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of deletions, which can cause CF, and parents of an affected child can carry different dele-
tions of CFTR gene. These mutations result in absent/near absent CFTR synthesis, a block
in CFTR regulation, or a destruction of Cl
transport.
3.
The
poly T tract/TG tract
is associated with CFTR-related disorders. The
poly T tract
is a
string of thymidine bases located in intron 8 with the 5T, 7T, and 9T the most common
variants. The
TG tract
is a repeat of thymidine and guanine bases just 5’ of the poly T tract
with repeats that commonly number 11, 12, or 13.
4. Sweat chloride test.
The pilocarpine iontophoresis for sweat chloride is the primary diag-
nostic test for CF.
[Cl
]
60 Eq/L
on two separate occasions is diagnostic.
5. Prevalence.
The prevalence of CF is 1/3,200 in the Caucasian population with a heterozy-
gote carrier frequency of 1/20. CF is less common in the African American population
(1/15,000) and in the Asian American population (1/31,000).
6. Clinical features include:
production of abnormally thick mucus by epithelial cells lining
the respiratory resulting in obstruction of pulmonary airways, recurrent respiratory bac-
terial infections, and end-stage lung disorder; pancreatic insufficiency with malabsorp-
tion; acute salt depletion, chronic metabolic alkalosis; and males are almost always ster-
ile due to the obstruction or absence of the vas deferens.
III. X-LINKED DOMINANT INHERITANCE
A. Introduction.
In X-linked dominant inheritance:
1.
The disorder is observed in
twice the number of females than males
(unless the disorder is
lethal in males; then the disorder is observed only in females).
2.
The characteristic
family pedigree is vertical
in that the disorder is passed from one gener-
ation to the next generation.
3. Father-to-son transmission does not occur
because males have only one X chromosome
(i.e., males are
hemizygous
for
X-linked genes so that there is no backup copy of the gene).
4. Males usually die (a genetic lethal).
5. Heterozygous females are mildly to overtly affected (never clinically normal) depending on the
skew of the X chromosome inactivation.
6. Homozygous females (double dose) are overtly affected
.
B. Genetic Risk Assessment.
The genetic risk associated with an X-linked dominant disorder is
as follows:
1. Example 1. Affected heterozygous mother and normal father.
In this example, the mother has
the disorder (X
D
X) and the father is normal (XY) because X-linked dominant disorders are
usually lethal in males. All possible combinations of alleles from the parents are shown in
a Punnett square below.
Conclusion:
There is a
50% chance
(1 out of 2 daughters) of having a daughter with the X-
linked dominant disorder. There is a
50% chance
(1 out of 2 sons) of having a son with the
X-linked dominant disorder.
2. Example 2. Normal mother and affected father.
In this example, the mother is normal (XX)
and the father has the disorder (X
D
Y). This is a rare situation because X-linked dominant
Mother
X
D
X
Father
X
X
D
X
XX
Y
X
D
Y
XY
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disorders are usually lethal in males. All possible combinations of alleles from the parents
are shown in a Punnett square below.
Conclusion:
There is a
100% chance
(2 out of 2 daughters) of having a daughter with the X-
linked dominant disorder. There is a
100% chance
(2 out of 2 sons) of having a normal son.
C. Examples of X-Linked Dominant Disorders.
1. Hypophosphatemic rickets (XLH).
a.
XLH is an X-linked dominant genetic disorder caused by various mutations in the
PHEX
gene
on
chromosome Xp22.1
for
phosphate regulating endopeptidase on the X chromosome
(PHEX)
which is a cell membrane-bound protein cleaving enzyme that degrades
phos-
phatonins
(hormonelike circulating factors that increase PO
4
3
excretion and decrease
bone mineralization).
b.
XLH is caused by missense, nonsense, small deletion, small insertion, or RNA splicing
mutations. These mutations result in the inability of PHEX to degrade phosphatonins
so that high circulating levels of phosphatonins occur, which causes
increased
PO
4
3
excretion
and
decreased bone mineralization.
These mutations also result in the
underexpression of Na
-PO
4
3
Cotransporter in the kidney, which causes a
decreased
PO
4
3
absorption.
c. Prevalence.
The prevalence of XLH is 1/20,000.
d. Clinical features include:
a vitamin D-resistance rickets characterized by a low serum
concentration of PO
4
3
and a high urinary concentration of PO
4
3
; short stature; dental
abscesses; early tooth decay; leg deformities appeared at the time of weight-bearing;
progressive departure from a normal growth rate.
2. Classic Rett syndrome (CRS).
a.
CRS is an X-linked dominant genetic disorder caused by various mutations in the
MECP2 gene
on
chromosome Xq28
for
methyl-CpG-binding protein 2 (MECP2)
which has a
methyl-binding domain (binds to 5-methylcytosine rich DNA) and a transcription
repression domain (recruits other proteins that repress transcription). The MECP2 pro-
tein mediates
transcriptional repression
of various genes and
epigenetic regulation
of
methylated DNA by binding to 5-methylcytosine rich DNA. Although MECP2 protein is
expressed in all tissues and seems to act as a global transcriptional repressor, mutations
in the MECP2 gene result in a predominately neurological phenotype.
b.
CRS is caused by missense, nonsense, small deletion, and large deletion mutations.
Most mutations in the MECP2 gene occur de novo. These mutations result in the inabil-
ity of MECP to bind 5-methylcytosine rich DNA and to repress transcription.
c. Prevalence.
The prevalence of CRS in females is 1/18,000 by 15 years of age.
d. Clinical features include:
a progressive neurological disorder in girls where develop-
ment from birth to18 months of age is normal; later, a short period of developmental
stagnation is observed followed by rapid regression in language and motor skills; pur-
poseful use of the hands is replaced by repetitive, stereotypic hand movements (hall-
mark); screaming fits; inconsolable crying; autism; and paniclike attacks.
IV. X-LINKED RECESSIVE INHERITANCE
(Figure 4-1E; Tables 4-1, 4-2, 4-3)
A. Introduction.
In X-linked recessive inheritance:
1.
The disorder is observed
only in males
(affected homozygous females are rare).
2.
The characteristic
family pedigree shows skipped generations
(representing transmission
through female carriers).
Mother
X
X
Father
X
D
X
D
X
X
D
X
Y
XY
XY
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Mendelian Inheritance
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3. Father-to-son transmission does not occur
because males have only one X chromosome
(i.e., males are
hemizygous
for X-linked genes so that there is no backup copy of the gene).
4. Males are usually sterile.
5. Heterozygous females are clinically normal but may be mildly affected depending on the skew
of the X chromosome inactivation.
6. Homozygous females (double dose) are overtly affected.
B. Genetic Risk Assessment.
The genetic risk associated with an X-linked recessive disorder is
as follows:
1. Example 1. Affected homozygous mother and normal father:
In this example, the mother has
the disorder (X
r
X
r
) and the father is normal (XY). All possible combinations of alleles from
the parents are shown in a Punnett square below.
Conclusion:
There is a
100% chance
(2 out of 2 daughters) of having a daughter who is a
carrier of the X-linked recessive allele (X
r
X). There is a
100% chance
(2 out of 2 sons) of hav-
ing a son with the X-linked recessive disorder (X
r
Y).
2. Example 2. Normal heterozygous mother and normal father:
In this example, the mother is a
carrier (X
r
X) and the father is normal (XY). All possible combinations of alleles from the
parents are shown in a Punnett square below.
Conclusion:
There is a
50% chance
(1 out of 2 daughters) of having a daughter who is a car-
rier of the X-linked recessive allele (X
r
X). There is a
50% chance
(1 out of 2 sons) of having
a son with the X-linked recessive disorder (X
r
Y).
3. Example 3. Normal mother and affected father:
If the father has an X-linked recessive disor-
der, the chances of having any children is very low because X-linked recessive males usu-
ally are sterile. However, there are a few cases of fertile X-linked recessive males. In this
example, the mother is normal (XX) and the father has the disorder (X
r
Y). All possible
combinations of alleles from the parents are shown in a Punnett square below.
Conclusion:
There is a
100% chance
(2 out of 2 daughters) of having a daughter who is a
carrier of the X-linked recessive allele (X
r
X). There is a
100% chance
(2 out of 2 sons) of hav-
ing a normal son (XY) (i.e., there is no father-to-son transmission).
4. Example 4. Normal heterozygous mother and affected father:
In this example, the mother is a
carrier (X
r
X) and the father has the disorder (X
r
Y). This may occur in rare cases (e.g., usu-
ally consanguineous unions). All possible combinations of alleles from the parents are
shown in a Punnett square below.
Mother
X
X
Father
X
r
X
r
X
X
r
X
Y
XY
XY
Mother
X
r
X
Father
X
X
r
X
XX
Y
X
r
Y
XY
Mother
X
r
X
r
Father
X
X
r
X
X
r
X
Y
X
r
Y
X
r
Y
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Conclusion:
There is a
50% chance
(1 out of 2 daughters) of having a daughter with the X-
linked recessive disorder (X
r
X
r
); this is unusual in X-linked recessive disorders. There is a
50% chance
(1 out of 2 daughters) of having a daughter who is a carrier of the X-linked
recessive allele (X
r
X). There is a
50% chance
(1 out of 2 sons) of having a son with the X-
linked recessive disorder (X
r
Y). There is a
50% chance
(1 out of 2 sons) of having a normal
son (XY).
C. Example of X-Linked Recessive Disorder. Duchenne Muscular Dystrophy (DMD).
1.
DMD is an X-linked recessive genetic disorder caused by various mutations in the
DMD
gene
on
chromosome Xp21.2
for
dystrophin
which anchors the cytoskeleton (actin) of skele-
tal muscle cells to the extracellular matrix via a transmembrane protein
(
-dystrophin and
(
-dystrophin)
thereby stabilizing the cell membrane. The DMD gene is the largest known
human gene.
2.
DMD is caused by small deletion, large deletion, deletion of the entire gene, duplication of
one of more exons, insertion, or single-based change mutations. These mutations result
in absent/near absent dystrophin synthesis.
3. Serum creatine phosphokinase (CK) measurement.
The measurement of serum CK is one of
the diagnostic tests for DMD. [serum CK]
10 times normal is diagnostic.
4. Skeletal muscle biopsy.
A skeletal muscle biopsy shows histological signs of fiber size vari-
ation, foci of necrosis and regeneration, hyalinization, and deposition of fat and connec-
tive tissue. Immunohistochemistry shows almost complete absence of the dystrophin
protein.
5. Prevalence.
The prevalence of DMD is 1/5,600 live male births. DMD has a 1/4,000 carrier
frequency in the U.S. population, although it is difficult to calculate because
33% of
DMD cases are new mutations.
6. Clinical features include:
symptoms appear in early childhood with delays in sitting and
standing independently; progressive muscle weakness (proximal weakness
distal weak-
ness) often with calf hypertrophy; progressive muscle wasting; waddling gait; difficulty in
climbing; wheelchair bound by 12 years of age; cardiomyopathy by 18 years of age; death
by
30 years of age due to cardiac or respiratory failure.
V. X CHROMOSOME INACTIVATION AND X-LINKED INHERITANCE
■
X chromosome inactivation is a process whereby either the
maternal X chromosome (X
M
)
or
paternal X chromosome (X
P
)
is inactivated resulting in a heterochromatin structures
called the
Barr body
which is located along the inside of the nuclear envelope in female
cells.
■
This inactivation process overcomes the sex difference in
X gene dosage.
Males have one
X chromosome and are therefore
constitutively hemizygous
but females have two X chro-
mosomes.
■
Gene dosage is important because many X-linked proteins interact with autosomal pro-
teins in a variety of metabolic and developmental pathways, so there needs to be a tight
regulation in the amount of protein for key dosage-sensitive genes.
■
X chromosome inactivation makes females
functionally hemizygous.
■
X chromosome inactivation begins early in embryological development at about the
late
blastula stage.
■
Whether the X
M
or the X
P
becomes inactivated is a
random and irreversible event.
Mother
X
r
X
Father
X
r
X
r
X
r
X
r
X
Y
X
r
Y
XY
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Mendelian Inheritance
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■
However, once a progenitor cell inactivates the X
M
, for example, all the daughter cells
within that cell lineage will also inactivate the X
M
(the same is true for the X
P
). This is
called clonal selection and means that
all females are mosaics
comprising mixtures of
cells in which either the X
M
or X
P
is inactivated.
■
X chromosome inactivation does not inactivate all the genes;
20% of the total genes
on
the X chromosome escape inactivation. These
20% inactivated genes include those
genes that have a functional homolog on the Y chromosome (gene dosage is not affected
in this case) or those genes where gene dosage is not important.
A. X-linked Dominant Inheritance.
In X-linked dominant inheritance, heterozygous females are
mildly to overtly affected (never clinically normal).
1. Why are heterozygous females mildly to overtly affected?
If the X chromosomes with the
normal recessive gene are inactivated in a large number of cells, the female will have a
large number of cells in which the one active X chromosome has the abnormal dominant
gene (X
D
). Therefore, the heterozygous female will be mildly to overtly affected (i.e., a
range of phenotypes is possible), depending on the skew of the X chromosome inactiva-
tion.
2. Can a female ever show overt signs of an X-linked dominant disorder?
The answer is
YES.
An
X-linked dominant disorder may also be observed in females who inherit both X chromo-
somes with the abnormal gene (i.e.,
double dose;
X
D
X
D
). In this case, the heterozygous car-
rier mother and the affected father pass on the X chromosome with the abnormal gene.
This used to be an extremely rare event, but with the advances in treatment, more males
affected with X-linked dominant disorders are surviving to reproductive age. So, the prob-
ability of inheriting an abnormal X chromosome from an affected father is increasing.
B. X-linked Recessive Inheritance.
In X-linked recessive inheritance, heterozygous females are
for the most part clinically normal.
1. Can heterozygous females ever show signs of an X-linked recessive disorder?
The answer is
YES.
If the X chromosomes with the normal dominant gene are inactivated in a large num-
ber of cells, the female will have a large number of cells in which the one active X chromo-
some has the abnormal recessive gene (X
r
). Therefore, the heterozygous female will be
mildly affected (i.e., a range of phenotypes is possible), depending on the skew of the X
chromosome inactivation.
2. Can a female ever show overt signs of an X-linked recessive disorder?
The answer is
YES.
An
X-linked recessive disorder may also be observed in females who inherit both X chromo-
somes with the abnormal gene (i.e.,
double dose; X
r
X
r
). In this case, the heterozygous carrier
mother and the affected father pass on the X chromosome with the abnormal gene. This
used to be an extremely rare event, but with the advances in treatment, more males
affected with X-linked recessive disorders are surviving to reproductive age. So, the proba-
bility of inheriting an abnormal X chromosome from an affected father is increasing.
VI. THE FAMILY PEDIGREE IN VARIOUS MENDELIAN INHERITED
A family pedigree is a graphic method of charting the family history using various symbols.
VII. SELECTED PHOTOGRAPHS OF MENDELIAN INHERITED
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