Human Inheritance Patterns
Remember…the autosomes are all of the chromosomes except for the sex
chromosomes. You have 22 pairs of autosomes – 44 total. Your two sex
chromosomes (XX or XY) bring the final total to 46.
• AUTOSOMAL RECESSIVE DISORDERS: Examples include cystic fibrosis (CF), phenylketonuria
(PKU), sickle cell disease (SCD), xeroderma pigmentosum (XP), Tay-Sachs disease, hereditary
hemochromatosis (HH), galactosemia, congenital fructose intolerance, lactose intolerance,
etc.
genotype:
phenotype:
AA
unaffected
Aa
unaffected carrier
aa
affected
In autosomal recessive inheritance, a person must receive 2 copies (aa) of the mutant
defective gene in order to be affected. People who receive only 1 copy (Aa) of the
defective allele are unaffected, but carry the defective gene and can pass it on to their
children – they are called unaffected carriers (or simply carriers.) They are unaffected
because the normal allele (A) codes for enough “good” protein to allow survival. People
who have 2 normal alleles (AA) are unaffected, of course. Autosomal recessive disorders
often, but not always, involve enzymes. Enzymes are special proteins that catalyze specific
chemical reactions in your body. If a person has two defective genes (aa) that code for a
specific enzyme, then he/she cannot produce that particular enzyme. As a result, some
specific chemical reaction in the body will not take place – that person is then affected with
a certain disorder.
• AUTOSOMAL DOMINANT DISORDERS: Examples include Marfan syndrome,
neurofibromatosis (NF), Huntington disease (HD), achondroplasia, tuberous sclerosis, familial
hypercholesterolemia (FH), Osler-Weber-Rendu syndrome, etc.
genotype:
phenotype:
AA
affected
Aa
affected
aa
unaffected
In autosomal dominant inheritance, a person only has to receive 1 copy (Aa) of the mutant
defective gene in order to be affected. Of course, people who receive 2 copies (AA) of the
defective allele also affected – sometimes more severely than those who are heterozygous
(Aa). [For example, all achondroplastic dwarfs who survive through infancy are Aa … but
AA babies typically die before birth, or shortly after birth.] People who are unaffected are
aa. They have two “normal” alleles that code for some specific protein. Autosomal
dominant disorders often, but not always, code for proteins other than enzymes – such as
structural proteins, protein receptors, regulatory proteins, etc. Having just one defective
gene (A) causes the production of enough “bad” protein to cause damage to
cells/tissues/organs. So even a heterozygous person (Aa) is affected with a certain disorder.
Constructing
Pedigrees
Directions ~
Draw pedigrees
and list all
possible genotypes for the following problems. Answer any questions that may follow.
1. You are a genetic counselor. The proposita has an autosomal recessive disorder and seeks your advice
before starting a family. Based on the following information, construct a 3-generation pedigree for your client:
(1)
(2)
(3)
(4)
The maternal grandfather of the proposita has the disorder; his wife does not.
The mother of the proposita is unaffected and is the youngest of five children, the three
oldest of which are males and the youngest of which are females. The father of the
proposita is unaffected.
The proposita has an affected older sister, but her youngest siblings are unaffected
twins – a boy and a girl born in that order.
All individuals who have the disorder have been identified in the statements above.
2. A propositus has an autosomal recessive disorder and seeks your advice. Based upon the data below,
construct a 3-generation pedigree for your client:
(1)
(2)
(3)
(4)
(5)
The propositus is the only child of a consanguineous (brother/sister) mating.
The mother of the propositus is the older sister of a girl who is affected with the disorder. The mother
of the propositus is younger than her brother.
The affected sister of the mother of the propositus is married to an unaffected man.
They have had one affected daughter, one unaffected child of unknown sex, and a
stillborn son, in that order. The phenotype of the stillborn baby is unknown.
The grandparents of the propositus are unaffected.
All individuals who have the disorder have been identified in the statements above.
Cleft Lip Inheritance
Sue
and Tim were referred for genetic counseling after they inquired
about
the risk of having a child with a cleft lip. Tim was born with a mild
cleft
lip that was surgically repaired. He expressed concern that his future
children could be at risk for a more severe form of clefting. Sue was
in her
twelfth week of pregnancy, and both were anxious about this
pregnancy because Sue had a difficult time conceiving. The couple
stated that they would not consider terminating the pregnancy for
any
reason but wanted to be prepared for the possibility of having a child
with a
birth defect. The genetic counselor took a three-generation family history from both Sue and Tim and
found that Tim was the only person to have had a cleft lip. Sue’s family history showed no cases of
cleft lip. Tim and Sue had several misconceptions about how clefting occurs, and the genetic
counselor spent time explaining how cleft lips occur and some of the known causes of this birth
defect. The following list summarizes the counselor’s discussion with this couple.
•
Fathers, as well as mothers, can pass on genes that cause clefting.
•
Some clefts are caused by environmental factors, meaning the condition didn’t come from the
father or the mother.
•
One child in 33 is born with some sort of birth defect. One in 700 is born with a cleft-related
birth defect.
•
Most clefts occur in boys; however, a girl can be born with a cleft.
•
If a person (male or female) is born with a cleft, the chances of that person having a child with
a cleft, given no other obvious factor, is 7 in 100.
•
Some clefts are related to identifiable syndromes. Of those, some are autosomal dominant. A
person with an autosomal dominant gene has a 50% probability of passing the gene to an offspring.
•
Clefting seems to be related to ethnicity, occurring most often among Asians, Latinos, and
Native Americans (1:500); next most often among persons of European ethnicity (1:700); and least
often among persons of African origin (1:1,000).
•
A cleft condition develops during the fourth to the eighth week of pregnancy. After that critical
period, nothing the mother does can cause a cleft. Sometimes a cleft develops even before the
mother is aware that she is pregnant.
•
Women who smoke are twice as likely to give birth to a child with a cleft.
•
Women who ingest large quantities of vitamin A or low quantities of folic acid are more likely to
have children with a cleft.
•
In about 70% of cases, the fetal face is clearly visible using ultrasound. Facial disorders have
been detected at the fifteenth gestational week of pregnancy. Ultrasound can be precise and reliable
when diagnosing fetal craniofacial conditions.
Question 1: After hearing this information, should Sue and Tim feel that their chances of
having a child with a cleft lip are increased over that of the general population?
Question 2: Can cleft lip be surgically corrected?
Question 3: If the child showed a cleft lip through ultrasound analysis, and the parents then started
blaming each other (because Sue is a smoker, and Tim was born with the defect), how would you
counsel them?
More Autosomal Recessive Pedigrees
Directions ~ Draw pedigrees and list all possible genotypes for the following problems.
Answer any questions that may follow.
1. You are a genetic counselor. Derek and Tami are parents of the proposita who has Tay
Sachs disease, a fatal autosomal recessive disorder. Tami is pregnant with her 4th child. They
seek your advice. Draw a pedigree based upon the following:
(1)
(2)
(3)
(4)
(5)
(6)
(7)
•
•
Derek and Tami, the parents of the proposita, are unaffected.
The proposita had an older brother who died from Tay Sachs, and has a younger
brother who is unaffected. Tami is pregnant for the 4th time. The sex of the fetus
is unknown as of this time.
Tami is the older sister of a boy who died from Tay Sachs. Her parents are
unaffected.
Derek is the youngest of three children. His oldest sibling, Amanda, is unaffected.
Amanda’s husband is unaffected. Derek’s other sister, Jana, died from the disease
at age two.
Derek’s parents are both unaffected.
Amanda and her husband currently have three children. Their oldest, Mark, is
unaffected; their next child, Susan, has Tay Sachs. Amanda next had twins – a boy,
Kevin, who is unaffected, and a girl, Kimi, who died from the disease.
All individuals suffering from the disease have been revealed in the statements
above.
Draw the pedigree and place all possible genotypes under each individual.
Draw a Punnett square for Derek and Tami to determine the odds that their next child
will have Tay Sachs disease. Use 5-step format, please.
2. John and Hannah are the paternal grandparents of the proposita who has
galactosemia, an autosomal recessive disorder. You offered genetic counseling to the
family. Construct a pedigree based upon this information:
(1) John and Hannah are unaffected and had five children.
(2) Hannah’s firstborn was an unaffected daughter, Elizabeth. Her second child, a
affected
boy died at an early age. Her next child, a female with galactosemia,
died at the age of
ten. Hannah’s next baby, a boy whose phenotype was
undetermined, was stillborn.
Her youngest child, Eric, is unaffected.
(3) Elizabeth’s husband is unaffected. The couple produced two children: a girl who
died
young and was affected with galactosemia, and a boy who is unaffected.
(4) The father of the proposita is married to an unaffected woman. They have three
children: the proposita, who is the eldest child and is affected, and MZ
(monozygotic)
twin boys, both of whom are unaffected.
(5) All individuals suffering from the disorder are revealed in the statements above.
•
Draw the pedigree and place all possible genotypes under each individual.
Mitochondrial Genes – Fact sheet
Mitochondria in humans contain several copies of mini-chromosomes that carry about 37 genes.
There is a high mutation rate in these 37 genes, because they lack DNA repair enzymes and the
mitochondrion is the site of energy reactions that produce free radicals that cause damage to DNA.
Mitochondria are maternally inherited, but cause sperm do not contain mitochondria.
Human cells have many mitochondria that can contain different alleles for the same gene.
Mitochondrial genes encode proteins that participate in protein synthesis and energy production. (24
of the genes encode RNA molecules that help assemble proteins and 13 genes encode proteins that
function in cellular respiration)
Heteroplasmy – because a cell has many mitochondria a mutation may be present in some
mitochondria chromosomes and not others. This causes a wide variety of expressivity.
Mitochondrial DNA is used as a forensic tool to link suspects to crimes and identify war dead.
Kearns-Sayre Syndrome and Mitochondrial Disorders
Florence is an active 44-year-old elementary school teacher who began
experiencing severe headaches and nausea. She told her physician that
her
energy level had been dramatically reduced the last few months, and her
arms
and legs felt like they “weighed 100 pounds each,” particularly after she
worked out in the gym. Her doctor performed a complete physical and
noticed that she did have reduced strength in her arms and legs and that
her
left eyelid was droopier than her right eyelid. He referred her to an
ophthalmologist who discovered that she had an unusual pigment accumulation on her retina, which had not
yet affected her vision. She then visited a clinical geneticist who examined the mitochondria in her muscles.
She was diagnosed with a mitochondrial genetic disorder known as Kearns-Sayre syndrome.
Mitochondria are responsible for the conversion of food molecules into energy to meet the cell’s energy needs.
In mitochondrial disorders, these biochemical processes are abnormal, and energy production is reduced.
Muscle tends to be particularly affected because it requires a lot of energy, but other tissues such as the brain
may also be involved. Under the microscope, the mitochondria in muscle from people with mitochondrial
disorders look abnormal, and they often accumulate around the edges of muscle fibers. This gives a particular
staining pattern, known as a “ragged red” appearance, and this is usually how mitochondrial disorders are
diagnosed.
Mitochondrial disorders affect people in many ways. The most common problem is a combination of mild
muscle weakness in the arms and legs together with droopy eyelids and difficulty in moving the eyes. Some
people do not have problems with their eye muscles, but have arm and leg weakness that gets worse after
exertion. This weakness may be associated with nausea and headaches. Sometimes muscle weakness is
obvious in small babies if the illness is severe, and they may have difficulties in feeding and swallowing. Other
parts of the body may be involved, including the electrical conduction system of the heart. Most mitochondrial
disorders are mildly disabling, particularly in people who have eye muscle weakness and limb weakness. The
age at which the first symptoms develop is variable, ranging from early childhood to late adult life.
About 20% of those with mitochondrial disorders have similarly affected relatives. Because only mothers
transmit this disorder, it was suspected that some of these conditions are caused by a mutation in the genetic
information carried by mitochondria. Mitochondria have their own genes, separate from the genes in the
chromosomes of the nucleus. Only mothers pass mitochondria and their genes on to children, whereas the
nuclear genes come from both parents. In about one-third of people with mitochondrial disorders, substantial
chunks of the mitochondrial genes are deleted. Most of these individuals do not have affected relatives, and it
seems likely that the deletions arise either during development of the egg or during very early development of
the embryo.
Deletions are particularly common in people with eye muscle weakness and the Kearns-Sayre syndrome.
Question 1: Why would mitochondria have their own genomes?
Question 2: How would mitochondria be passed from mother to offspring during egg formation? Why doesn’t
the father pass on mitochondria to offspring?
Pearson Syndrome
A 34-year-old woman and her 1-month-old newborn were seen by a
genetic counselor in the neonatal intensive care unit in a major medical
center. The neonatologist was suspicious that the newborn boy had a
genetic condition and requested a genetic evaluation. The newborn was
very pale, was failing to thrive, had diarrhea, and had markedly increased
serum cerebrospinal fluid lactate levels. In addition, he had severe muscle
weakness with chart notes describing him as “floppy,” and he had already
had two seizures since birth. The neonatologist reported that the infant was currently suffering from
liver failure, which would probably result in his death in the next few days. The panel of tests
performed on the infant led the neonatologist and genetic counselor to the diagnosis of Pearson
syndrome. The combination of marked metabolic acidosis and abnormalities in bone marrow cells is
highly suggestive of Pearson syndrome.
Pearson syndrome is associated with a large deletion of the mitochondrial (mt) genome. The way the
deletion containing mtDNA molecules are distributed during mitosis is not known. However, it is
assumed that during cell division daughter cells randomly receive mitochondria carrying wild type
(WT) or mutant mtDNA. Mitochondrial DNA is, theoretically, transmitted only to offspring through the
mother via the large cytoplasmic component of the oocyte. Nearly all cases of Pearson syndrome
arise from new mutational events. Mitochondria have extremely poor DNA repair mechanisms, and
mutations accumulate very rapidly. Most infants with Pearson syndrome die before age 3, often due
to infection or liver failure.
A diagnosis of Pearson syndrome results in an extremely grave prognosis for the patient.
Unfortunately, at this point, treatment can be directed only toward symptomatic relief.
Question 1: Why doesn’t the mother have the disease if she has mutant mitochondrial DNA?
Question 2: How would you react to hearing this diagnosis? How would you counsel a couple
through this kind of situation?
Question 3: How would a large deletion in the mitochondrial genome cause a disease?
CF and Genetic Testing
Todd and Shelly Z. were referred for genetic counseling because of
advanced maternal age (Shelley was over 40 years old) in their
current pregnancy. While obtaining the family history, the counselor
learned that during their first pregnancy, the couple had elected to
have
an amniocentesis for prenatal diagnosis of cytogenetic abnormalities
because Shelly was 36 years old at the time. During that pregnancy,
Shelly and Todd reported that they were also concerned that Todd’s
family
history of cystic fibrosis (CF) increased their risk for having an affected child. Todd’s only sister had
CF, and she had severe respiratory complications.
The genetic counseling and testing was performed at an outside institution, and the couple had not
brought copies of the report with them. They did state that they had completed studies to determine
their CF carrier status and that Todd was found to be a CF carrier, but Shelly’s results were negative.
The couple was no longer concerned about their risk of having a child with CF based on these
results. To support their belief, they had a healthy 5-year-old son who had a negative sweat test at
the age of 4 months. The counselor explained the need to review the records and scheduled a followup appointment.
The test report from their first pregnancy only tested for the delta F508 mutation, the most common
mutation in CF. The report confirmed that Shelly is not a carrier of this mutation and that Todd is. This
report reduced Shelly’s risk status from 1 in 25 to about 1 in 300. More information has been learned
about the different mutations in the CF gene since the last time they received genetic counseling. The
counselor conveyed the information about recent advances in CF testing to the couple, and Shelly
decided to have her blood drawn for CF mutational analysis with an expanded panel of mutations.
Her results showed that she is a carrier for the W1282X CF mutation. The family was given a 25%
risk for CF for each of their pregnancies based on their combined molecular test results. They
proceeded with the amniocentesis because of the risks associated with advanced maternal age and
requested fetal DNA analysis for CF mutations. The fetal analysis was positive for both parental
mutations, indicating that the fetus had a greater than 99% chance of being affected with CF.
Question 1: How is it that the fetus has a greater than 99% chance of being affected with CF if each
parent carries a different mutation? Is the fetus homozygous or heterozygous for these mutations?
Question 2: If this child has CF, what are the chances that any future child will have this disease?
Does the fact they have a healthy 5-year-old son affect the chances of having future children with
CF?
Cystic Fibrosis Gene
It is May1989 and the scene is a crowded research laboratory with beakers, flasks, and pipettes
covering the lab bench. People and equipment take up every possible space. One researcher, Joe,
passes a friend staring into a microscope. Another student wears gloves while she puts precisely
measured portions of various liquids into tiny test tubes. Joe glances at the DNA sequence results he
is carrying. Something is wrong. There it is, a unique type of genetic mutation in a DNA sequence.
The genetic information required to make a complete protein is missing, as if one bead had fallen
from a precious necklace. Instead of returning to his station, Joe rushes to tell his supervisor, Dr. Tsui
(pronounced “Choy”), that he has found a specific mutation in a person with cystic fibrosis (CF), but
he does not see this same mutation in a normal person’s genes. CF is a fatal disease that kills about
1 out of every 2,000 Caucasians (mostly children). Dr. Tsui examines the findings and is impressed
but wants more evidence to prove that the result is real. He has had false hopes before, so he is not
going to celebrate until they check this out carefully. Maybe the difference between the two gene
sequences is just a normal variation among individuals. Five months later, Dr. Tsui and his team
identify a “signature” pattern of DNA on either side of the mutation, and using that as a marker, they
compare the genes of 100 normal people with the DNA sequence from 100 CF patients.
By September1989, they are sure they have identified the CF gene. After several more years, Tsui
and his team discover that the DNA sequence with the mutation encodes the information for a protein
called CFTR (cystic fibrosis transmembrane conductance regulator), a part of the plasma membrane
in cells that make mucus. This protein regulates a channel for chloride ions. Proteins are made of
long chains of amino acids. The CFTR protein has 1,480 amino acids. Most children with CF are
missing one single amino acid in their CFTR. Because of this, their mucus becomes too thick,
causing all the other symptoms of CF. Thanks to Tsui’s research, scientists now have a much better
idea of how the disease works. We can now easily predict when a couple is at risk for having a child
with CF. With increasing understanding, scientists may also be able to devise improved treatments
for children born with this disease.
CF is the most common genetic disease among those of European ancestry. Children who have CF
are born with it. Half of them will die before they are 25 and few make it past 30. It affects all parts of
the body that secrete mucus: the lungs, stomach, nose, and mouth. The mucus of children with CF is
so thick sometimes they cannot breathe. Why do 1 in 25 Caucasians carry the mutation for CF? Tsui
and others think that people who carry it may also have resistance to diarrhea-like diseases.
Question 1: Dr. Tsui’s research team discovered the gene for cystic fibrosis. What medical advances
can be made after a gene is cloned?
Question 2: Why do you think a change in one amino acid in the CF gene can cause such severe
effects in CF patients? Relate your answer to the CFTR protein function and the cell membrane.
Hardy-Weinberg and CF
Jane, a healthy woman, was referred for genetic counseling because
she
had two siblings, a brother Matt and a sister Edna, with cystic fibrosis
who
died at the ages of 32 and 16, respectively. Jane’s husband, John,
has
no family history of cystic fibrosis. Jane wants to know the probability
that
she and John will have a child with cystic fibrosis. The genetic
counselor used the Hardy-Weinberg model to calculate the
probability that this couple will have an affected child. The counselor
explained that there is a two-in-three chance that Jane is a carrier for
the
mutant CFTR allele. She used a Punnett square to illustrate this. The
probability that John is a carrier is equal to the population carrier frequency (2pq). The probability that
John and Jane will have a child who has cystic fibrosis equals the probability that Jane is a carrier
(2/3) multiplied by the probability that John is a carrier (2pq) multiplied by the probability that they will
have an affected child if they are both carriers (1/4).
Question 1: Using the heterozygote frequency for cystic fibrosis among white Americans to estimate
the probability that John is a carrier, what is the likelihood that their child would have the disease?
Question 2: If you were their genetic counselor, would you recommend that Jane and John be
genetically tested before they attempt to have any children?
Question 3: It is now possible to use preimplantation testing, which involves in vitro fertilization plus
genetic testing of the embryo before implantation, to ensure that a heterozygous couple has a child
free of cystic fibrosis. Do you see any ethical problems or potential future dangers associated with
this technology?
Notes: Autosomal Dominant Inheritance
Remember: The following genotypes and phenotypes apply in
autosomal dominant inheritance:
AA = affected
Aa = affected
aa = unaffected
Please notice there are no carriers in this inheritance pattern.
Sometimes (depending on the disorder) the AA genotype is more
seriously affected than is the Aa genotype. An example is the AA
genotype for achondroplasia. Called “double-dominant dwarfs,” these fetuses typically die
before birth – or shortly after birth. So all achondroplastic dwarfs in the general population
are Aa heterozygotes.
You need to know the following additional vocabulary terms for autosomal dominance…
1. VARIABLE EXPRESSIVITY = when the symptoms of a disorder vary (differ) in intensity in
different affected people. For example, some people with NF – neurofibromatosis – have
very mild symptoms, while others with NF have more severe symptoms.
2. PENETRANCE = when a person inherits a disorder-causing dominant allele and displays
(expresses) its symptoms.
3. LACK OF PENETRANCE (INCOMPLETE PENETRANCE) = when a person inherits a disordercausing dominant allele, yet does not display its symptoms. A person could be Aa for NF
and not show a single symptom of the disorder! He may never even know he has the
mutant gene and could pass it on to his offspring – and those children could express the
disorder.
4. PERCENT PENETRANCE = is calculated mathematically. For example, if 85 out of 100
people who inherited a dominant gene (and are Aa) actually express symptoms, but 15 of
them do not express symptoms, then the allele is said to be “85% penetrant.” You could also
say the gene shows “85% penetrance.”
5. FRESH (SPONTANEOUS) MUTATION = is fairly common in many human autosomal
dominant disorders. A fresh mutation can occur in an egg, a sperm cell, or in the zygote. It
is estimated that 85% of all cases of achondroplasia are the result of fresh mutations.
6. DELAYED ONSET = when a person inherits a dominant allele, but does not begin to
express the symptoms of the disorder until later in life. For example, in Huntington disease,
symptoms do not typically arise until persons are in their 30s or 40s.
7. PLEIOTROPY = is pronounced (PLY – uh – tropee). This is when a certain mutant allele
codes for a protein that affects different parts of the body. For example, in Marfan
syndrome, a mutant allele codes for a defective type of protein called fibrillin, an elastic
connective tissue found in many places in the body. Defective fibrillin causes multiple
symptoms – it has pleiotropic effects – such as eye lens dislocation, spindly fingers, chest
abnormalities, and weakened aorta. The Marfan gene is pleiotropic.
An Autosomal Dominant Pedigree
Directions: Read the following bits of information, and then construct a 3-generation
pedigree. List all possible genotypes under each of the symbols in the pedigree.
Kristi (proposita), a 15-year-old high school sophomore, has a severe case of
neurofibromatosis (NF). She has two brothers, one older and the other younger than she,
both of whom are unaffected. Kristi’s father has no disfiguring tumors, but he does have
eight, large, brown, café-au-lait spots on his stomach, back, and right leg – this means he is
mildly affected. Kristi’s mother, and Kristi’s maternal and paternal grandparents are
unaffected.
•
Construct a 3-generation pedigree, listing all possible genotypes under each symbol,
using the space below.
•
Using a Punnett square, with 5-step format, show how it was possible for Kristi’s parents
to produce a child with NF.
♀
x
♂
genotypes:
phenotypes:
•
Explain how it is possible that Kristi’s unaffected paternal grandparents produced a
son with NF? [Be as specific as possible, please.]
Dominant Hereditary Ataxia Pedigree
Important Information: Carly, the proposita, has a rare autosomal dominant disorder called
dominant hereditary ataxia, a delayed-onset, degenerative neurological disorder. It is fatal.
The gene has 100% penetrance. Here is some pertinent information concerning her family:
(1) Carly is 30 years old. She has a 32-year-old, unaffected sister, and an affected 29-yearold sister. Carly’s mother, Andrea, is unaffected. Carly’s father, Adam, had no apparent
symptoms of the disorder. He died when trampled in a buffalo stampede while on a hunting
expedition in Montana nearly twenty years ago. Adam was only 33 years old at the time of
his death.
(2) Adam was the eldest son of Richard and Helen. Richard died of ataxia. Helen was
unaffected. Richard and Helen had a middle child, Jacob, who died of the disorder.
Jacob’s younger sister, Beth, is affected.
(3) Jacob had married an unaffected woman. They produced two children, a 30-year-old,
affected son and a 29-year-old, unaffected daughter. A third pregnancy resulted in a
stillborn baby boy.
(4) Beth married an unaffected man. She now has a 33-year-old, affected son, in addition to
32-year-old, unaffected, monozygotic (MZ or identical) twin sons, and a 27-year-old
daughter who was recently diagnosed with the disorder.
(5) Richard’s father was affected; his mother was not. Helen’s parents were unaffected.
Helen died while running with the bulls in Pampalona, Spain. Both pairs of Carly’s paternal
great-grandparents are deceased.
•
Construct a 4-generation pedigree, listing all possible genotypes under each symbol,
using another piece of paper.
•
How could Adam and Andrea have affected children? Please give two possibilities.
Then tell which of the two is the more probable of the two.
•
Imagine for a moment that you are the child of a father who has died of ataxia. Your
mother is alive, well, and unaffected by the disorder. You are about to receive a
phone call from a research team at UCSD. They are going to ask you whether or not
you would be willing to participate in a scientific study to help determine the function
of the ataxia gene. But first, they need a blood sample. They will test your white blood
cells' DNA to determine if you have the dominant gene. You have been promised
that the results will be kept strictly confidential - even you don't have to know the
results...unless you wish.
Would you take the gene test to aid the researchers?
Would you want to know your test results? Why or why not?
Achondroplasia
A couple was referred for genetic counseling because they wanted to
know
the chances of having a child with dwarfism. Both the man and
woman had achondroplasia, the most common form of short-limbed
dwarfism. The couple knew that this condition is inherited as an
autosomal dominant trait, but they were unsure what kind of physical
manifestations a child would have if it inherited both genes for the
condition. They were each heterozygous for the FGFR3 gene that
causes achondroplasia, and they wanted information on the chances of having a child homozygous
for the FGFR3 gene. The counselor briefly reviewed the phenotypic features of individuals who have
achondroplasia. These include the facial features (large head with prominent forehead; small, flat
nasal bridge; and prominent jaw), very short stature, and shortening of the arms and legs. Physical
examination and skeletal x-ray films are used to diagnosis this condition. Final adult height is
approximately 4 feet. Because achondroplasia is an autosomal dominant condition, a person with this
condition has a 1 in 2, or 50%, chance of having children with this condition. However, approximately
75% of individuals with achondroplasia are born to parents of average size. In these cases,
achondroplasia is due to a new mutation. This couple is at risk for having a child with two copies of
the changed gene or double homozygosity. Infants with homozygous achondroplasia are either
stillborn or die shortly after birth. The counselor recommended prenatal diagnosis via serial
ultrasounds. In addition, a DNA test is available to detect the homozygous condition prenatally.
Achondroplasia occurs in 1 in every 14,000 births.
Question 1: What is the chance this couple will have a child with two copies of the dominant mutant
gene? What is the chance that the child will have normal height?
Question 2: Should the parents be concerned about the heterozygous condition as well as the
homozygous mutant condition?
Question 3: Why would the achrondroplasia gene be more susceptible to mutation than other genes?