Single gene defects

Basic pedigree structure

The pedigree structure is one of the
most used tools of medical genetics. It
illustrates the relationships among family
members that affected or not affected by a
genetic disease. Typically an arrow donates
the proband or the index case, the first
individual diagnosed in the pedigree .
When discussing relatives in families, one
often refer to degree of relationship. First
degree relatives are those who are related
at the parent-offspring or sibling (brother
and sister) level. Second degree relatives
are those who are removed by one
additional generation "step" ( e.g.
grandparents and grandchildren,
uncles/ants and nieces and nephews). Third
degree relatives would include first cousins,
great-grandchildren, and so on.
Punnett square is a table specifying the
genotypes that can arise from the gametes
contributed by a mating pair individuals.
We call the individual homozygous when
the two alleles at a locus are the same. It
will be heterozygous when he has two
different alleles at a locus, and hemizygous when a genes present in only a
single copy ( most commonly refers to genes on the single male X
chromosome)

Mendelian inheritance:
1. Autosomal dominant
 Characteristic features of autosomal dominant diseases.
• Vertical transmission of disease phenotype.
• Need only one copy of the genes to be affected for the disease to
be apparent phenotypically (heterozygous for the affected gene.
• Lack of skipped generation.
• Roughly equal no. of affected males and females
• The recurrence risk is 50% in each pregnancy.
• There is male to male transmission.
• Fresh mutation is a possible cause.
• Unaffected individual cannot transmit disease assuming full
penetrance

A a
A AA Aa
A AA Aa
Punnett square for an autosomal dominant disease shows the
probabilities ("AA" normal genotype and phenotype, "Aa" is affected
genotype and phenotype)

2. X linked dominant

Characteristic features of X linked dominant diseases.

• Vertical transmission of disease phenotype.
• Need only one copy of the genes to be affected for the disease to
be apparent phenotypically (heterozygous for the affected gene.
• Lack of skipped generation.
• females twicely affected as males
• if the mother affected the recurrence risk 50% for males and
females in each pregnancy
• There is NO male to male transmission, I.e. if the father affected
non of his sons will get the disease, and all his daughters will be
affected .
 • Fresh mutation is a possible cause.
• Expression of the disease is less in heterozygote's than an affected
males.

X X
Y XY XY
x Xx Xx

Punnett square for X linked dominant disease shows the probabilities if

the father is affected (small x carry the abnormal gene) all his sons will be
normal, and all his daughters will be affected

X x
Y XY Yx
X XX Xx

Punnett square for X linked dominant disease shows the probabilities if

the mother is affected (small x carry the abnormal gene), 50% of her sons will
be affected, and 50% of her daughters will be affected

3. X linked recessive

Characteristic features of X linked recessive diseases.

• Oblique type of transmission.
• Absence of father son transmission.
• Skipped generations when genes are passed through females carriers.
• Fresh mutation is a possible cause.
• We refer to the affected male hemizygous for the affected gene as the
only copy of the gene is affected
• Heterozygous females are carriers (phenotyically normal but
genotypically abnormal)
• 50% of daughters of carrier females will be carriers, and 50% of her
sons will be affected
• All daughters of affected males are carriers

X X
Y XY XY
x Xx Xx

Punnett square for X linked recessive disease shows the probabilities if

the father is affected (small x carry the abnormal gene) all his sons will be
normal, and all his daughters will be carriers

X x
Y XY Yx
X XX Xx

Punnett square for X linked recessive disease shows the probabilities if

the mother is carrier (small x carry the abnormal gene), 50% of her sons
will be affected, and 50% of her daughters will be carriers

4. autosomal recessive

Characteristic features of autosomal recessive diseases.

• Transverse mode of transmission ( clustered among siblings).
• Affected individual may have common grand father
• Need the two copies of the genes to be affected for the disease
to be apparent phenotypically (homozygous for the affected
gene.
 • Heterozygous individuals are carriers (phenotyically normal but
genotypically abnormal)
• Fresh mutation is a remote cause.
• If one allele affected lead to carrier and can transmit the disease.
• Males are equally affected as females
• If two unaffected carriers mat , 25% of their siblings will be
affected, 75% will be phenotypically normal (50% are carriers)

A a
A AA Aa
a Aa aa

Punnett square for an autosomal recessive disease shows the

probabilities ("AA" normal genotype and phenotype, "Aa" carrier i.e. normal
phenotype and abnormal genotype, "aa" abnormal geno and phenotype)

MULTIFACTORIAL/POLYGENIC INHERITANCE

Multifactorial inheritance refers to traits that are caused by a combination

of inherited, environmental, and stochastic factors. Multifactorial traits differ
from polygenic inheritance, which refers to traits that result from the additive
effects of multiple genes. Multifactorial traits segregate within families but do
not exhibit a consistent or recognizable inheritance pattern.

Characteristics include the following:

1. There is a similar rate of recurrence (typically 3-5%) among all 1st-degree
relatives (parents, siblings, offspring of the affected child). It is unusual to find a
substantial increase in risk for relatives related more distantly than 2nd degree to
the index case.
2. The risk of recurrence is related to the incidence of the disease.
3. Some disorders have a sex predilection, as indicated by an unequal male :
female incidence. Pyloric stenosis is more common in males, whereas congenital
dislocation of the hips is more common in females. Where there is an altered sex
ratio, the risk is higher for the relatives of an index case in the less commonly
affected sex. The risk to the son of an affected female with infantile pyloric
stenosis is 18% compared with the 5% risk for the son of an affected male. The
female has passed on a greater genetic susceptibility to her offspring.
4. The likelihood that both identical twins will be affected with the same
malformation is less than 100% but much greater than the chance that both
members of a nonidentical twin pair will be affected. The frequency of
concordance for identical twins ranges from 21% to 63%. This distribution
contrasts with that of mendelian inheritance, in which identical twins always
share a disorder due to a single mutant gene.
5. The risk of recurrence is increased when multiple family members are
affected; these instances are often the most problematic for distinguishing
multifactorial from mendelian etiology. A simple example is that the risk of
recurrence for unilateral cleft lip and palate is 4% for a couple with one affected
child and increases to 9% with two affected children.
6. The risk of recurrence may be greater when the disorder is more severe. The
infant who has long-segment Hirschsprung disease has a greater chance of
having an affected sibling than the infant who has short-segment Hirschsprung
disease.