BRS Genetics - R. Dudek (Lippincott)

4. Mendelian Inheritance

I. Autosomal Dominant Inheritance (Figure 4-1A, B and Tables 4-1, 4-2, and 4-3)

A. Introduction

In autosomal dominant inheritance:

1.   The disorder is observed in an equal number of females and males who are heterozygous for the mutant gene.

2.   The characteristic family pedigree is vertical in that the disorder is passed from one generation to the next generation.

3.   Transmission by the mother or father (i.e., mother-to-son; mother-to-daughter; father-to-son; father-to-daughter).

4.   Although homozygotes for some autosomal dominant disorders do occur, they are rare because homozygosity for an autosomal dominant disorder is generally a genetic lethal.

B. Genetic Risk Assessment

The genetic risk associated with an autosomal dominant disorder is as follows:

1.   Example 1. Affected heterozygous mother and normal homozygous father: In autosomal dominant disorders, the affected parent is usually a heterozygote because homozygosity for an autosomal dominant allele is frequently a genetic lethal (where those with the disorder die before they reproduce). In this example, the heterozygous mother has the disorder caused by the autosomal dominant allele “D” and the father is a normal homozygous individual. All possible combinations of alleles from the parents are shown in a Punnett square below.

 

Mother

D

d

Father

   

d

Dd

dd

d

Dd

dd

2.   Conclusion: There is a 50% chance (2 out of 4 children) of having a child with the autosomal dominant disorder (Dd) assuming complete penetrance. There is a 50% chance (2 out of 4 children) of having a normal child.

3.   Example 2. Affected heterozygous mother and affected heterozygous father: In some autosomal dominant disorders (e.g., achondroplasia), it is not unusual for individuals to choose partners who have the same condition. The parents may actually be more concerned about the chances of having a child with normal stature than one with achondroplasia. As mentioned above, homozygosity for an autosomal dominant allele is frequently a genetic lethal so that both parents with achondroplasia would be heterozygous. In this example, the heterozygous mother and the heterozygous father have the disorder caused by the autosomal dominant allele “D.” All possible combinations of alleles from the parents are shown in a Punnett square below.

 

Mother

D

d

Father

   

D

DD

Dd

d

Dd

dd

Conclusion: There is a 50% chance (2 out of 4 children) of having a child with achondroplasia (Dd); a 25% chance (1 out of 4 children) of having a normal child (dd); and a 25% chance (1 out of 4 children) of having a child with a lethal condition (DD).

4.   Example 3. Affected homozygous mother and normal homozygous father: In some autosomal dominant disorders (e.g., Noonan syndrome), homozygosity for an autosomal dominant allele is not a genetic lethal so that the affected individual would be homozygous. This situation is exceedingly rare and would most likely occur in cases of consanguinity, where the parents are related. In this example, the homozygous mother has the disorder caused by the autosomal dominant allele “D” and the father is a normal homozygous individual. All possible combinations of alleles from the parents are shown in a Punnett square below.

 

Mother

D

D

Father

   

d

Dd

Dd

d

Dd

Dd

5.   Conclusion: There is a 100% chance (4 out of 4 children) of having a child with Noonan syndrome (Dd).

6.   If the parents of the proband are normal, the risk to the siblings of the proband is very low but greater than that of the general population because the possibility of germ line mosaicism exists.

C. New Mutations

In autosomal dominant disorders, new mutations are relatively common. In these cases, there will be an affected child with no family history of the disorder. There is a low recurrence risk (1%–2%) due to the possibility of germ line mosaicism. Germ line mosaicism is the presence of more than one cell line in the gametes in an otherwise normal parent and is the result of a mutation during the embryonic development of that parent. There is an increased risk for a new dominant mutation in fathers over 50 years of age.

D. Reduced Penetrance

In a reduced penetrance, many individuals have the disorder mutation but do not develop disorder symptoms. However, they can still transmit the disorder to their offspring. Example: Breast cancer whereby many women have mutations in the BRCA1 gene and BRCA2 gene but do not develop breast cancer. However, some women have mutations in the BRCA1 gene and BRCA2 gene and do develop breast cancer.

E. Variable Expressivity

In variable expressivity, the severity of the disorder can vary greatly between individuals. Some people may have such mild disorder that they do not know they have it until a severely affected child is born. Example: Marfan syndrome whereby a parent is tall and has long fingers, but one of his children is tall, has long fingers, and has serious cardiovascular defects.

F. Pleiotropy

Pleiotropy refers to a situation when a disorder has multiple effects on the body. Example: Marfan syndrome whereby the eye, skeleton, and cardiovascular system may be affected.

G. Locus heterogeneity

In locus heterogeneity, genes at more than one locus may cause the disorder. Example: Osteogenesis imperfecta whereby collagen a-1 (I) chain protein and collagen a-2(I) chain protein are encoded by the COL1A1 gene on chromosome 17q21.3-q22 and COL1A2 gene on chromosome 7q22.1, respectively (i.e., two separate genes located on different chromosomes). A mutation in either gene will cause osteogenesis imperfecta.

H. Example of an Autosomal Dominant Disorder. Noonan Syndrome (NS)

1.   NS is an autosomal dominant genetic disorder caused by mutations in the following genes:

a.   The PTPN11 gene on chromosome 12p12.1 which encodes for tyrosine-protein phosphatase non-receptor type 11 in ≈50% of NS cases. This is an extracellular protein that plays a key role in the cellular response to growth factors, hormones, and cell adhesion molecules.

b.   The RAF1 gene on chromosome 3p25 which encodes for RAF proto-oncogene serine/ threonine-protein kinase in 3–17% of NS cases. This protein plays a key role in the signal transduction pathway for epidermal growth factor (EGF) action.

c.   The SOS1 gene on chromosome 2p22 – p21, which encodes for son-of-sevenless homolog 1 in ≈10% of NS cases. This protein plays a key role in the signal transduction pathway for receptor tyrosine kinase action.

2.   Many NS individuals have de novo mutations. However, an affected parent is recognized in 30% to 75% of families. In simplex cases (i.e., those with no known family history), the mutation is inherited from the father.

3.   Prevalence. The prevalence of NS is 1/1,000 to 2,500 births.

4.   Clinical features include: short stature, congenital heart defects, broad or webbed neck, unusual chest shape (e.g., superior pectus carinatum, inferior pectus excavatum), apparently low-set nipples, cryptorchidism in males, characteristic facial appearance (e.g., low-set, posteriorly rotated ears; vivid blue irides; widely-spaced eyes; epicanthal folds; and thick, droopy eyelids).

II. Autosomal Recessive Inheritance (Figure 4-1C; Tables 4-1, 4-2, and 4-3)

A. Introduction

In autosomal recessive inheritance:

1.   The disorder is observed in an equal number of females and males who are homozygous for the mutant gene.

2.   The characteristic family pedigree is horizontal in that the disorder tends to be limited to a single sibship (i.e., the disorder is not passed from one generation to the next generation).

3.   Mother and father each transmit a recessive allele to their sons or daughters.

4.   Both parents are obligate heterozygous carriers whereby each parent carries one mutant allele and is asymptomatic (unless there is uniparental disomy or consanguinity, which increases the risk for autosomal recessive disorders in children).

B. Genetic Risk Assessment

The genetic risk associated with an autosomal recessive disorder is as follows:

1.   Example 1. Normal heterozygous mother and normal heterozygous father: In autosomal recessive disorders, both parents are carriers of a single copy of the responsible gene. In this example, the mother and father are normal heterozygous carriers of the autosomal recessive allele “r.” All possible combinations of alleles from the parents are shown in a Punnett square below.

 

Mother

R

r

Father

   

R

RR

Rr

r

Rr

rr

2. 

3.  

4.   Conclusion: There is a 25% chance (1 out of 4 children) of having a child with the autosomal recessive disorder (rr), a 50% chance (2 out of 4 children) of having a normal child that will be a heterozygous carrier (Rr), and a 25% chance (1 out of 4 children) of having a normal child that will not be a carrier (RR).

5.   In autosomal recessive disorders, one can calculate the genetic risk for the normal children being homozygous or heterozygous. In this calculation, the child with the autosomal recessive disorder (rr = X) is eliminated from the calculation. In this example, the mother and father are normal heterozygous carriers of the autosomal recessive allele “r.” All possible combinations of alleles from the parents are shown in a Punnett square below.

 

Mother

R

r

Father

   

R

RR

Rr

r

Rr

X

6.   Conclusion: There is a 66% chance (2 out of 3 children) of having a normal child that is a heterozygous carrier (Rr). There is a 33% chance (1 out of 3 children) of having a normal child that is homozygous (RR).

7.   Example 2. Affected homozygous mother and normal homozygous father: In this example, the mother has the disorder caused by the autosomal recessive allele “r” and the father is a normal homozygous individual. All the possible combinations of alleles from the parents are shown in a Punnett square below.

 

Mother

r

r

Father

   

R

Rr

Rr

R

Rr

Rr

8.   Conclusion: There is a 100% chance (4 out of 4 children) of having a child who is a normal heterozygous carrier (Rr).

9.   Example 3. Affected homozygous mother and normal heterozygous father: In this example, the mother has the disorder caused by the autosomal recessive allele “r” and the father is a normal heterozygous carrier. All the possible combinations of alleles from the parents are shown in a Punnett square below.

 

Mother

r

r

Father

   

R

Rr

Rr

r

rr

rr

10.       Conclusion: There is a 50% chance (2 out of 4 children) of having a child with the autosomal recessive disorder (rr). There is a 50% chance (2 out of 4 children) of having a child who is a normal heterozygous carrier (Rr).

C. Example of an Autosomal Recessive Disorder. Cystic Fibrosis (CF)

1.   CF is an autosomal recessive genetic disorder caused by >1,000 mutations (almost all are point mutations or small deletions 1-84 bp) in the CFTR gene on chromosome 7q31.2 for the cystic fibrosis transmembrane conductance regulator which functions as a chloride ion (Cl-) channel. The Cl- ion channel normally transports Cl- out of the cell and H2O follows by osmosis. The H2O maintains the mucus in a wet and less viscous form.

2.   CF is most commonly (≈70% of cases in the North American population) caused by a three base deletion which codes for the amino acid phenylalanine at position 508 (delta F508) such that phenylalanine is missing from CFTR. However, there are a large number of deletions, which can cause CF, and parents of an affected child can carry different deletions 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 diagnostic 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 heterozygote 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 bacterial infections, and end-stage lung disorder; pancreatic insufficiency with malabsorption; acute salt depletion, chronic metabolic alkalosis; and males are almost always sterile due to the obstruction or absence of the vas deferens.

III. X-Linked Dominant Inheritance (Figure 4-1D and Table 4-1, 4-2, 4-3)

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 generation 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 (XDX) 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.

 

Mother

XD

X

Father

   

X

XDX

XX

Y

XDY

XY

2.   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.

3.   Example 2. Normal mother and affected father. In this example, the mother is normal (XX) and the father has the disorder (XDY). This is a rare situation 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.

 

Mother

X

X

Father

   

XD

XDX

XDX

Y

XY

XY

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 phosphatonins (hormonelike circulating factors that increase PO43- 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 PO43-excretion and decreased bone mineralization. These mutations also result in the underexpression of Na1-PO43- Cotransporter in the kidney, which causes a decreased PO43- 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 PO43- and a high urinary concentration of PO43-; 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 protein 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 inability 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 development 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; purposeful use of the hands is replaced by repetitive, stereotypic hand movements (hallmark); 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).

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 (XrXr) and the father is normal (XY). All possible combinations of alleles from the parents are shown in a Punnett square below.

 

Mother

Xr

Xr

Father

   

X

XrX

XrX

Y

XrY

XrY

2.   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 (XrX). There is a 100% chance (2 out of 2 sons) of having a son with the X-linked recessive disorder (XrY).

3.   Example 2. Normal heterozygous mother and normal father: In this example, the mother is a carrier (XrX) and the father is normal (XY). All possible combinations of alleles from the parents are shown in a Punnett square below.

 

Mother

Xr

X

Father

   

X

XrX

XX

Y

XrY

XY

4.   Conclusion: There is a 50% chance (1 out of 2 daughters) of having a daughter who is a carrier of the X-linked recessive allele (XrX). There is a 50% chance (1 out of 2 sons) of having a son with the X-linked recessive disorder (XrY).

5.   Example 3. Normal mother and affected father: If the father has an X-linked recessive disorder, the chances of having any children is very low because X-linked recessive males usually 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 (XrY). All possible combinations of alleles from the parents are shown in a Punnett square below.

 

Mother

X

X

Father

   

Xr

XrX

XrX

Y

XY

XY

6.   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 (XrX). There is a 100% chance (2 out of 2 sons) of having a normal son (XY) (i.e., there is no father-to-son transmission).

7.   Example 4. Normal heterozygous mother and affected father: In this example, the mother is a carrier (XrX) and the father has the disorder (XrY). This may occur in rare cases (e.g., usually consanguineous unions). All possible combinations of alleles from the parents are shown in a Punnett square below.

 

 

Mother

Xr

X

Father

   

Xr

XrXr

XrX

Y

XrY

XY

Conclusion: There is a 50% chance (1 out of 2 daughters) of having a daughter with the X-linked recessive disorder (XrXr); 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 (XrX). There is a 50% chance (1 out of 2 sons) of having a son with the X-linked recessive disorder (XrY). 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 skeletal muscle cells to the extracellular matrix via a transmembrane protein (α-dystrophin and (β-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 variation, foci of necrosis and regeneration, hyalinization, and deposition of fat and connective 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 weakness) 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 (XM) or paternal X chromosome (XP) 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 chromosomes.

· Gene dosage is important because many X-linked proteins interact with autosomal proteins 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 XM or the XP becomes inactivated is a random and irreversible event.

 

· However, once a progenitor cell inactivates the XM, for example, all the daughter cells within that cell lineage will also inactivate the XM (the same is true for the XP). This is called clonal selection and means that all females are mosaics comprising mixtures of cells in which either the XM or XP 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 (XD). 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 inactivation.

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 chromosomes with the abnormal gene (i.e., double dose; XDXD). 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 dominant disorders are surviving to reproductive age. So, the probability 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 number of cells, the female will have a large number of cells in which the one active X chromosome has the abnormal recessive gene (Xr). 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 chromosomes with the abnormal gene (i.e., double dose; XrXr). 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 probability of inheriting an abnormal X chromosome from an affected father is increasing.

VI. The Family Pedigree in Various Mendelian Inherited Disorders (Figure 4-1)

A family pedigree is a graphic method of charting the family history using various symbols.

VII. Selected Photographs of Mendelian Inherited Disorders (Figure 4-2)

 

Figure 4-1. (A) A prototype family pedigree and explanation of the various symbols. (B) Pedigree of autosomal dominant inheritance. The disorder is observed in an equal number of females and males who are heterozygous for the mutant gene. The characteristic family pedigree is vertical in that the disorder is passed from one generation to the next generation. (C) Pedigree of autosomal recessive inheritance. The disorder is observed in an equal number of females and males who are homozygous for the mutant gene. The characteristic family pedigree is horizontal in that affected individuals tend to be limited to a single sibship (i.e., the disorder is not passed from one generation to the next generation). (D) Pedigree of X-linked dominant inheritance. The disorder is observed in twice the number of females than males. There is no father-to-son transmission. All daughters of an affected man will be affected because all receive the X chromosome bearing the mutant gene from their father. All sons of an affected man will be normal because they receive only the Y chromosome from the father. (E) Pedigree of X-linked recessive inheritance. The disorder is observed only in males (affected homozygous females are rare). There is no father-to-son transmission.

 

Figure 4-2. Selected photographs of Mendelian inherited disorders. (A) Noonan syndrome. Photograph shows a young boy with Noonan syndrome. See text for various physical features. (B,C,D) Cystic fibrosis. (B) Light micrograph shows a bronchus that is filled with thick mucus and inflammatory cells (arrow). Smaller bronchi may be completely plugged by this material. In addition, surrounding the bronchus there is a heavy lymphocytic infiltration (*). (C) PA radiograph shows hyperinflation of both lungs, reduced size of the heart because of pulmonary compression, cyst formation, and atelectasis (collapse of alveoli) in both lungs. (D) CT scan shows dilated, thick-walled bronchi (large arrow), collapse of the right middle lobe (small arrows) which contains dilated airways (A). (E,F,G) Hypophosphatemic rickets. (E) Photograph shows a young girl with typical bowing of the legs. (F) Radiograph shows typical bowing of the legs, near-normal mineralization of the bones, and pronounced widening of the epiphyseal growth plates medially at the knees (arrows). (G) Light micrograph shows a wide epiphyseal growth plate where the chondrocytes in the zone of proliferation do not form neatly arranged stacks but instead are disorganized into irregular nests. (H) Rett syndrome. Photograph shows a 5-year-old girl with the typical hand position characteristic of this disorder. (I,J,K,L,M) Duchenne muscular dystrophy. (I) Photograph shows a young boy with pseudohypertrophy of the calves. Note how the boy braces himself by grabbing onto nearby furniture with his left hand. These patients are often late walkers. (J) Light micrograph shows fibrosis of the endomysium (arrows) surrounding the individual skeletal muscle cells. (K) Light micrograph shows the replacement of skeletal muscle cells by adipocytes (arrows) in the later stages of the disorder, which causes pseudohypertrophy. (L) Light micrograph (immunofluorescent staining for dystrophin) shows intense staining at the periphery skeletal muscle cells from a normal individual. In an individual with Duchenne muscular dystrophy, there would be complete absence of dystrophin staining. (M)Radiograph shows the typical appearance of a dilated cardiomyopathy with a water-bottle configuration and dilatation of the azygous vein (arrow). See Color Plate.

 

Table 4-1 Summary Table of Major Features of Mendelian Inheritance and Mitochondrial Inheritance*

 

Sex Ratio

Transmission Pattern

Other

Autosomal dominant

Disorder is observed in an equal number of females and males

Family pedigree is vertical (disorder is passed from one generation to the next generation)
Transmission by the mother or father

Homozygosity is generally a genetic lethal
Nuclear inheritance

Autosomal recessive

Disorder is observed in an equal number of females and males

Family pedigree is horizontal (disorder tends to be limited to a single sibship)
Mother and father each transmit a recessive allele

Both parents are obligate heterozygous carriers (unless there is uniparental disomy or consanguinity)
Nuclear inheritance

X-linked dominant

Disorder is observed in twice the number of females than males (unless the disorder is lethal in males)

Family pedigree is vertical (disorder is passed from one generation to the next generation)
Father-to-son transmission does not occur

Males usually die (a genetic lethal)
Heterozygous females are mildly to overtly affected (never clinically normal) depending on the skew of the X chromosome inactivation
Homozygous females (double dose) are overtly affected
Nuclear inheritance

X-linked recessive

Disorder is observed only in males (affected homozygous females are rare)

Family pedigree shows skipped generations (representing transmission through female carriers)
Father-to-son transmission does not occur

Males are usually sterile
Heterozygous females are clinically normal but may be mildly affected depending on the skew of the X chromo-some inactivation
Homozygous females (double dose) are overtly affected
Nuclear inheritance

Mitochondrial

Disorder is observed in equal number of females and males

Family pedigree is vertical (disorder is passed from one generation to the next generation)
Maternal transmission only

A range of phenotypes is seen in affected females and males due to heteroplasmy
Show a threshold level of mitochondria for disorder to be apparent
Cells with a high requirement of ATP are more seriously affected
Extranuclear inheritance

*Mitochondrial inheritance will be discussed in Chapter 6

 

Table 4-2 Summary Table of Risk Assessment in Mendelian Inheritance and Mitochondrial Inheritance*

 

Parents

Children

Autosomal dominant

Affected heterozygous mother

50% chance of having an affected child

+

50% chance of having a normal child

Normal homozygous father

Affected heterozygous mother

50% chance of having an affected child

+

25% chance of having a normal child

Affected heterozygous father

25% chance of having a lethal condition

Affected homozygous mother

100% chance of having an affected child

+

 

Normal homozygous father

Autosomal recessive

Normal heterozygous mother

25% chance of having an affected child

+

50% chance of having a normal heterozygote child (carrier)

Normal heterozygous father

25% of having a normal homozygous child (noncarrier)
66% chance of having a normal heterozygote child (carrier)
33% chance of having a normal homozygous child (noncarrier)

Affected homozygous mother

100% chance of having a normal heterozygote child (carrier)

+

 

Normal homozygous father

Affected homozygous mother

50% chance of having an affected child

+

50% chance of having a normal heterozygote child (carrier)

Normal heterozygous father

X-linked dominant

Affected heterozygous mother

50% chance of having an affected daughter

+

50% chance of having an affected son

Normal father

Normal mother

100% chance of having an affected daughter

+

100% chance of having a normal son

Affected father

X-linked recessive

Affected homozygous mother

100% chance of having a carrier daughter

+

100% chance of having an affected son

Normal father

Normal heterozygous mother

50% chance of having a carrier daughter

+

50% chance of having an affected son

Normal father

Normal mother

100% chance of having a carrier daughter

+

100% chance of having normal son

Affected father

Normal heterozygous mother

50% chance of having an affected daughter

+

50% chance of having a carrier daughter

Affected father

50% chance of having an affected son
50% chance of having a normal son

Mitochondrial

Affected mother

100% chance of having an affected daughter or son (both with a range of phenotypes)

+

 

Normal father

Normal mother

0% chance of having an affected daughter or son

+

 

Affected father

*Mitochondrial inheritance will be discussed in Chapter 6

 

 

Table 4-3 Partial List of Single Gene Mendelian Inherited Disorders by Type

Autosomal Dominant

Autosomal Recessive

X-linked

Achondroplasia
Acrocephalosyndactyly
Adult polycystic kidney disorder
Alport syndrome
Apert syndrome
Bor syndrome
Brachydactyly
Charcot-Marie-Tooth disorder
Cleidocranial dysplasia
Crouzon craniofacial dysplasia
Craniostenosis
Diabetes associated with defects in genes for glucokinase, HNF-1
α, and HNF-4α
Ehlers-Danlos syndrome (Type IV)
Epidermolysis bullosa simplex
Familial adenomatous polyposis
Familial hypercholesterolemia (Type IIa)
Goldenhar syndrome
Heart-hand syndrome
Hereditary nonpolyposis Colorectal cancer (HNPCC)
Hereditary spherocytosis
Huntington disorder
Marfan syndrome
Monilethrix
Myotonic dystrophy 1 and 2
Neurofibromatosis
Noonan syndrome
Osteogenesis imperfecta (Type I & IV)
Pfeiffer syndrome
Piebaldism
Retinoblastoma
Treacher Collins syndrome
Spinocerebellar ataxia 1,2,3.6,7,8,11,17
Uncombable hair syndrome
Von Willebrand disorder
Waardenburg syndrome
Williams-Beuren syndrome

α1-Antitrypsin
Deficiency Adrenogenital
Syndromes Albinism
Alpha thalassemia
Alkaptonuria
Argininosuccinic aciduria
Ataxia telangiectasia
Beta thalassemia
Bloom syndrome
Branched chain ketonuria
Childhood polycystic kidney disorder
Cystic fibrosis
Cystinuria
Dwarfism
Ehlers-Danlos syndrome (Type VI)
Erythropoietic porphyria
Fanconi anemia
Friedreich ataxia
Fructosuria
Galactosemia
Glycogen storage disorder
   Von Gierke (Type Ia)
   Pompe (Type II)
   Cori (Type IIIa)
      Andersen (Type IV)
      McArdle (Type V)
      Hers (Type VI)
      Tarui (Type VIII)
Hemoglobin C disorder
Hepatolenticular degeneration
Histidinemia
Homocystinuria
Hypophosphatasia
Hypothyroidism
Junctional epidermolysis bullosa
Juvenile myoclonus epilepsy
Lawrence Moon syndrome
Lysosomal storage disorders
   Tay Sachs
   Gaucher
   Niemann-Pick
   Krabbe
   Sandhoff
   Schindler
   GM1 gangliosidosis
   Metachromatic
   leukodystrophy
Mucopolysaccharidoses
   Hurler
   Sanfilippo A-D
   Morquio A&B
   Maroteaux-Lamy
   Sly
Osteogenesis imperfecta (Type II & III)
Oculocutaneous albinism (Type I & II)
Peroxisomal disorders
Phenylketonuria
Premature senility
Pyruvate kinase deficiency
Retinitis pigmentosa
Sickle cell anemia
Trichothiodystrophy
Tyrosinemia
Xeroderma pigmentosa

Dominant
Hypophosphatemic rickets
Rett syndrome
Goltz syndrome
Incontinentia pigmenti
Orofaciodigital syndrome
Recessive
Duchenne muscular
   dystrophy
Ectodermal dysplasia
Ehlers-Danlos (Type IX)
Fabry disorder
Fragile X syndrome
G6PD deficiency
Hemophilia A & B
Hunter syndrome
Ichthyosis
Kennedy syndrome
Kinky hair syndrome
Lesch-Nyhan syndrome
Testicular feminization
Wiskott-Aldrich syndrome

Review Test/Answers and Explanations

1. Which of the following is the risk that an unaffected full sibling of a patient with cystic fibrosis (CF) carries a mutated CF gene?

(A) 1 in 2

(B) 1 in 4

(C) 3 in 4

(D) 2 in 3

1. The answer is (D). If the full sibling's status was unknown, he would have a 1 in 4 risk of being unaffected and not carrying a CF mutation gene, a 2 in 4 risk of being unaffected but a carrier of a CF mutation and a 1 in 4 risk of having CF. Because he is unaffected, there are 3 possible independent outcomes. He now has a 1 in 3 chance of not carrying a mutated CF gene, but a 2 in 3 chance of being a carrier of a CF mutation.

2. What is III-1's risk to be a carrier of Alport syndrome, an X-linked recessive condition?

(A) 0

(B) 25%

(C) 50%

(D) 100%

2. The answer is (C). Because her mother is an obligate carrier of Alport syndrome, there is a 50% chance that she passed on the X chromosome with the mutation and a 50% chance that she passed on the normal X chromosome.

3. What is the risk that the child of a mother with cystic fibrosis will be a carrier of the disease?

(A) 100%

(B) 75%

(C) 50%

(D) 25%

3. The answer is (A). The mother is homozygous for a CF mutation (aa) so she can only pass along a mutated gene (a). The father is presumably homozygous for the normal gene (AA), so he can only pass on a normal gene (A). Therefore, all their children will be heterozygotes (Aa), or carriers of a CF mutation.

4. Which pedigree best represents X-linked dominant inheritance for a nonlethal condition?

(A) pedigree A

(B) pedigree B

(C) pedigree C

4. The answer is (C). In Pedigree C, the condition appears in every generation in both sexes. Pedigree A is a possibility, but only males are affected and Pedigree B the condition “skips” a generation and only males are affected.

5. In X-linked recessive lethal disorders, the mutant gene is not always inherited from a carrier female (Haldane's rule). What approximate percentage of affected males is attributable to a new mutation?

(A) 100%

(B) 75%

(C) 66%

(D) 33%

5. The answer is (D). In lethal disorders, all the mutated genes are lost in each generation and these represent a third of the alleles for that mutated gene. In a population at equilibrium, the number of new mutations equals the number of genes lost, so that number of new mutations replacing those lost is one-third, or 33%.

6. Mutations in different autosomal recessively inherited genes may result in the development of leukemia in Fanconi anemia patients. Which of the following best describes why this can happen?

(A) locus heterogeneity

(B) allelic heterogeneity

(C) genotype-phenotype correlation

(D) de novo mutations

(E) variable expressivity

6. The answer is (A). Because different genes (loci) can be involved in the development of leukemia, there is locus heterogeneity.

7. A 15-year-old boy is referred to a genetics clinic to rule out neurofibromatosis 1. He reports having ~25 café-au-lait spots and has started getting lumps and bumps on his skin since he hit puberty. During the family history, he describes his brother as being born with bowed legs and reports that he died at age 12 from a tumor in his neck that had been there since birth. He remembers that his brother had some birthmarks, but not nearly as many as he has. He does not recall his parents having any birthmarks, but they are not with him at the appointment. What inheritance pattern for the disease is occurring in this family?

(A) autosomal dominant

(B) autosomal recessive

(C) X-lined dominant

(D) X-linked recessive

(E) multifactorial

7. The answer is (A). Neurofibromatosis 1 (NF1) is an autosomal dominant disease with variable expressivity. The family history and the clinical findings in the patient confirm the diagnosis of NF1. The fact that the patient's brother had it means that it probably was not due to a new mutation. One of the parents would probably be found to have some mild manifestation of the disease upon examination, as it is fully penetrant.

8. In Marfan syndrome, the affected protein, Fibrillin-1, is active in three parts of the body: the aorta, the suspensory ligaments of the lens, and the periosteum or connective tissue. This is an example of which of the following?

(A) germline mosaicism

(B) reduced penetrance

(C) variable expressivity

(D) pleiotropy

(E) locus heterogeneity

8. The answer is (D). Pleiotropy is when a gene mutation produces diverse phenotypic events. Marfan syndrome is one of the best examples of pleiotropy.

The following pedigree applies to questions 9 and 10.

9. Baby John was diagnosed with achondroplasia shortly after birth. What inheritance pattern should be discussed with the parents?

(A) autosomal dominant

(B) autosomal recessive

(C) X-linked dominant

(D) X-linked recessive

(E) multifactorial

9. The answer is (A). Achondroplasia is an autosomal dominant disease. There is no family history because achondroplasia is often caused by a new mutation.

10. What is the recurrence risk for the couple to have another child with achondroplasia?

(A) 50%

(B) 25%

(C) 3%–5%

(D) 1%–2%

(E) ~0%

10. The answer is (E). Because the cause of achondroplasia in John is a new mutation, it is extremely unlikely to happen again so the risk is ~0.

11. Britney and Kevin have two healthy sons, Preston and Jaden. Britney has a full brother, Brian, with G6PD deficiency. Britney's mom, Lynne, has two brothers with G6PD deficiency. Britney is currently 10 weeks pregnant by her new partner, Isaa. What is the risk the current fetus has G6PD deficiency?

(A) 1/2

(B) 1/4

(C) 1/8

(D) 1/16

(E) 1/32

11. The answer is (C). G6PD deficiency is X-linked. The risk that Britney received the mutation from her mother Lynne, an obligate carrier, is 50% or 0.5. The chance that the fetus will be a girl is 50% or ½. The chance that the girl will be a carrier is 50% if the mother is a carrier. So, ½ × 0.5 ÷ ½ = 1/8.

12. Sally has a paternal uncle with hemophilia B, an X-linked recessive disease. Her risk of having a child with hemophilia B is best described as which of the following?

(A) near 100%

(B) near 0%

(C) 50% with all male children

(D) 50% for all children

12. The answer is (B). Because Sally's father does not have hemophilia B, he does not have the X chromosome with the mutated gene to pass on to Sally. Therefore, the risk for Sally to have a child with hemophilia B is near 0.

13. Joe's brother has cystic fibrosis. What is the risk that Joe is a carrier?

(A) 1/3

(B) 2/3

(C) 1/4

(D) 1/2

13. The answer is (B). Because Joe is unaffected, he can be a carrier or not be a carrier. He has a 1 in 3 chance of not being a carrier and a 2 in 3 chance of being a carrier.

14. Female carriers of X-linked recessive diseases sometimes exhibit some symptoms of the disease. The cause of this is which of the following?

(A) variable expressivity of the X-linked gene

(B) mitochondrial inheritance

(C) skewed X chromosome inactivation

(D) incomplete penetrance of the X-linked gene

14. The answer is (C). If sufficient numbers of normal X chromosomes are inactivated, there may not be enough of the normal gene product present for proper functioning. In these cases, there may be a partial or complete disease phenotype due to the fact that the majority of the gene product produced will be defective or nonfunctional.

Using the following information, choose the best answer to questions 15-18.

Alan has hemophilia A. His sister, Alice, has one son, Blaine. Blaine also has hemophilia A. Alan and his wife Annette have 2 children, Bart and Barbara. Barbara has a daughter, Cassie, and a son Chip. Cassie and Blaine are married and have a son, Daniel, with hemophilia A. They are now expecting fraternal twins, a boy and a girl.

15. What is Barbara's risk to be a carrier of hemophilia A?

(A) 0%

(B) 25%

(C) 50%

(D) 75%

(E) 100%

15. The answer is (E). Because Barbara's daughter Cassie has a son with hemophilia A, Cassie must have received the mutation from her mother. The mutation could not have come from Blaine because he cannot pass on his X chromosome to his son. Both Barbara and Cassie are obligate carriers.

16. What is Cassie and Blaine's daughter's (the fraternal twin) risk to be affected with hemophilia A?

(A) 0%

(B) 25%

(C) 50%

(D) 75%

(E) 100%

16. The answer is (C). Because Blaine has hemophilia A, he can only pass on an X chromosome with the mutation. Cassie is an obligate carrier with one X chromosome carrying the mutation and a normal X chromosome. The female fraternal twin can either receive a mutated X chromosome from both parents and have hemophilia A, or receive the mutated X from Blaine and a normal X from Cassie and be a carrier. The risk of being affected with hemophilia A is thus 50%.

17. What is Cassie and Blain's son's (the fraternal twin) risk to have hemophilia A?

(A) 0%

(B) 25%

(C) 50%

(D) 75%

(E) 100%

17. The answer is (C). Blaine can only pass on a Y chromosome to sons. Cassie can either pass on the X chromosome with the mutation and her son will have hemophilia A, or pass on the normal X chromosome, in which case her son would be normal and not affected with hemophilia A. The risk of being affected with hemophilia A is thus 50%.

18. How are Barbara and Blaine related?

(A) first cousins

(B) first cousins once removed

(C) second cousins

(D) second cousins once removed

18. The answer is (A). Alan is Barbara's father and his sister Alice is Blaine's mother. Alan is Blaine's uncle and his daughter Barbara is Blaine's first cousin.

19. Fragile X syndrome is one of the most common causes of mental retardation in humans. It generally acts like an X-linked recessive disease, but some males do not have the disease yet they can pass it on, and some females are affected. The cause of the disease explains these observations. Fragile X syndrome is caused by which one of the following mechanisms?

(A) a deletion of the Prader-Willi/Angelman gene on the father's X chromosome

(B) a triplet repeat expansion

(C) chromosome breakage

(D) having two X chromosomes

19. The answer is (B). In Fragile X syndrome the triplet repeat expansion, CGG, must reach a certain number of repeats before there is clinical manifestation of the disease. The repeat expands with succeeding generations and eventually will reach the critical number. That is why males without the disease can pass it on to subsequent generations where it appears because the threshold number of repeats has been reached. Females with a high number of repeats may also express some manifestations of the disease because of skewed X inactivation.

20. In myotonic dystrophy, the severity of the disease increases with each succeeding generation. This phenomenon is called:

(A) anticipation

(B) incomplete penetrance

(C) genomic imprinting

(D) variable expressivity

20. The answer is (A). Myotonic dystrophy is caused by a triplet repeat expansion that expands with each succeeding generation. The larger the repeat, the earlier the onset and the more severe the disease is. This phenomenon is called anticipation and differs from incomplete penetrance and variable expressivity in that once the critical repeat threshold is reached, the disease is manifested with severity depending on the number of repeats.