 47,XY,+mar.ish r(8)(D8Z1+)
g. 46,XX,rob(13;21)(q10;q10),+21
h. 45,XY,rob(13;21)(q10;q10)

Answer 128

(a) Paracentric inversion of the X chromosome, between bands Xq21 and Xq26, determined by karyotyping.
(b) Terminal deletion of 1p in a female, determined by karyotyping.
(c) Female with deletion within band q11.2 of chromosome 15, determined by in situ hybridization with probes for the SNRPN gene and D15S10 locus.
(d) Female with interstitial deletion of chromosome 15, between bands q11 and q13, determined by karyotyping. In situ hybridization analysis confirmed deletion of sequences within 15q11.2, with use of probes for the SNRPN gene and D15S10 locus.
(e) Female with deletion of sequences in band 1q36.3, determined by array CGH with the three BAC probes indicated.
(f) Male with an extra marker chromosome, determined by karyotyping. Marker was identified as an r(8) chromosome by in situ hybridization with a probe for D8Z1 at the centromere.
(g) Female with Down syndrome, with a 13q;21q Robertsonian translocation in addition to two normal chromosome 21s,

determined by karyotyping.

(h) Presumably normal male carrier of a 13q;21q Robertsonian translocation, in addition to a single normal chromosome 21 (and a single normal chromosome 13), as determined by karyotyping.