1. Genetic disorders and modes of inheritance

2. Genetic disorders Gene alterations can be cateogorized further into:
Monogenic
They are caused by a single gene
They are also known as Mendelian genetic disorders
They are usually confined to an organ system
However, there can be widespread effects if an enzyme or protein is needed by several tissues or organs
Multigenic
They involve mutations of several genes
The environment may play a role as well
Such disorders are complex and unpredictable

3. Mendelian traits
They can be categorized based on the location of the gene and how many copies of the mutant allele are required to express the phenotype:
autosomal recessive inheritance
autosomal dominant inheritance
Sex-linked disorders
mitochondrial inheritance

4. Mendelian genetic disorders
Most of Mendelian disorders are autosomal (~12,000)
Followed by X chromosome-linked (760)
The remaining few are Y chromosome-linked and mitochondrial disorders
In one survey, 9% of pediatric deaths were due to a Mendelian disorder,
3% were due to chromosomal disorders and
38% were due to partly genetic disorders
About 2% of the population has a monogenic disorder
68% of them are dominant conditions
26% are recessive disorders, and
6% are X-linked single gene disorders

5. Mendelian genetic disorders
Mendelian genetic diseases predominantly affect young individuals,
25% of phenotypes being apparent at birth, and
90% by the end of puberty

6. Family history
A complete medical history should always include a family history
The most obvious sign of a genetic disease is the high frequency of familial occurrence
However, many fundamentally genetic conditions can arise spontaneously without any prior family history of hereditary disease

7. Pedigree analysis
Family history is summarized as a pedigree graph

8. Symbols

9. Autosomal Recessive Inheritance
Recessive conditions are clinically apparent only when an individual has two copies of the mutant allele.
When just one copy of the mutant allele is present, an individual is a carrier of the mutation, but does not develop the condition.
The great majority of disorders due to metabolic enzyme deficiencies are autosomal recessive.

10. Criteria Parents of affected people are usually asymptomatic carriers.
Autosomal recessive inheritance may be characterized by a clustering of the disease phenotype among children.
The risk to each sibling of carrier individuals of showing the phenotype is 25%.
Psuedodominance: children of an affected individual and a carrier (50% chance)
Consanguinity (marriages of relatives) significantly increases the risk of manifesting a recessive phenotype.
Males and females are equally likely to be affected.

11. Pedigree analysis Affected children are born to unaffected parents
(affected individuals are indicated by solid black symbols and unaffected carriers are indicated by the half black symbols)

12. Locus heterogeneity
Locus heterogeneity: Similar or even identical clinical syndromes can result from mutations at different genes.
Individuals with the same condition due to mutations in different genes

13. Allelic heterogeneity
Allelic heterogeneity: A genes having different mutations resulting in the same clinical syndrome.
Compound heterozygote: If an individual has one mutant allele on one chromosome and a different mutant allele on the other chromosome at the same locus
Since both alleles are abnormal, the individual will be affected.
Most autosomal recessive disorders result from being compound heterozygosity (except cases of consanguineous marraiges).

14. Examples 1. Phenylketonuria
Normally
Abnormally
Phenylpyruvic acid, a compound that interferes with the development of the nervous system, leading to mental retardation

15. Other examples Cystic fibrosis Thalassemia Sickle cell anemia
Most of enzymatic pathway diseases are recessive.
Exceptions include acute intermittent porphyria, which caused by mutation in the gene encoding hydroxymethylbilane synthase
Defective enzyme leads to defects in the biosynthesis of heme

16. Autosomal Dominant Inheritance
A typical pedigree

17. Criteria
The phenotype appears in every generation, and each affected individual has an affected parent
A child of an affected homozygous parent has a 50% chance of inheriting the trait
Males and females are equally at risk

18. Examples Pseudoachondroplasia, which is a type of dwarfism
Huntington’s disease
Neurofibromatosis
Wilson disease, and
Galactosemia

19. Pleiotropy
Pleiotropy: a mutation in one gene causes multiple and/or variable phenotypic traits in the organism.
Example:
Mutations in Lamin A gene can cause multiple diseases:
Emery Dreifuss muscular dystrophy
Limb girdle muscular dystrophy type 1B
Dilated cardiomyopathy with conduction system disease
Charcot Marie Tooth disease type 2
Familial partial lipodystrophy; Dunnigan type
Hutchinson–Gilford progeria syndrome
Mandibuloacral dysplasia
Restrictive dermopathy

20. Penetrance
Penetrance is an all or none phenomenon-either the abnormal phenotype is present or it is absent
If the phenotype is absent, then it is nonpenetrant
If the phenotype is apparent, then it is penetrant

21. Incomplete (reduced) penetrance
Autosomal dominant mutations and traits often show variable intensity of the phenotype resulting in a phenomenon known as variable expressivity.
There are cases where an individual carries a dominant mutation of a gene, but the phenotype is normal.
This is explained by incomplete penetrance.

22. Why is there incomplete penetrance?
Decreased expression of the mutated gene by
the presence of modifier genes, (i.e., other genes within an individual's genome), can interact with the abnormal gene to either increase or decrease its expression
individual heterogeneity can affect expression
The presence of different mutations within one gene (allele heterogeneity), both causing different degrees of clinical severity
Environmental factors can improve or aggravate the disease process

23. Huntington’s disease
Huntingtin [sic] (HTT) locus has (CAG)n repeat near 5' end
A nuclear protein that binds to a number of transcription factors
Number of copies in affected individuals inversely correlated with severity & age of onset
Phenotype is a consequence of presence of modified protein.
HD alleles 'dominate' standard alleles.

24. Sex-linked inheritance
Human body cells contain 2 sex chromosomes. In females, there is a pair of identical sex chromosomes called the X chromosomes. In males, there is a nonidentical pair, consisting of one X and one Y
At meiosis in females, the two X chromosomes pair and segregate like autosomes so that each egg receives one X chromosome. Hence the female is said to be the homogametic sex
At meiosis in males, the X and the Y pair over a short region, so sperm cells receive either X or Y. Therefore the male is called the heterogametic sex

25. X chromosome inactivation
In the XX female, one X chromosome in each cell becomes genetically inactive at an early stage in embryogenesis
The inactive X becomes a Barr body
The inactivation of the X chromosome is random
Generally, maternally and paternally derived X chromosomes are inactivated in equal numbers

26. Dosage compensation
In addition, although females have an extra chromosome, gene expression is equal in both males and females
This is called dosage compensation and is due to the inactivation of one X chromosome in females

27. X-linked disorders
Diseases caused by genes on the X chromosome are said to be X-linked
Because males have only one X chromosome (hemizygous), the presence of an abnormal gene on the X chromosome is expressed
However, in females who have two X chromosomes, the presence of one abnormal recessive gene is usually compensated by the presence of a normal gene on the other X chromosome (heterozygous)

28. Features of X-linked recessive disease inheritance
Affects mainly males (1 in 2 chance)
Affected males are usually born to unaffected parents; the mother is normally an asymptomatic carrier
Females may be affected if the father is affected and the mother is a carrier or affected

29. Female carrier
A women who carries X-linked recessive disease genes is physically normal
There is a 50% chance that a carrier female will have an affected son and a carrier daughter

30. Male carrier (affected)
Affected males have normal offspring
Their sons, receiving the Y, are free of the trait
Their daughters, receiving the abnormal X, are obligate carriers

31. Significance of X inactivation
A recessive gene in a carrier female is occasionally expressed due to the inactivation of a significant number of the X chromosomes containing the normal gene
A dominant trait in a carrier female can escape expression because of inactivation of a majority of the X chromosomes with the abnormal gene

32. Cellular distribution of active X chromosome
Since the X chromosome inactivation is random, it is just as likely that either the normal X or the abnormal X is inactivated
Thus, X chromosome inactivation creates normal cells and abnormal cells depending on whether the normal X or the abnormal X is active
Since an organ (e.g., the liver) originates from a small cluster of cells, a large number of the cells within the organ could have a normal functioning X (or an abnormal functioning X)

33. Complete expression of X-linked recessive disease
The allele frequency for the disorder is high, so they can inherit the mutated gene from both parents
A female hemizygous for an X-linked trait, such as a 45, X0 (Turner’s syndrome) female, or a woman with a deletion of the same allele of the normal X chromosome
Faulty X-inactivation, where both alleles are inactivated.
Skewed X inactivation: only the faulty X chromosome is inactivated.
X-autosome translocation: Duschenne muscular dystrophy.

34. features of X-linked dominant disease inheritance
Affects either sex, but more females than males
The child of an affected heterozygous female, regardless of its sex, has a 50% chance of being affected
For an affected male, all his daughters but none of his sons are affected
Male-to-male transmission never occurs

35. Examples-Hemophilia
Mutations affecting the coagulation cascade result in hemophilia (locus heterogeneity)
The most common type of hemophilia is caused by the absence or malfunction of factor VIII (hemophilia A)
Over 620 different mutations are known to affect the factor VIII clotting factor gene resulting in allelic heterogeneity
Hemophilia B results from mutations of the factor IX gene, which also lies on the X chromosome

36. Duchenne muscular dystrophy
The most common muscular dystrophy is caused by a mutation of a gene on the X chromosome
Duchenne muscular dystrophy (DMD) affects young boys
Although they are generally normal at birth and for their first few months of life, boys affected by this disease develop weakness in proximal muscles

37. X-autosome translocation
Following translocation, there is preferential inactivation of the correct X-chromosome to express genes on the translocated autosomal chromosome.

38. Anticipation
The signs and symptoms of some genetic conditions tend to become more severe and appear at an earlier age as the disorder is passed from one generation to the next.
This phenomenon is called anticipation.
It is most often seen with certain genetic disorders of the nervous system, such as Huntington disease, myotonic dystrophy, and fragile X syndrome.
Anticipation typically occurs with disorders that are caused by trinucleotide repeat expansion.

39. Fragile X Mental retardation (FMR)
This syndrome is the most common form of inherited mental retardation
It is evidenced cytologically by a fragile site in the X chromosome that results in a break in vitro
The fragile X syndrome results from mutations in a (CGG)n repeat in the coding sequence of the FMR-1 gene

40. Molecular cause of FMR
The inheritance of fragile X syndrome is unusual in that 20 percent of the males with a fragile X chromosome are phenotypically normal but transmit the affected chromosome to their daughters, who also appear normal
These males are said to be normally transmitting males (NTMs)
However, the sons of the daughters of the NTMs frequently display symptoms

41. Premutations
Why do symptoms develop in some persons with a fragile X chromosome and not in others? The answer seems to lie in the number of CGG repeats in the FMR-1 gene
Humans normally show a considerable variation in the number of CGG repeats in the FMR-1 gene, ranging from 6 to 54
Both NTMs and their daughters have a much larger number of repeats, ranging from 50 to 200
These increased repeats have been termed premutations
All premutation alleles are unstable.
The males and females with symptoms of the disease, as well as many carrier females, have additional insertions of DNA ranging from 200 to 1300.

42. Penetrance of FRAXA
The fragile X phenotype is X-linked dominant, but incompletely penetrant
An asymptomatic son with the abnormal X (a normal transmitting male) always has daughters with normal intelligence, but these heterozygous daughters have sons with a 40% chance of being retarded, and their daughters a 16% chance of retardation.
This incomplete penetrance is due to first the development of a permutation

43. Y-linked inheritance Only males inherit genes
The gene that plays a primary role in maleness is the SRY gene, sometimes called the testis-determining factor
The SRY gene has been located on the Y chromosome
Individuals with 46, XY who have deletions of this critical region of the Y chromosome develop as females
The SRY gene encodes a protein that likely is a transcription factor that controls a gene or genes involved in testes development
Abnormal meiotic recombination during spermatogenesis leading to the gain of the Sry by the X chromosome results in the development of males with 46, XX

44. Y-linked inheritance

45. Mitochondrial inheritance
Mitochondrial DNA is maternally transmitted and affected fathers do not transmit disorders with a mitochondrial mode of inheritance to their children
Many genetic diseases in which mitochondrial defects occur do not demonstrate mitochondrial inheritance. This is because many proteins essential for normal function of mitochondria are encoded by the nuclear genome

46. Mitochondrial disorders
An inherited disease in humans caused by a mutation in mitochondrial DNA can be recognized by its passage from affected mothers to both their daughters and their sons, with the daughters only producing grandchildren with the disease
As expected from the random nature of mitotic segregation, the symptoms of these diseases vary greatly between different family members in terms of severity, age of onset, and affected tissue

47. Other modes of inheritances
Mosaicism
Uniparental disomy (UPD)
Imprinting

48. Mosaicism Post-zygotic mutations are frequent
Post-zygotic mutations produce mosaics with two (or more) genetically distinct cell lines
Mosaicism can affect somatic and/or germ line tissues
Germline mosaicism: parents are fine, but children are affected.

49. Mosacism-based abnormalities
Only if a somatic mutation results in the emergence of a substantial clone of mutant cells is there a risk to the whole organism
This can happen in two ways:
the mutation occurs in an early embryo, affecting a cell which is the progenitor of a significant fraction of the whole organism.
the mutation causes abnormal proliferation of a cell, thus generating a clone of mutant cells

50. Uniparental disomy (UPD)
refers to a pair of chromosomes being inherited from one parent and none from the other parent
Cystic fibrosis (CF) may be secondary to uniparental disomy where both number 7 chromosomes, with the F508 mutation, come from one parent.

51. Imprinting
A type of epigenetic inheritance where only the allele from either the mother or father is expressed resulting in monoallelic expression

52. Example of genomic imprinting
Prader–Willi and Angelman syndromes are caused by deletion of distinct genes within the 15q11-13 region
The Prader–Willi gene with deletion of paternal gene or maternal uniparental disomy.
The Angelman syndrome with deletion of maternal gene or paternal uniparental disomy.
Angelman syndrome
Prader-Willi syndrome

53. Multifactorial and complex traits

54. Multifactorial inheritance
The most common cause of genetic disorders is multifactorial or polygenic inheritance
Traits that are due to the combined effects of multiple genes are polygenic (many genes)
When environmental factors also play a role in the development of a trait, the term multifactorial is used

55. Polygenic and oligogenic traits
Polygenic traits caused by many different genes, each having only a limited impact on the phenotype
Oligogenic traits caused by relatively few genes some of which have a larger effect on the phenotype (susceptibility genes) acting in a dominant pattern with variable expressivity with the interplay of environmental factors

56. Genetic predisposition
Diseases with multifactorial inheritance are not genetically determined, but rather a genetic mutation may predispose an individual to a disease
Identical twins who are exactly alike genetically, do not always have the same condition when inheritance is multifactorial
This indicates that there are nongenetic factors that also play a role in the expression of multifactorial traits

57. BRCA1 inheritance
The BRCA1 gene is linked to development of breast and ovarian cancers
Fathers can be carriers and pass the mutation onto offspring
Not all people who inherit the mutation develop the disease, thus patterns of transmission are not always clear

58. Quantitative traits
Some phenotypes (traits) are determined by more than one gene (polygenic)
These are called quantitative traits
Such traits are said to exhibit continuous variation
They are also influenced by the environment

59. Examples Height Weight Blood pressure Skin color
Note the additive effect of genes (the effect of genes is cumulative).

61. Disorders with multifactorial inheritance
Congenital
Acquired
Cleft lip/palate
Congenital dislocation of the hip
Congenital heart defects
Neural tube defects
Pyloric stenosis
Talipes
Cardiovascular diseases (Hypertension, Ischemic heart disease, Ischemic stroke)
Asthma
Neurological diseases (Autism, Epilepsy, Manic depression, Parkinson disease, Schizophrenia)
Autoimmune diseases (Diabetes mellitus , Multiple sclerosis, Inflammatory bowel (Crohn) disease ulcerative colitis, Psoriasis Rheumatoid arthritis)

62. Important points
Multifactorial conditions tend to run in families, but the pattern of inheritance is not as predictable as with single gene disorders
The chance of recurrence is also less than the risk for single gene disorders
The closer the degree of relationship, the higher the risk is for multifactorial inheritance of a disease
The degree of risk also increases with the degree of severity of the disorder
It can also be sex-dependent

63. The Threshold Model
All individual have a certain degree of susceptibility to develop a polygenic disease
If the susceptibility exceeds a critical threshold value, the disease is developed
Liability: The combination of genetic and environmental factors of an individual in a population

64. Proportion of genes shared
Familial genetics
Relationship
Proportion of genes shared
First degree (Parents, Siblings, Children)
1/2
Second degree (Uncles and aunts, Nephews and nieces, Grandparents  and Grandchildren, Half-siblings)
1/4
Third degree (First cousins, Great-grandparents, Great-grandchildren)
1/8
Multifactorial diseases run in families

65. The Threshold Model in families
The threshold is fixed, but the average susceptibility, and hence the recurrence risk, rises with an increasing number of previous affected children

66. Risk is greatest in close relatives and decreases rapidly in distant relatives
in spina bifida: risks to first-, second- and third-degree relatives index are: 4%, 1% and less than 0.5%, respectively

67. Considerations of the Threshold model
Risks are different from Mendelian inheritance risks
Risks vary among different families (it is a probability)
The risk increases with the number of affected relatives
The risk increases among close relatives
The differential risk to relatives decreases as the frequency of the disease increases in the general population
A lower threshold results in a smaller difference

68. Considerations of the Threshold model
The risk increases with the severity of the malformation or disease
in cleft lip/palate: proportion of affected first-degree relatives is:
6% if index patient has bilateral cleft lip and palate
2% if the index patient has a unilateral cleft lip

69. Considerations of the Threshold model
When the sex ratio deviates significantly from norm, offspring of affected probands of the less frequently affected sex are at higher relative risk

70. Example
More boys than girls are affected, but the recurrence risk is higher for relatives of an affected girl.

71. Heritability
Twin studies can distinguish genetic contributions to a trait from environmental influences
The concordance rate in monozygotic twins is compared to the that in dizygotic (fraternal) twins to estimate the genetic component (heritability) of the trait
If the trait is truly 100% genetic, monozygotic twins will be 100% concordant while dizygotic twins will have a lower concordance rate
If the trait is 100% environmental, monozygotic twins and dizygotic twins will have the same concordance rate

72. Examples MZ DZ

73. Estimating concordance and heritability
The concordance rate for a disease is calculated as follows:
Concordance Rate = [Both Affected / (One Affected + Both Affected)] x 100
Traits with a large genetic component will show a higher concordance rate for MZ twins than for DZ twins
For 100% genetic trait, should be 1.0 in MZ twins and 0.5 for DZ of same sex.
Concordance ratio: MZ/ DZ (the higher it is, the more genetic a trait is)
Higher degree of concordance in MZ twins interpreted as higher heritability:
Heritability = 2(rmz-rdz)

74. Summary of the characteristics of multifactorial inheritance
Although the disorder is familial, there is no distinctive pattern of inheritance within a single family.
The risk to first-degree relatives, determined from family studies, is approximately the square root of the population risk. The risk is sharply lower for second-degree than for first-degree relatives, but it declines less rapidly for more remote relatives.
The recurrence risk is higher when more than one family member is affected.
The more severe the malformation, the greater the recurrence risk.
If a multifactorial trait is more frequent in one sex than in the other, the risk is higher for relatives of patients of the less susceptible sex.
If the concordance rate in DZ twins is less than half the rate in MZ twins, the trait cannot be autosomal dominant, and if it is less than a quarter of the MZ rate, it cannot be autosomal recessive.
An increased recurrence risk when the parents are consanguineous suggests that multiple factors with additive effects may be involved.