Patterns of Single Patterns of Single Gene InheritanceGene Inheritance

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Classification of Genetic Classification of Genetic DisordersDisorders

• Single Gene / Mendelian disorders

• Chromosomal disorders

• Multifactorial disorders

• Mitochondrial disorders

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Single Gene DisordersSingle Gene Disorders

• Single defective allele at a locus, on one or both members of a pair of chromosomes. - Segregate within families

- characteristic pedigree (family tree)

- Individual defects rare, but combined impact significant.

- Mostly pediatric, ~ 10% after puberty, ~ 1% in post-reproductive period.

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Single Gene InheritanceSingle Gene Inheritance Definitions and ConceptsDefinitions and Concepts

• Locus – gene location on chromosome• Alleles – paired genes at a locus, identical or alternative

forms, one on each homologous chromosome.– Wild type allele: normal version of the gene. – Mutant allele: differs from WT allele, may cause disease

• Haplotype given set of alleles at a locus OR cluster of loci on a chromosome

• Polymorphism: occurrence of two or more normal alleles at a locus in the population. – Normal variants as a result of harmless mutations.

• Genotype – genetic make up of an individual.• Phenotype – expression of a genotype: morphological,

biochemical or a molecular trait• Polymorphism at least two relatively common “normal”

alleles at a locus in population

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Single Gene InheritanceSingle Gene InheritanceDefinitions and Concepts, cont’d.Definitions and Concepts, cont’d.

• Homozygous – Genotype with identical alleles at a given locus, on a pair of

homologous chromosomes.

• Heterozygous – Genotype with two different alleles at a given locus, on a pair of

homologous chromosomes – Typically, one allele is the normal form, the other is mutant; also

two different normal alleles

• Compound heterozygote – Individual or a genotype with two different mutant alleles at a

given locus

• Hemizygous – Males in X-linked inheritance

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Single Gene InheritanceSingle Gene InheritanceDefinitions and Concepts, cont’d.Definitions and Concepts, cont’d.

• Dominant – Phenotype expressed in heterozygotes

• Codominant – Both alleles of a pair are expressed in the

heterozygous state

• Incomplete Dominance – Phenotype is different from both homozygous

phenotypes and severity is intermediate between them

• Recessive – NOT phenotypically expressed in heterozygotes

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Single Gene InheritanceSingle Gene InheritanceDefinitions and Concepts, cont’d.Definitions and Concepts, cont’d.

• Autosome– Any nuclear chromosome other than the sex chromosomes;

22 pairs in human karyotype

• X-linkage – Genes on the X chromosome; traits determined by such genes

are X-linked • Note: distinguish between genes physically located on sex

chromosomes and those that only show X-linkage or Y-linkage

• A gene may be located on an autosome or on a sex chromosome, and may be dominant or recessive in its expression, relative to its allelic counterpart

• 4 types of single gene inheritance:– Autosomal dominant or recessive– X-linked dominant or recessive

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Dominant vs. RecessiveDominant vs. Recessive

• Arbitrary and based on clinical phenotypes• Recessive phenotype – clinically

asymptomatic in heterozygotes but many AR traits do have some heterozygous manifestations, – e.g. in sickle cell disease

• Homozygous hemolytic anemia• Heterozygous

– normal and mutated beta globin allele expressed (HbA &HbS) codominant on molecular level

– incompletely dominant on physiologic level some sickling

– recessive on clinical level only a mild anemia

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Dominant vs. RecessiveDominant vs. Recessive• Dominant disorders occur when one normal

copy of a gene is not sufficient to prevent disease

• Seen in 4 situations– Haploinsufficiency– Dominant negative effect– Simple gain of function– Inherited dysfunction

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Dominant vs. RecessiveDominant vs. Recessive, cont’d., cont’d.

• Haploinsufficiency – normal physiology requires more than 50% of

gene product– Ex: mutations in Transcription factors,

structural proteins, receptors

• Dominant negative effect – abnormal protein interferes with function of

gene product from normal allele– Ex: Osteogenesis imperfecta

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Dominant vs. RecessiveDominant vs. Recessive, cont’d., cont’d.

• Simple gain of function – Enhanced function of mutated gene product may

lead to toxicity– Ex: Achondroplasia, Huntington’s disease

• Inherited dysfunction Followed by second hit– Ex: dominantly inherited cancers like

retinoblastoma

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• Incompletely Dominant– Heterozygous genotype produces phenotype

that is different from the phenotype seen in both homozygote genotypes and

– Severity is intermediate between them

• Codominant– Expression of each allele can be detected even

in the presence of the other

Dominant vs. RecessiveDominant vs. Recessive, cont’d., cont’d.

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Single Gene InheritanceSingle Gene InheritancePedigreePedigree

● Pedigree – A diagram of an extended family indicating the

family members, their relationship to the proband, and their status with respect to a particular hereditary condition.

● Proband/Propositus– The family member through whom the family is

ascertained – If affected index case

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• Consultand – person who brings family to attention by consulting a geneticist

• Sibs – brothers and sisters; entirety of siblings – sibship• Kindred – entire family• Relatives:

– First degree – parents, sibs, offspring of proband

– Second degree – grandparents, grandchildren, uncles, aunts, nephews, nieces, half-sibs

– Third degree – first cousins

PedigreePedigree

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• Consanguineous – couples who have one or more common ancestors

• Isolated case – if there is only one affected member in a family

• Sporadic case – disease determined to occur due to a new mutation

PedigreePedigree

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Pedigree SymbolsPedigree Symbols

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Confused???? – Now What?

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Other Pedigree PatternsOther Pedigree Patterns

• Apparent single-gene pattern may mask a more complex situation– Teratogenic effects

– Balanced translocations that cause contiguous gene syndrome or microdeletion syndromes (closely linked genes deleted)

– Environmental exposure shared among family members

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Penetrance and ExpressivityPenetrance and Expressivity• Penetrance

– Probability that a gene will have any phenotypic expression at all

– All or nothing concept– Complete penetrance 100%– Reduced penetrance less than 100%

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Penetrance and ExpressivityPenetrance and Expressivity

• Expressivity– Severity of phenotype expression– Same disease, different individuals– Variable expressibity– Symptoms may range from mild to severe– Neurofibromatosis

• See case #29 on page 292• Discussed in detail in the AD lecture

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Factors Affecting Pedigree Factors Affecting Pedigree PatternsPatterns

• Age of Onset – Not all genetic disorders are congenital– Age of onset depends on disease– Develop prenatally – birth defects

• Prenatally lethal• Expressed from infancy onwards• Appear later at various ages

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Factors Affecting Pedigree Factors Affecting Pedigree PatternsPatterns

• Other factors– Small family size patient may be the only

case– New mutations esp. for Dominant and X-

linked– Absent or variable expression– Other genes and environmental factors– Death in utero– Accurate information lacking

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Genetic HeterogeneityGenetic Heterogeneity

• A genetic disorder may show heterogeneity

phenotypes that are similar but are actually determined by different genotypes– Allelic Heterogeneity– Locus Heterogeneity

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Genetic HeterogeneityGenetic Heterogeneity, cont’d. , cont’d.

• Locus Heterogeneity: – Mutations at different loci– Genetic disease may be expressed in several

variations and may display different modes of inheritance, which may be AR, AD, or X-linked

• Retinis pigmentosa: Currently 3 X-linked, 12 AD and 5 AR forms

• Ehlers-Danlos Syndrome: more than 10 different loci associated

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Genetic HeterogeneityGenetic Heterogeneity, cont’d. , cont’d.

• Allelic Heterogeneity – Different mutations at same locus

• Mutations in RET gene• Hirschsprung Disease

– Loss of function mutations

• failure of colonic ganglia development: defective colonic motility, severe constipation.

• Multiple endocrine neoplasia, type II – Point mutations activate tyrosine kinase – See also case #20 on page 272

• Cystic Fibrosis– Discussed in detail during Biochemical Genetics– See also case 10 on page 252