11 Inheritance Patterns

8/22/2019 11 Inheritance Patterns

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Pedigreeo Generations are assigned Roman numeralso individuals within each generation are indicated by Arabic

numerals.o The arrow points at the proband, the person in whom the genetic

disorder was first diagnosed.

Autosomal recessive inheritanceo condition is expressed only in persons who have two copies of (ie, are

homozygous for) the mutant allele

o often observed with enzyme deficiencies (MCQ)o What is margin of safety effect.

heterozygotes express 50% of normal activity. (MCQ) However, 50% of normal enzyme activity in these cases permits

normal

physiologic function because expression of enzyme from thenormal allele is sufficient to provide for the needs of the cell.

o Both parents of an affected person must have one normal and onemutant allele, making them obligate carriers barring very rare new

mutations.o The likelihood of a person being homozygous for an autosomal recessive

trait increases in consanguineous matings because of the existence of acommon ancestor. (MCQ)

o Rare autosomal recessive diseases also occur with high frequency amonggenetically isolated populations due to inbreeding. (MCQ)

o Pedigree charts show the following: The disease phenotype is expressed by siblings but not by their

parents or offspring. (MCQ)

Equal occurrence in males and females. (MCQ) Recurrence riskfor each sibling is 25%.(MCQ) Possible consanguinity. (MCQ)


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Recessive inheritance is shown in pedigrees A and B.


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o Autosomal dominant inheritance

o this condition is expressed even if a single mutant allele is present, ie, inthe heterozygous state

o Following are four possible situations by which having one normal copyof a gene is insufficientto prevent disease, leading to a dominant

Situation 1 :

When the presence of50% normal activity (ordinarily themargin of safety) is not generous enough to allow normal

physiologic function, a condition called haploinsufficiency.

(MCQ) Situation 2 :

When the defective allele produces a malfunctioningprotein product that binds to and interferes with functionof the normal gene productthe dominant negative

effect.

Situation 4 :

When the mutant protein has an enhanced function thatoverrides normal controls or is cytotoxic

Situation 5 :

When the phenotype appears as dominant inheritanceeven though the actual allele is recessive at the level of

function in individual cells.

o

The homozygous mutant state usually produces a more severe clinicalcondition than the heterozygous condition in autosomal dominantdiseases.

o Pedigree charts for an autosomal dominant disorder The disease phenotypeappears in all generations, with each

affected person having an affected parent. (MCQ)

There is an equal occurrence in males and females, except incases when expression of the trait is influenced by the persons

sex (ie, sex-limited). (MCQ)

Risk of transmission of the mutant allele is 50%, but becausethere usually are so few persons in a family, there may be

deviations from this expectation. (MCQ) Potential forsome cases to be due to a new mutation, which is

more likely for a dominant condition because disease symptoms

would be expressed in heterozygotes. (MCQ)


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Dominant inheritance is shown in pedigree, in which every affected personhas an affected parent.

o An autosomal dominant disorder exhibiting anticipationo In pedigree , the age of onset, indicated next to the symbols for

affected individuals, becomesprogressively earlier with eachgeneration.

o X-linked recessive inheritance patterno there can be no male-to-male transmission because the sex of male

offspring is determined by contribution of a Y chromosome from the

father. (MCQ)

o Because they have only one X chromosome, the sons ofheterozygous

mothers have a 50% chance of being affected. (MCQ)o Pedigree charts


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Incidence of disease is higher in males than in females.(MCQ)

Female heterozygotes are usually unaffected carriers. (MCQ) Affected men transmit the gene to all daughters, but never to

sons. (MCQ)

New mutations cause a significant number ofisolated cases inmales due to unopposed expression of the mutant allele.

(MCQ)

o X-linked dominant diseases are relatively rareo Such genes may be transmitted either to sons or daughtersby an

affected mother but only to daughters by an affected father.

o disorders with X linked dominant inheritance

Xg blood group vitamin Dresistant rickets. (MCQ) Rett syndrome Most cases of Alport syndrome Incontinentia pigmenti CharcotMarieTooth disease(MCQ)

o Pedigree charts All daughters of affected men are affected but never their

sons, which may lead to prevalence of affected females over

affected males. (MCQ)

Recurrence risk is 50% for both male and female offspring of

an affected female. (MCQ) Absence of affected males in several generations may suggest

prenatal lethality for the hemizygous state. (MCQ)


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Pedigrees illustrating X-linked recessive (A) and dominant (B) inheritancepatterns. Note the absence of male-to-male transmission in both pedigreesand the predominance of affected males over females in the X-linkedrecessive pedigree.

o Incompletely dominant disorderso occur in cases where the heterozygous genotype produces a different

phenotype from that seen in the homozygous genotype.

o The effect is often ofintermediate severity between the unaffected andfully affected phenotypes.

o For example, in sickle cell anemia, the normal allele is incompletelydominant in heterozygotes. (MCQ)

o Mitochondrial disorderso The mitochondrial chromosome (mtDNA) is a 16.5 kb circular plasmid.o The mtDNA bears 37 genes encoding rRNAs, tRNAs, and some genes foro proteins involved in oxidative phosphorylation. (MCQ)

o are maternally transmitted because the ovum provides all mitochondriato the fertilized embryo

o What is heteroplasmy(MCQ) In these disorders, affected cells usually have a mixture of

mitochondria, some with mutant mtDNA and others with wild-

type mtDNA, a condition called heteroplasmy.

o Segregation of mitochondria during cell division is not as tightlycontrolled as for nuclear chromosomes, leading to random distribution

of mitochondria carrying normal and mutant mtDNA to ova.

o This contributes to variable expression and reduced penetrance of thephenotype among persons within kindreds with mitochondrial disorders.


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inheritance of a mitochondrial disorder . note the similarity to the X-linked

dominant inheritance pattern but incomplete penetrance as exemplifiedby individuals II-4 and III-4.

o Major Concepts in Human Geneticso When similar phenotypes or disease conditions can be caused by

different geno- types, this may produce heterogeneity.

o Allelic heterogeneity(MCQ) occurs when different alleles of thesame gene produce clinically

similarconditions.

Allelic heterogeneity may account forphenotypic variability insome families with genetic disease.

o Locus heterogeneity(MCQ) refers to the condition when mutations of more than one gene or

locus can producesimilar disease states.

This genotypic variability is responsible fordifferent inheritancepatterns ofsome disorders.

For example, Ehlers-Danlos syndrome may be caused bymutations at more than 10 known loci, producing inheritance

patterns ranging from autosomal recessive or dominant to X-

linked. (MCQ)

o Variable expression arises when the nature and severity of the phenotype for a

genetic condition varies from one person to another.o Pleiotropy

refers to a condition in which a mutant allele may have differentphenotypic effects in various organ systems in an affected person.

o Genomic imprinting expression of an allele differs depending on whether it is inherited

from the mother or the father.

A gene that is shut offwhen inherited from the motherismaternally imprinted. (MCQ)

A gene that is silenced when inherited from the father ispaternally imprinted. (MCQ)


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Imprinting involves an epigenetic mechanism, ie, an alteration inphenotype that does not result from a change in the genotype.

(MCQ)

Expression of the imprinted genes is silenced or shut off bymethylation of certain chromatin regionsafter DNA replication

during gametogenesis. The imprint is reversible upon passage through gametogenesis in

the next generation.

o Genetic Anticipation Certain inherited disorders exhibit increased severity of phenotype

ordecreased age of onsetas the disease gene is passed from one

generation to the next, an effect known as anticipation

Examples of genetic diseases that show anticipation areHuntington disease, Fragile X syndrome(MCQ)

disorders that arise from trinucleotide repeat expansion showGenetic anticipation(MCQ)

Disease symptoms occur only when the length of the trinucleotiderepeatregion exceeds a threshold.

o Mosaicism It is defined as the presence ofcells in the body that are

genetically different.

Somatic mosaicism

mutation of a gene occurs in a non-germline (somatic) cellat some point during early development of the person, and

all cells descendent from that progenitor are genetically

distinct.

Germline mosaicism

a mutation that occurred in the parents gonadal make-upis transmitted throughsome gametes, but not all.

All females are technically mosaic for the genes of theirXchromosomes due to inactivation of one or the other X

chromosomes early in development, a phenomenon termed

the Lyon hypothesis or lyonization. (MCQ)

Because X inactivation is random, this phenomenonaccountsfor variable expression of some X-linked

disorders, depending on whether the diseaseallele or wild-

type allele was inactivated. (MCQ)

Distribution of cells from the early embryo to the tissuesmay be imbalanced, so that expression of the disease

phenotype is not uniform among the organs.

Up to 25% of patients with Turner syndrome exhibit amosaic karyotype, in which only some cells have the 45,X

karyotype classically associated with the condition. (MCQ)

o Uniparental disomy refers to a condition in which one or more cells of the body have

two identical chromosomes derived from a single parent, which

increases the likelihood of expression of recessive alleles inherited

from that parent. (MCQ)


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11 Inheritance Patterns