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Patterns of Single Gene Inheritance

Classification of Genetic Disorders

Single Gene / Mendelian disorders Chromosomal disorders Multifactorial disorders Mitochondrial disorders

Single 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.

Single Gene Inheritance

Definitions 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

Single Gene Inheritance

Definitions and Concepts, contd.
Genotype with identical alleles at a given locus, on a pair of homologous chromosomes.

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

Males in X-linked inheritance

Single Gene Inheritance

Definitions and Concepts, contd.

Phenotype expressed in heterozygotes

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

6 NOT phenotypically expressed in heterozygotes

Single Gene Inheritance

Autosome 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 Ylinkage

Definitions and Concepts, contd.

Any nuclear chromosome other than the sex chromosomes; 22 pairs in human karyotype

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 X-linked dominant or recessive dominant or recessive

Dominant 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

Dominant 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

Dominant vs. Recessive, contd.

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


Dominant vs. Recessive, contd.

Simple gain of function
Enhanced function of mutated gene product may lead to toxicity Ex: Achondroplasia, Huntingtons disease

Inherited dysfunction Followed by second hit

Ex: dominantly inherited cancers like retinoblastoma


Dominant vs. Recessive, contd.

Incompletely Dominant
Heterozygous genotype produces phenotype that is different from the phenotype seen in both homozygote genotypes and Severity is intermediate between them

Expression of each allele can be detected even in the presence of the other


Single Gene Inheritance 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.

The family member through whom the family is ascertained If affected index case


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

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


Pedigree Symbols


Confused???? Now What?


Other 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

Penetrance and Expressivity

Probability that a gene will have any phenotypic expression at all All or nothing concept Complete penetrance 100% Reduced penetrance less than 100%


Penetrance and 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


Age of Onset

Factors Affecting Pedigree Patterns

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


Factors Affecting Pedigree Patterns

Other factors Small family size patient may be the only case New mutations esp. for Dominant and Xlinked Absent or variable expression Other genes and environmental factors Death in utero Accurate information lacking


Genetic Heterogeneity
A genetic disorder may show heterogeneity phenotypes that are similar but are actually determined by different genotypes
Allelic Heterogeneity Locus Heterogeneity


Genetic Heterogeneity, contd.

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


Genetic Heterogeneity, contd.

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