1. Patterns of inheritance
Suna Onengut-Gumuscu, PhD
Center for Public Health Genomics

2.
Human Genetics and Genomics (2006), Korf, 3rd edition, ISBN
Thompson and Thompson Genetics in Medicine (2007), Nussbaum, McInnes, Willard, 7th edition, ISBN

3. Patterns of inheritance
Family history/ Pedigree
Autosomal recessive
Autosomal dominant
Sex-linked traits
Penetrance and Expressivity
Genetic imprinting
Genetic anticipation

4. Human genome
46 chromosomes
22 pairs of autosomes
XY male
XX female

5. Classification of Genetic Disorders
Chromosomal disorders: Defect is due to an excess or a deficiency in whole chromsomes or chromsome segments (trisomy 21,Turner syndrome, Klinefelter syndrome)
Single gene defects: Caused by individual mutant genes
Multifactorial inheritance: Combination of multiple genes and environmental factors. (Complex disease: diabetes mellitus, Crohn’s disease, Multiple sclerosis)

6. Single gene disorders/ Common disease
More then 3900 single gene defects have been catalogued
Rare single gene disorders: usually less then 1 in births
Common diseases: determined by combinations of genes interacting with one another and with the environment. Do not fit the characteristic patterns of inheritance observed in single gene defects.

7. Patterns of Inheritance
Gregor Mendel ( ) was the first person to describe how certain traits are inherited from generation to generation.
Early 20th century Archibald Garrod recognized the existence of families in which traits segregated according to Mendel’s laws

8. Pedigrees in genetics
Single-gene disorders show patterns of transmission in families
Family history: 1st step in establishing pattern of inheritance
Pedigree: A diagram of a family history indicating the family members, their relationship to the proband, and their status with respect to a particular heredity condition
Some traits cluster in families.

9. Family history In diagnosis To clarify pattern of inheritance
Provide information if there is variation in expression among family members
Natural history of a disease

10. Main symbols used in pedigrees

11. Inheritance patterns
Recessive: expressed only when both chromosomes of a pair carry mutant alleles at a locus (2 mutant copies)
Dominant: expressed when one chromosome of a pair carries a mutant allele at a locus . (1 mutant copy)

12. Inheritance patterns Sex-linked: on the X or Y chromosomes
Autosomal: on any of the other 22 chromosome pairs
In general autosomal disorders will effect affect males and females equally

13. Genetic Terms Allele: one variant of a gene or marker
Genotype: genetic composition for a trait
Phenotype: physical manifestation of a trait

14. Inheritance patterns
Autosomal recessive

15. Genotype and phenotype correlation with gene locus for an autosomal recessive trait
Dominant allele
Recessive allele
Genotype:
Phenotype:
Homozygous
unaffected
Heterozygous
unaffected
Homozygous
affected

16. Autosomal Recessive Inheritance
Autosomal recessive traits are only expressed in individuals who carry two mutant alleles inherited from each parent.
Autosomal recessive traits usually arise in children of phenotypically normal parents A a Aa
sperm
eggs AA Aa aa

17. Segregation of an autosomal recessive trait in a pedigree

18. Autosomal recessive: increased incidence of parental consanguinity

19. Autosomal Recessive Inheritance
Usually parents are heterozygous carriers
Affected individuals are usually born to unaffected parents
Affected children are homozygous for mutant gene
In most autosomal recessive diseases males and females are equally likely to be affected
Carrier couple has a 1 in 4 chance of having affected offspring
There is an increased incidence of parental consanguinity
Mutant alleles for recessive disorders are generally rare.
2. In heterozygote individuals one normal gene copy is able to compensate for the mutant allele and prevent the disease from occurring.

20. Autosomal Recessive Inheritance
These traits are only expressed in individuals who carry two mutant alleles inherited from each parent.
Usually due to mutations that reduce or eliminate the function of the gene product (loss-of-function)
In many cases: mutations that impair or eliminate the function of an enzyme

21. Oculocutaneous Albinism
Lack of pigmentation
Fair skin and hair
Decreased visual acuity
Lack of stereoscopic vision
Mutations in the gene encoding Tyrosinase (lack of Melanin)
Autosomal Recessive Genetic Transmission

22. Metabolic pathways involving tyrosine
Phenylalanine is converted to tyrosine by phenylalanine hydroxylase, the enzyme blocked in phenylketonuria.
Lack of homogentisic acid oxidase leads to alkaptonuria.
Deficiency of tyrosinase leads to albinism.

23. Most enzyme deficiencies are transmitted as autosomal recessive
A heterozygote still has enough wild type enzyme to carry out the reaction while individuals homozygote for a mutation does not make enough enzyme to complete the reaction.

24. Mutations responsible for recessive traits usually leads to:
Lack of gene expression (eg: promoter mutations)
Lack of protein production (eg:mutations that lead to premature termination of translation)
Production of a protein with reduced or absent function (eg: amino acid substitution)

25. Inheritance patterns
Autosomal recessive
Autosomal dominant

26. Genotype and phenotype correlation with gene locus for an autosomal dominant trait
Dominant allele
Recessive allele
Genotype:
Phenotype:
Homozygous
Heterozygous
unaffected
affected
Phenotype expressed in both homozygotes and heterozygotes for a mutant allele

27. Pedigree illustrating autosomal dominant transmission

28. Autosomal Dominant Inheritance
Expressed in heterozygous or homozygous individuals
Affects an individual of either sex
Transmitted by either sex
An affected person usually has at least one affected parent
Transmitted to 50 % of offspring

29. Osteogenesis Imperfecta Type I
Autosomal Dominant
Marked by extreme fragility of bones
Deficient production of the protein collagen leading to abnormal bone matrix
Muations in COL1A1 or COL1A2 lead to reduced amounts of normal collagen
Mutations in genes for structural proteins often result in dominantly transmitted disorders
Collagen: major structural protein of the body; it represents a complex family of subunits that aggregate in different combinations in different tissues.

30. Autosomal Dominant inheritance/structural gene mutations
Only 25 % of the collagen triple helices formed are fully functional

31. Gain-of-function mutation is achondroplasia
p.Gly380Arg
Mutation in the fibroblast growth factor type 3 receptor (FGFR3) leads to Achondroplasia (a form of dwarfism)
FGFR3 promotes differentiation of cartilage into bone.
Gain-of-function mutation constitutively activates the receptor causing premature conversion of the growth plate into bone.

32. Inheritance patterns Autosomal recessive Autosomal dominant
Sex-linked traits

33. X-linked inheritance Male Female X Y X Y Homozygous Wild-type
Unaffected
Affected
Female
Males: Males are hemizygous for genes on the X chromosome
Homozygous
Wild-type
Heterozygous
Homozygous
mutant

34. X-linked recessive inheritance
Affects mainly males
Affected males are usually born to unaffected parents
Females may be affected if the father is affected and the mother is a carrier, or occasionally as a result of nonrandom X-inactivation
X-linked dominant and recessive patterns of inheritance are distinguished based on phenotypes of heterozygous females.
Random X-inactivation in females cause some difficulty in determining inheritance pattern.
X-linked transmission lack male to male transmission

35. X-linked dominant inheritance
Affects either sex
Females are often more mildly and more variably affected than males
The child of an affected female has a 50 % chance of being affected
For an affected male, all his daughters but none of his sons are affected

36. Y-linked inheritance Affects only males
Affected males always have an affected father
All sons of an affected man are affected
Mutations in Y-linked genes usually lead to male infertility therefore usually not passed on to future generations.

37. Penetrance and Expressivity
Penetrance: The proportion of individuals of a specified genotype who show the expected phenotype aa Aa
Penetrance: Not all individuals who carries a genotype associated with a phenotype will express the phenotype. Penetrance is less then 100% when individuals who have the appropriate genotype phenotypically are normal.
- Autosomal dominant traits occasionally may skip a generation
-Rate of penetrance applies to a population not an individual

38. Age-related penetrance in late-onset diseases:
In late –onset disease although genotype is present at birth the phenotype may not manifest until adult life (Huntigton disease, progressive neurodegenaration)

39. Penetrance and Expressivity
Penetrance: The proportion of individuals of a specified genotype who show the expected phenotype
Expressivity: The range of phenotypes expressed by a given genotype
- Penetrance is high
- Wide range of expressivity
Neurofibromatosis type 1
(Autosomal dominant)
Tumors along peripheral nerves
Patches of brown pigmentation on skin
Bone deformities
Learning disabilities
Brain tumors

40. Genomic Imprinting
Certain genes are expressed only from the maternal or paternal chromosome
Genomic Imprinting: Differential expression of maternally and paternally derived genes.
Expression of the disease phenotype depends on whether the mutant allele has been inherited from the mother or the father.

41. Genomic Imprinting
The specific gene copy to be inactivated is always determined by the parent of origin
Is a dynamic process: the “imprint” has to be erased and reset in each generation
The “imprint” is reset in germ cells
If a mutant gene is imprinted, sex of the parent it was inherited from plays a role in the expression of the disease phenotype

42. Deletions on chromosoome 15 can result in Prader-Willi or Angelman syndrome
Prader-Willi Syndrome
-initial failure to thrive
-distinctive facial features
-developmenta delay
-hypogonadism
Angelman Syndrome
-seizures
-jerky, uncoordinated movements
-unprovoked smiling/laughter
-lack of speech
-severe developmental delay
Paternal
Maternal

43. Anticipation
Symptoms in certain genetic disorders tend to be more severe and have earlier age of onset from generation to generation.
Unstable repeat expansions: characterized by expansion of a segment of DNA consisting of repeating units of three or more nucleotides in tandem
Many genes include regions of simple sequence repeats (di-, tri-, tetra-repeats). Usually the copy number an individual carries has no impact on phenotype. But there is a subset of genes where the copy number of repeats may have a significant effect on phenotype once a certain number of repeat sequence is present (Huntington Disease, Fragile-X, Myotonic dystrophy)

44. Slipped mispairing mechanism in the expansion of unstable repeats

45. Unstable Repeat expansion Diseases
Inheritance pattern
Repeat
Gene
Repeat Numbers
Normal Affected
Huntington Disease
Autosomal dominant
CAG HD
<36
>40
Fragile-X
X-linked
CGG
FMR1
<60
>200
Myotonic dystrophy
CTG
DMPK
<30
Friedrich ataxia
Autosomal recessive
AAG
FRDA
<34
36-100

46. Huntington Disease
Triplet repeat expansion (CAG repeat leading to expansion of polyglutamine)
Autosomal dominant
Progressive neurodegenerative disorder
Anticipation: there is an earlier and earlier age of onset from generation to generation

47. Age of onset/ number of CAG repeats

48. Pathogenesis of disease due to unstable repeat expansions
Expansion of noncoding repeats that cause a loss of protein function by impairing transcription.
- Fragile X syndrome: Presence of more then 200 copies of CGG repeat in the 5’ UTR of FMR1 leads to over methylation of cytosines in the promoter
Expansion of noncoding repeats that confer novel properties on the mRNA.
- Myotonic dystrophy 1: (3’ UTR of DMPK) CTG >80 copies. Excessive binding of RNA-binding proteins quench normal RNA splicing mechanism in the cell
Expansion of a codon leading to novel features
- Huntington Disease: CAG>40 long polyglutamine sequences, damage specific neurons

49. Factors affecting pedigree patterns
Penetrance
Expressivity
Age of onset
Imprinting
Anticipation
Occurrence of new mutations
X inactivation

50. OMIM http://www.ncbi.nlm.nih.gov/sites/entrez?db=omim
Online Mendelian Inheritence in Man
A catalog of genes and human traits
Each entry has a unique six-digit MIM number. Entries that begin with 1
( )
Autosomal loci or phenotypes (entries created before May 15, 1994) 2
( ) 3
( )
X-linked loci or phenotypes 4
( )
Y-linked loci or phenotypes 5
( )
Mitochondrial loci or phenotypes 6
( )
Autosomal loci or phenotypes (entries created after May 15, 1994)

51. Mouse Genome informatics: http://www.informatics.jax.org/
OMIA – Online Mendelian Inheritance in Animals: