1. Patterns of Inheritance
In the name of ALLAH
Patterns of Inheritance
Dr. R. Jazayeri
Alborz University of Medical Sciences

2. Mendelian inheritance
The Online Mendelian Inheritance in Man (OMIM) database is a catalog of, among other things, genes in which Mendelian traits cause disease.
Gregor Mendel
“Father of Genetics”

3. Causes of Anomalies Genetical(30-40%): Chromosomal(6%)
Single gene (7.5%)
Multi factorial(20-30%)
Environmental(5-10%)
Unknown (50%)

4. Single Gene Disorders Caused by mutation in or around a gene.
Can lead to critical errors in the genetic information.
Exhibit characteristic pedigree pattern of inheritance (Mendelian Inheritance).
Occur at a variable frequency in different population.
May be:
Autosomal
Sex linked

5. Standard symbols used in pedigrees

7. Autosomal Inheritance
This is the inheritance of the gene present on the Autosomes (1-22).
Both sexes have equal chance of inheriting the disorder.
Two types:
Autosomal dominant inheritance, if the gene is dominant.
Autosomal recessive inheritance, if the gene is recessive.

8. Autosomal dominant inheritance
Affected individuals are the product of a carrier parent.
Phenotypically normal family members are unlikely to transmit the disease to their offspring.
Males and females are usually equally affected
The character is apparent in each generation. (There are exceptions)
Half of descents of an affected individual will be affected.
Consanguinity is not elevated.
It is largely or completely expressed in heterozygote.
The homozygous state is either unknown or very rare, much more severe or even lethal.

9. Autosomal dominant inheritance
Most frequent instance: Aa x aa
( marriage of an affected individual HEZ with a normal individual).

10. Autosomal Dominant Inheritance

11. Autosomal Dominant Inheritance
“Vertical” pattern of inheritance
Confirm with male-male transmition (i.e. father to son)

12. A form of progressive sensorineural deafness (DFNAI)

13. Examples of AD diseases
Huntigton Disease
Polydactyly
Porphyria variegata
Myotonic dystrophy
Achondroplasia
Familial hyperchlosterolemia

14. Autosomal dominant inheritance
In theory : is the simplest mode of genetic counseling .
but
In practice: it provides the most difficult problems.
Why?

15. Pleiotropy
The multiple (>=2) apperantly unrelated effects of an AD gene
Manifest in different systems of the body in different ways
Example:
Tuberous Sclerosis
Learning difficulties
Epilepsy
Facial rash
(adenoma sebaceum)

16. Tuberous Sclerosis

18. Reduced Penetrance
A dominant gene wich does not manifest itself in a proportion of heterozygotes.
An individual who has the genotype for a disease may not exhibit the disease phenotype at all, even though he or she can transmit the disease gene to the next generation: “skipping a generation”
Example:
Retinoblastoma
AD malignant eye tumor
About 10% of the heterozygotes of the RB susceptibility gene, do not have the disease

19. Variable expressivity
The variation in the severity of phenotypic features of AD disorders from person to person.
Example:
AD Polycystic kidney disease
Renal failure in early childhood
Just a few renal cysts, not significant effect on renal function

20. New Mutation
Frequent cause of appearance of genetic disease in individual with no prior family history of disorder .
Recurrence risk for individual’s siblings is very low.
May be substantially elevated for individual’s offspring.
Example:
Achondroplasia
7/8 of all cases of achondroplasia are due to new mutations.
1/8 transmitted from achondroplastic parents.
must know adequate family history to distinguish.

21. Germline Mosaicism
Two or more offspring will present with an AD or x-linked disease when there is no family history of disease.
Because mutation is rare event, it is unlikely that this would be due to multiple mutations in the same family.
Occurs when all or part of a parent’s germline is affected by a disease mutation, but somatic cells are NOT affected.
Elevates recurrence risk for future offspring of mosaic parent.
Examples:
Osteogenesis imperfecta
Duchenne muscular dystrophy

22. Delayed Age of Onset late-onset-diseases .
Can cause difficulty in deducing mode of inheritance.
Not possible until later in life to determine whether an individual carries a mutation.
Examples:
Huntington Disease
Familial Alzheimer disease
AD form of breast cancer

23. Locus Heterogeneity
The phenomenon of a disorder being to mutations in more than one gene or locus.
Hereditary disorders that can show different patterns of inheritance.
Examples:
Cerebellar ataxia: AD, AR
Polycystic Kidney disease: AD, AR
Ichtyosis: AD, AR, XR
Retinitis pigmentosa: AD, AR, XR, M

24. Anticipation
The tendency for some AD diseases to manifest at an earlier age and/or to increase in severity with each succeeding generation.
An earlier age of onset and more severe phenotype in subsequent generation
Example:
Myotonic Dystrophy (MD)
Huntington’s Disease (HD)

25. Autosomal recessive inheritance
The Great majority of the affected indivuduals are born to healthy but heterozygous (obligatory carrier) parents.
Males and females are often equally affected
The risk of occurrence for each sib of the affected proband is 1 in 4.
An affected individual who marries a normal, non consanguineous person, usually has normal children.
The frequency of consanguineous families is elevated and more so if the disease is rare.

26. Autosomal recessive inheritance

27. “Horizontal “ transmission.?

28. Autosomal recessive inheritance

29. Consanguinity
‘Consanguinity’ comes from two Latin words: con meaning shared and sanguis that means blood.
Consanguineous Marriage is between blood relatives who have at least one common ancestor no more remote than great-great grand parent.
This means that they are more likely to carry identical alleles inherited from this common ancestor and could both transmit an identical allele to their offspring, who would then be homozygous for that allele

30. Pseudodominant inheritance Pedigree
A woman homozygous for an autosomal recessive disorder whose husband is heterozygous for the same disorder.
Their children have a 1 in 2 (50%) chance of being affected (pseudodominant)

31. Locus heterogenity
The phenomenon of a disorder being due to mutations in more than one gene or locus.
Sensoryneural hearing loss

32. Mutational (allelic) heterogenity
The occurrence of more than one mutation in a particular single-gene disorder. i. e. thalassemia
Compound heterozygote: an individual who is affected with an AR disorder having two different mutations in homologus genes.
Promoter elements
a promoter is a region of DNA that facilitates the transcription of a particular gene. Promoters are located near the genes they regulate, on the same strand and typically upstream (towards the 5' region of the sense strand
Core promoter - the minimal portion of the promoter required to properly initiate transcription [1]
Transcription Start Site (TSS)
Approximately -35 bp upstream and/or downstream of the start site
A binding site for RNA polymerase
RNA polymerase I: transcribes genes encoding ribosomal RNA
RNA polymerase II: transcribes genes encoding messenger RNA and certain small nuclear RNAs
RNA polymerase III: transcribes genes encoding tRNAs and other small RNAs
General transcription factor binding sites
Proximal promoter - the proximal sequence upstream of the gene that tends to contain primary regulatory elements
Approximately -250 bp upstream of the start site
Specific transcription factor binding sites
Distal promoter - the distal sequence upstream of the gene that may contain additional regulatory elements, often with a weaker influence than the proximal promoter
Anything further upstream (but not an enhancer or other regulatory region whose influence is positional/orientation independent)

33. Examples of AR diseases
Phenyl Keton Uria
Thalassemia
Albinism
Cystic Fibrosis

34. Sex- linked Inheritance
Some human traits are located on the sex (usually X )chromosomes.
They may be inherited as
X-linked recessive, or
X-linked dominant
Y-linked (holandric)

35. X linked recessive inheritance
Affected individuals are usually male and born of normal parents.
It is transmitted by healthy heterozygous female carriers to affected males.
It is transmitted by affected males to their obligate carrier daughters, with consequent risk to male grandchildren through these daughters.
Always expressed in hemizygous males. (a male with a mutant allele on his single X chromosome is said to be hemizygous for that allele)

36. Hemophilia

37. X linked recessive inheritance
“diagonal” or “knight’s move” pattern of transmission

38. Example: hemophilia A P
Predict possible fetal outcomes

39. X linked recessive inheritance
Most frequent case: heterozygote woman, a normal carrier who marries a normal man.

40. Particular cases of XLR inheritance
Mating normal female / affected male
Parental genotype : XX * xY
All boys are normal and carry no mutation.
All girls are normal but are HEZ carriers.

41. Particular cases of XLR inheritance
Marriage HEZ female / affected male
Parental genotype: Xx / xY

42. XLR inheritance
---> The fact that the disease is restricted to males is not an absolute criterion of X linked inheritance.
The criterion of non transmission from father to son is more objective.
---> (it allows to differentiate between autosomal dominant diseases with sex limitation).

43. Examples of XLR diseases
Colour blindness
Hemophilia A and B
Angiokeratosis (Fabry disease)
Duchenne muscular dystrophy
Agammaglobulinemia, Bruton type
G6PD deficiency

44. X-linked Dominant Inheritance
Expressed with one copy.
An excess of affected females in families.
Males are often more severely affected (Typically associated with miscarriage or lethality in males).
Daughters and sons of the affected mother: 50% healthy, 50% affected.
Direct male-to-male transmission cannot occur.
All daughters of affected male are affected.

45. X-linked dominant pedigree

46. Examples of XLD diseases
Only a few disorders have XLD inheritance pattern.
Vitamin D resistance rickets
X-linked form of Charco-Marie-Tooth
Rett syndrome
Incontinentia pigmenti type 2
Aicardi syndrome
Rett syndrome, incontinentia pigmenti type 2 and Aicardi syndrome are usually fatal in males either in utero or shortly after birth, and are therefore predominantly seen in females.

47. Y-linked (Holandric)Traits
The Y chromosome is relatively small and contains very few genes.
Trait expression and transmission is only in males.
If a male has a trait, so should his father and paternal grandfather as well as his sons and their sons.
No females should exhibit the trait.

48. Y-linked pedigree

49. Examples of Y-linked (Holandric)Traits
Male Infertility
Excessive hair on the ear pinna (Hypertrichosis pinnae)
Y-linked infertility is not transmitted

51. Sex-influenced inheritance
Some autosomal traits are expressed more frequently in one sex than another.
Examples:
Gout (AD)
Presenile baldness (AD)
Hemochromatosis (AR)

52. Sex-limited inheritance
Some autosomal traits are expressed only in one sex.
Examples:
Virilization of female infants affected with CAH (Congenital AdrenalHyperplasia )(AR )
Familial testotoxicosis (AD)