Genetics for Nurses in Adult Disciplines

1
Genetics for Nurses in Adult Disciplines

• A guide to recognition and referral of congenital
  and genetic disorders
• AUTHORS
• Golder N. Wilson MD PhD,1 Vijay Tonk PhD,2
• REVIEWERS
• Shirley Karr BSN RN,3 Joanna K. Spahis BSN CNS,4
  Shirley Myers,5 RNC, MSN, FNP, and Sherry
  Letalian RN6
• 1Clinical Professor of Pediatrics, Texas Tech
  University Health Science Center at Lubbock and
  Private Practitioner, KinderGenome Genetics,
  Dallas Texas 2Professor of Pediatrics and
  Obstetrics-Gynecology Director, Cytogenetics
  Laboratory, Texas Tech University Health Science
  Center at Lubbock3Genetics Coordinator,
  Maternal-Fetal Medicine and Genetics, Texas Tech
  University Health Sciences Center at
  Amarillo4Pediatric Clinical Nurse Specialist in
  Genetics and Coordinator of the Down Syndrome
  Clinic, Department of Genetics, Childrens
  Medical Center of Dallas5Womens Health Nurse
  Practitioner, Maternal-Fetal Medicine and
  Genetics, Texas Tech University Health Sciences
  Center at Amarillo6Pediatric Clinic Coordinator,
  Department of Pediatrics, Texas Tech University
  Health Sciences Center, Lubbock
• Acknowledgement
• This presentation was designed as part of the
  GEN-ARM (Genetics Education Network for Nursing
  Assessment, Recognition, and Management) for the
  Mountain States Region Genetics Collaborative
  (MSRGCC) contact www.mostgene.org or Ms. Joyce
  Hooker at joycehooker_at_mostgene.org

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Genetic Disorders are Common
Genetic diseases affect 5-10 of children Nurses
can recognize and refer genetic disorders without
need for esoteric genetic knowledge We will now
present cases where your nursing skills and
alertness (REYDARRecognize, EYDentify, Assess,
Refer) can greatly benefit children with genetic
diseases. These cases will introduce you to
simple principles of genetics that will give you
confidence in recognizing these patients and
foster a medical home These cases and
principles are geared to the nursing genetics
primer and resources on the GENARM CD
3
Think genetics when something is unusual or
extreme

• Case A A term AGA newborn product of a pregnancy
  with little prenatal care has an enlarged and
  distorted head, blue-gray sclerae (whites of the
  eyes), and deformed limbs. X-rays show multiple
  fractures, and the mother blames this on an auto
  accident at 7 months gestation. Do you agree?

Newborn with large head and deformed bones with
fractures by x-ray
4
This unusual presentation should prompt REYDAR
for a genetic disease

• More detailed family history would be useful,
  although many genetic disorders occur as new
  changes (new mutations)
• The symptoms of blue sclerae and multiple
  fractures could be searched on the website Online
  Mendelian Inheritance in Man (go to
  http//www.ncbi.nlm.nih.gov/entrez/ or enter OMIM
  in search engine). They point to a disorder
  called osteogenesis imperfecta (166210
• OMIM contains gt6000 diseases that can be searched
  by symptom, name, or number associated databases
  contain genetic education, medical literature
  (PubMed), and even the complete human genome
  sequence/gene map.
• Also useful is the companion database
  www.genetests.org that lists testing (when
  available) for the particular genetic disease (go
  to the clinical laboratory section and search by
  disease name

5
Suspicion of genetic disease underlying this
unusual infant led to referral and genetic
counseling for this autosomal dominant
diseasemothers guilt about her accident was
assuaged and she learned she had a 50 chance
each of her future children would have OI
The family history indicated that the mother and
other relatives had mild features of osteogenesis
imperfecta or brittle bone disease (see Chapter 2)
Family history
Pedigree
6

• Case example 1 Nurses in adult disciplines might
  have identified the mother or maternal relatives
  with OI, giving them the advantages of genetic
  counseling for a 50 recurrence risk and
  potential therapy with pamidronate that can
  decrease the risk for fractures

7
Think genetics when something is unusual or
extreme

• Case example 2 A school physical
• A 14-year-old male is seen for a routine school
  physical and asks clearance to participate in
  sports. His mother mentions he has had surgery
  for fused sutures (craniosynostosis) including
  reconstruction of his nasal bridge. He has also
  had a history of mild mental disability, and the
  school nurse notices long fingers and a concave
  chest, prompting recall about Marfan syndrome and
  heart disease. The nurse decides to postpone
  approval for sports participation and refers the
  young man for genetic evaluation. Do you agree?

8

• In case example 2, the recollection of Marfan
  syndrome (154700) was appropriate because of the
  boys long spider fingers (arachnodactyly).
  Echocardiographic studies would show a dilated
  aorta and he should certainly not participate in
  collision or high-intensity sports. Genetics
  referral would establish that this child had a
  disorder called Shprintzen-Goldberg syndrome
  (118212) that was similar to Marfan but different
  in having craniosynostosis and mental disability.
  Shprintzen-Goldberg syndrome is also autosomal
  dominant, meaning that the boys normal parents
  would have a minimal recurrence risk for future
  affected children and the boy himself would have
  a 50 chance to transmit the condition with each
  future pregnancy. Preventive management in his
  case allowed protection from harmful activities
  and access to medications such as propranolal or
  Losartan that may be helpful in treating aortic
  aneurysms.

9

• Case example 2 Recognition of a genetic
  condition and preventive management for this
  teenager allowed protection from harmful
  activities and access to medications such as
  propranolal or Losartan that may be helpful in
  treating aortic aneurysms. A family with Marfan
  syndrome is discussed in chapter 2, showing the
  advantages of recognizing this disease with its
  risks for heart and eye complications.

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• Note that simple recognition and assessment of
  possible genetic disease, not sophisticated
  knowledge, optimized nursing care of for the
  example families.
• Nurses with additional interest in genetics can
  learn to construct pedigrees, interpret
  inheritance mechanisms, and provide recurrence
  risks for the parents (genetic counseling)
• Nurses are ideally positioned to be genetic
  counselors with their hands-on contact, emphasis
  on education, and focus on prevention
• Read chapters 2-4 in the primer to acquire the
  skills for genetic counseling

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Genetic disease can be defined by abnormal genes,
tissues, or chromosomes (genetic testing)
Categories of genetic disease relate to the steps
from gene to family (genetic hierarchy)

• A family has people with unusual symptoms
• A person has abnormal form or function (disease)
• A tissue (cell to organ) has abnormal structure
  (metabolic disorders)
• A chromosome is extra or missing (chromosome
  disorders)
• Several genes (plus environment) are abnormal
  (multifactorial disorders or susceptibilities)
• A gene (DNA to RNA to protein) is abnormal
  (Mendelian disorders

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Categories of genetic or congenital disease
13

• Mendelian diseases like osteogenesis imperfecta
  have distinctive family patterns
• The pattern of affected relatives is caused by
  transmission of single genes, each with a unique
  position (locus) on the chromosome.
• The paired chromosomes 1-22 and XX in females
  imply paired genes except for X and Y genes in
  the male
• Dominant or recessive diseases result when one or
  both gene partners (alleles) are abnormal.
• Abnormal alleles can be predicted (genetic risks)
  and sometimes diagnosed through their abnormal
  DNA sequence or RNA/protein expression.

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• Sickle cell anemia is recessive, requiring both
  ß-globin alleles to be abnormal (SS versus AS
  trait or AA normal).
• Sickle cell anemia can be predicted (25 risk for
  next child) and tested (abnormal S protein or
  gene)
• Other inherited anemias can be related to
  different abnormal globin alleles (C, D, E,
  thassemias).

A or S
15

• OI is caused by one abnormal allele at a collagen
  gene (genotype Oo)
• Different phenotypes of OI relate to different
  collagen alleles
• The gt6000 Mendelian diseases thus relate to a
  similar number of different genes and abnormal
  alleles.
• Characterization of abnormal alleles provides DNA
  testingfew of the gt1600 characterized disease
  genes are available to the clinic.
• Simultaneous analysis of multiple genes (DNA
  chips, arrays) is not yet practical in the way
  that karyotypes define any abnormal chromosomes

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Know categories, not rare diseases

• Mendelian diseases reflect transmission of single
  genes (abnormal alleles) DNA diagnosis

• Single genes altering development cause birth
  defects and syndromes
• Single genes altering enzyme pathways cause
  inborn errors of metabolism
• Single genes altering organ function(s) produce
  extreme or earlyonset
• examples of common disease (e.g.,
  neonatal diabetes)

Multifactorial diseases reflect multiple abnormal
genes plus environment DNA/HLA markers
Many genes altering development cause isolated
birth defects like cleft palate Many genes
altering enzyme pathways cause common metabolic
diseases (e.g., adult-onset
diabetes, hyperlipidemia) Many genes altering
organ function(s) produce adult diseases (e.g.,
schizophrenia)
Chromosomal diseases imbalance multiple genes
and cause multiple birth defects Karyotype
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REYDAR of common adult presentations
Recognition ? Category ? Referral ? Medical home

• Case 10PDiabetic woman who becomes pregnant
• Case 11PA pregnant couple and cystic fibrosis
  screening
• Case 12PA pregnant couple with infertility and
  two miscarriages
• Case 13PCouple with maternal history of mental
  retardation
• (see Chapter 1)

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Case 10P. Diabetic woman who is 10 weeks pregnant

• A 25-year-old woman with juvenile diabetes has
  been managed by her family practitioner for
  several years. She calls and asks for referral to
  obstetrics because she is approximately 6 weeks
  pregnant. She has had several hospitalizations
  for diabetic control and states that her blood
  sugars have been high for the past few weeks. The
  obstetric nurse discusses the risks of
  hypoglycemia, respiratory distress, and
  polycythemia for infants of poorly controlled
  diabetic mothers, but does not mention another
  risk for the fetus, which is?

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• Women with poorly controlled diabetes have a 3-5
  fold increased risk for congenital anomalies in
  their fetus that can be remembered by
  3Cscranial, cardiac, and caudal anomalies.
  Cranial defects can include anencephaly as in
  case 9P or holoprosencephaly (photo at right)
  caudal defects underdevelopment of the
  sacrum/lower limbs (caudal regression) or spina
  bifida. Anomaly patterns like the VATER
  association (192350) or Goldenhar syndrome
  (164210) also occur at higher frequency in
  infants of diabetic mothers.

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Preconception counsel

• Stringent diabetic control in later pregnancy can
  eliminate neonatal physiologic changes like
  hypoglycemia, hypocalcemia, polycythemia, and
  respiratory problems. Lowering the risks of
  diabetic pregnancy illustrates the potential
  collaboration of pediatric or adult and obstetric
  nurses in preconception counsel. Nurses in adult
  disciplines can recognize women or couples with
  increased pregnancy risks and refer them for
  pregnancy planning.

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Case 14P Man whose father had heart attack at
age 41 (hypercholesterolemia) A nurse
practitioner in a family practice clinic performs
a routine physical on a man of 35 for insurance
purposes. He notes on his preassessment form
mention of the mans father who died of a heart
attack at age 41. He completes a more detailed
family history indicating that the man has two
older brothers and two younger sisters, and that
one of the older brothers has had two heart
attacks and bypass surgery at age 45. The mans
father was adopted, and his mother is in good
health with no heart disease in her family. What
concerns should be raised?
22

• Case 14P Discussion
• Besides revealing patterns of disease suggestive
  of Mendelian inheritance, a family history can
  reveal susceptibilities or risk factors that lead
  to screening preventive strategies. Common
  disorders like isolated birth defects, coronary
  artery disease, diabetes mellitus, or
  hypertension follow a model of multifactorial
  determination. This model implies the interaction
  of multiple genes with the environment and a
  threshold above which susceptibility becomes
  disease. A growing number of laboratory tests are
  being devised to measure individual gene effects
  that combine with other genetic and environmental
  factors to produce disease. Coronary artery
  disease follows the multifactorial model and is
  associated with several genetic and environmental
  risk factorsblood lipid or homocystine levels,
  obesity, hypertension, diabetes, and certain
  clotting factors.

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• Case 14P Discussion
• A family member with extreme or unusual
  presentation of a common disease (e.g., young age
  or multivessel obstruction in coronary artery
  disease) indicates increased susceptibility to
  that disease (lower threshold) that may be
  transmitted to offspring. The mans father with
  an early onset coronary gives him a higher risk
  (3-5) to develop coronary artery disease and
  justifies laboratory testing for the disease
  (e.g. stress test for early coronary occlusion)
  or factors (e.g., blood pressure, blood
  sugar-cholesterol-lipoprotein-homocysteine-clottin
  g factor abnormalities) that predispose to
  disease.

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• Case 14P Discussion
• Abnormal laboratory findings can lead to medical
  (statins, heparin) or dietary (low cholesterol,
  folic acid) therapies and improved outcome when
  the hereditary risks are recognized. Among the
  several genes interacting to cause multifactorial
  diseases may be occasional ones of major
  effectsuch was the case for the low-density
  lipoprotein receptor where mutations caused very
  high cholesterol in the dominant condition
  familial hypercholesterolemia ( 144010). Extreme
  or unusual presentations of common diseases may
  also point to Mendelian disorders as well as to
  predisposing risk factors. The Surgeon General
  has recommended that all individuals know their
  family histories, an obligation that nurses of
  all disciplines can greatly assist.

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Review of genetic testing

• Mendelian disordersDNA tests for specific mutant
  alleles. LIMITATION Only a few diseases are
  sufficiently common that DNA testing is
  commercially feasible
• Chromosome disordersroutine karyotypes on blood,
  amniocytes, bone marrow or solid tumors FISH
  testing for subtle changes. LIMITATION
  Chromosome testing cannot analyze component genes
• Multifactorial disordersDNA tests for associated
  DNA variants (DNA markers) that indicate
  susceptibility to disease. LIMITATION DNA
  marker testing is still in the research stage

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• Single gene (Mendelian disorders) that are
  sufficiently common can be diagnosed by DNA
  testing for changes in gene sequence or
  structure the man with family history of heart
  attacks (case 14) could have blood cholesterol
  studies and DNA testing for mutations in the LDL
  receptor

Diagram of gene and its encoded LDL receptor
protein that imports cholesterol into cellsthe
position of mutation (shown below gene) determine
the severity of hypercholesterolemia
27

• Chromosome disorders can be diagnosed by a
  routine karyotype, performed on cells from
  individuals (blood) or fetuses (blood by
  fetoscopy, dividing villus cells from chorionic
  villus sampling, amniotic fibroblasts from
  amniotic fluid). This testing requires at least
  5-7 days for results.

28

• Now a rapid FISH test is available that does not
  require stimulation of cell division and gives
  results within 2-4 hours. Rapid FISH highlights
  chromosomes commonly involved in disorderse.g.,
  13 (Patau syndrome), 18 (Edwards syndrome), or 21
  (Down syndrome), showing three versus the normal
  two FISH signals in each cell nucleus (X and Y
  probes also show Turner syndrome or document sex
  in cases of ambiguous genitalia)

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Chromosome disorders

• Miscarriages (50-60), liveborn children (0.5),
  cancer tissue (many have diagnostic
  changes)--over 200 chromosomal diseases due to
  extra or missing chromosome or parts of
  chromosomes (p small or q long arms)
• Hallmarks are multiple major or minor anomalies
  (unusual appearance) with mental disability
• Most recognized by a routine karyotype, but FISH
  is required to detect submicroscopic deletions
  (e.g., DiGeorge) or the 3 of suspect children
  who have changes on subtelomere FISH after normal
  karyotypes
• Individual submicroscopic deletions are found in
  Williams (7q), hereditary retinoblastoma (13q),
  Prader-Willi (15q), Shprintzen-DiGeorge spectrum
  (22q), and 15 others.
• Consider chromosomes in any child with
  unexplained mental disability and/or multiple
  birth defects, couples with gt2 miscarriages,
  prenatal diagnosis for women over age 35
• Prenatal diagnosis of chromosome disorders can be
  performed by preimplantation diagnosis (first
  week), chorionic villus sampling (10-12 weeks),
  or amniocentesis (15-18 weeks).
• See Chapter 7 for more information

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Multifactorial Disorders
Table 4.1. Multifactorial Disorders in the
United States
Ranks first for neonatal causes of death
approximate scale (100 of predisposition
due to genetic factors as for Mendelian
disorders) to (20 of predisposition due to
genetic factors)
31
Multifactorial Disorders

• Most isolated birth defects like cleft palate,
  hypospadias, heart defects, spina bifida
• Many common diseases like diabetes mellitus,
  hypertension, mental illness, mild
  mental/learning disabilities
• Multiple genes involved, giving lower
  transmission risks (about 3 for offspring of
  affected parent, sibling to affected child)
• Therapeutic goals are to manipulate environment
  (e.g., folic acid) either generally or for
  specific high-risk individuals identified by
  associated DNA markers (more diverse and
  sensitive than HLA haplotypes

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Multifactorial disorders For some (e.g.,
coronary artery disease), single genes of major
effect (e.g., those regulating cholesterol) are
good risk markers)
Recognizing at-risk children or adolescent
females provides important opportunities for
nursing education and prevention (see chapter 4)
33

• Case 14P Discussion
• A major initiative of modern genetics is to
  expand recognition of disease susceptibilities by
  examining variable regions of DNA. The human
  genome project revealed a difference in DNA
  sequence for unrelated individuals every 1 in 200
  to 500 nucleotides, implying at least a million
  DNA differences per person. Most of these are
  single base pair differences that do not lead to
  clinical differencessingle nucleotide
  polymorphisms (SNPs). DNA markers that travel
  with disorders like schizophrenia (OMIM 181500)
  or Alzheimer disease (OMIM 104300, others)
  potentially allow measurement of individual
  susceptibility in the way that cholesterol
  conveys risk for coronary artery disease. With
  further study, DNA markers may provide tests for
  susceptibility and even prevention through
  modified expression of their associated genes.

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• Case 15P Woman whose mother and grandmother had
  breast cancer at young ages.
• An obstetric nurse assesses a woman aged 37 who
  is about 6 weeks along in her current pregnancy.
  The woman has two prior children and has no
  chronic illnesses her husband is age 40 with a
  benign family history. The nurse ascertains that
  the woman has two sisters, aged 35 and 32, each
  with two children and no health problems. The
  womans mother is a breast cancer survivor,
  having her first cancer at age 31. Her mothers
  mother also had early breast cancer at age 36,
  dying by age 45. Her mother has two sisters, one
  of whom died from ovarian cancer at age 47 and
  another who has had cautery for cancer in situ of
  the cervix. What information should the nurse
  provide to this couple?

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• Case 15P Discussion
• Besides recognition of advanced maternal age
  with discussion of increased risks for chromosome
  abnormalities, the nurse should address increased
  susceptibility to breast and ovarian cancer.
  Although not necessarily pertinent to the current
  pregnancy, the woman has increased risks for
  breast cancer and should know about options for
  breast cancer gene testing. Mutations in the
  breast cancer genes BRCA1 (OMIM 113705) and
  BRCA2 (OMIM 600185) account for about 10 of
  breast cancer, characterized by its early onset
  and association with ovarian cancer. Testing
  would ideally be performed on one of the womans
  affected relatives, ascertaining the presence of
  BRCA mutations versus usually multifactorial
  breast cancer. If positive, the woman should be
  informed about her 50 risk to transmit the
  mutation to each child.

36

• Case 15P Discussion
• Cancers are additional examples of multifactorial
  disorders like coronary artery disease that were
  discussed in the previous section. Most will
  confer low risks for family members unless the
  same cancer is present in multiple relatives or a
  given cancer has an unusual or extreme
  presentation (e.g., early onset, associated
  features). Single gene diseases can also be
  concealed amidst multifactorial cancers,
  exemplified by the BRCA genes or cancer syndromes
  like Li-Fraumeni (bone, breast, brain
  cancersOMIM 151623) or Gardner disease (colon
  cancer-- OMIM 175100) that are due to single
  gene mutations. Alertness for early onset or
  recurrent types of cancers in families allows
  evaluation for a growing number of cancer genes
  or susceptibility markers.

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Rules from Chapter 1

• RULE Recognition of family histories with
  multiple affected individuals or those with
  unusual/extreme presentations of common diseases
  (e.g., heart attacks) allows definition of risk
  factors (e.g., cholesterol) and preventive
  management.

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. Case 13P Couple with maternal history of
mental retardation Bob and June present to a
nurse practitioner for prenatal care at an
estimated 6 weeks of pregnancy. Bob is 26, June
24, and they had a normal daughter Karen two
years ago with no pregnancy or delivery problems.
Both are healthy and of Caucasian ancestry, and
Bobs family history is normal The nurse finds
that June is an only child, but that her mother
Gail has two brothers who have mental
retardation. In addition, Gail has a sister Joan
with with two boys and a girl, and one boy Eric
has mental retardation thought due to birth
injury. Gails other sister Jill has three boys
and two girls, and her eldest son Jim has mental
retardation of unknown cause. One of Jills
daughters has also had learning problems that
caused her to drop out of high school, and she
has a preschool son Bert with speech delay. What
concerns should the nurse address?
39

• Case 13P Discussion
• Besides the usual options for genetic and fetal
  screening (ultrasound, quad screen, cystic
  fibrosis screening), the nurse should recognize
  the positive family history and recommend genetic
  evaluation. The presence of several relatives
  with the same condition (mental disability)
  brings up the possibility of Mendelian disease,
  and sketching of the family pedigree (below)
  would suggest an X-linked disorder associated
  with mental retardation. Genetic evaluation would
  inform June that her mother Gail has a 50 chance
  and she a 25 chance to be a carrier for the
  X-linked disease.

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• Case 13P Discussion
• The X-linked fragile X syndrome (OMIM 300624) is
  the most common genetic cause of mental
  disability with an estimated incidence of 1 in
  2000 males. Since June is early in her pregnancy,
  a fragile X DNA test could be performed on one of
  her male relatives to confirm or exclude this
  diagnosis. It would be ideal if one of her
  affected male relatives could be evaluated by a
  clinical geneticist so that the diagnosis of
  fragile X syndrome or another of the gt20
  syndromes associated with X-linked mental
  disability could be suspected.

41

• If the diagnosis of fragile X were confirmed in a
  male relative, June could have fragile X DNA
  testing to determine if she was a carrier. If her
  relatives were not available, or if their
  evaluation could not be accomplished in a time
  frame to accomplish Junes testing and options
  for prenatal diagnosis, then June could have the
  fragile X DNA test but realize that a negative
  result would not exclude other X-linked mental
  retardation syndromes. Preconception knowledge of
  fragile X syndrome in her family with recognition
  of her carrier status would have allowed Jill and
  Bob to consider other options such as surrogate
  egg donor or in vitro fertilization with
  preimplantation genetic diagnosis (PGD) and
  implantation of an unaffected embryo. Their case
  emphasizes the value of recognizing suspect
  family histories as early as possible in order to
  provide genetic counseling and reproductive
  options.

42
Common disorders (like mild mental or learning
disabilities often exhibit multifactorial
determination

• Case 13P Discussion
• If Jill or Bob had only one relative with mental
  disability with no obvious pedigree pattern, then
  multifactorial determination of the mental
  disability would be most likely. The odds of
  multifactorial disability would be increased if
  the affected person was mild and did not have an
  unusual appearance or biochemical abnormalities.
  Multifactorial disorders confer a 2-3 risk for
  primary relativesi.e., siblings/parents/children.
  Since Jill and Bob had normal intellect, their
  risks from one relative with mental disability
  would be less than 2-3.

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Review Questions

• 11. A woman is diagnosed with Crohns disease,
  and wishes to know the risk that her daughter
  will develop the disease. She is otherwise
  normal with an unremarkable family history. The
  likely inheritance mechanism and her daughters
  risk would be
• Autosomal dominant with a 50 risk
• Autosomal recessive with a 25 risk
• X-linked recessive with a 25 risk
• Chromosomal with a 10-15 risk
• Multifactorial determination with a 5-7 risk

44

• 12. A 24-year-old Ashkenazi Jewish woman develops
  bilateral breast cancer. Her mother and
  grandmother died of ovarian cancer, and a
  maternal aunt also had early onset breast cancer.
  She has two daughters aged 12 and 16. The most
  probable mechanism and risk to her daughters
  would be
• Multifactorial determination with a 1-2 risk
• Autosomal dominant with a 50 risk
• Autosomal dominant with a 25 risk
• X-linked dominant with a 50 risk
• X-linked dominant with a 25 risk

45

• 13. A male teenager presents for a school
  physical with tall stature, thin body build,
  concave chest (pectus), long fingers, flat feet,
  and increased joint laxity. His father died at
  age 35 with a heart attack. He wants approval to
  play basketball. An important disease category
  and disorder to consider would be
• Coronary artery disease and myocardial infarction
• Coronary artery disease and congestive heart
  failure
• Connective tissue disease and aortic dilatation
• Connective tissue disease and myocardial
  infarction
• Connective tissue disease and aortic coarctation

46

• 14. A 30-year-old man has hypertension
  controlled by diet and medication, and one of his
  three siblings is affected. His father died of
  kidney failure, and one of the mans three sons
  had urinary tract infections with cystic kidneys
  on ultrasound. The most likely diagnosis is
• Multifactorial predisposition to renal failure
• Isolated congenital anomaly of the urinary tract
• Autosomal dominant polycystic kidney disease
• Autosomal recessive polycystic kidney disease
• X-linked recessive polycystic kidney disease

47
Answer 1E

• 1. Crohns disease is a multifactorial disorder
  with a 7.5 risk for siblings of affected
  individuals to develop the disease (see Chapters
  4 and 12). Approximately the same risk would
  apply to other primary relatives such as the
  womans daughter.

48
Answer 12B

• 12. The early onset and family history of cancer
  is suggestive of Mendelian disease (e.g.,
  BRCA113705--or Li-Fraumeni syndrome112480--gene
  mutations, see chapter 12). The daughters would
  be at 50 risk for breast cancer, and DNA testing
  on the mother could determine if a particular
  BRCA1, BRCA2, or p53 (Li-Fraumeni) tumor
  suppressor gene were present. BRCA mutations are
  more common in Ashkenazi Jews. The BRCA genes
  account for about 10 of breast cancer, the rest
  being multifactorial. Thus, negative DNA tests do
  not eliminate the need for annual screening.
  Testing of the minor daughters would raise the
  ethical issues of informed consent and autonomy
  (parent versus child), but would probably be
  pursued because of the advantages of early
  screening or prophylactic mastectomy.

49
Answer 13C

• 13. The physical findings are characteristic of
  diseases with loose connective tissue, and the
  father-son affliction most suggestive of
  autosomal dominant diseases like Marfan syndrome
  (154700). These individuals are at risk for
  aortic dissection and sudden death and should not
  participate in collision or high intensity
  sports. Note that the history of heart attack
  in the father was probably an aortic dissection,
  stressing the need for medical and autopsy
  information to discriminate among cardiac causes
  of sudden death (see Chapter 12).

50
Answer 14C

• 14. The family history and presence of
  hypertension is suggestive of an autosomal
  dominant renal disorder, and the dominant form of
  polycystic kidney disease (173900) could be found
  in OMIM. This disease may be silent, causing
  severe hypertension and presenting with strokes
  at an early age. Early diagnosis in at-risk
  individuals (this man was at 50 risk) is
  important for treatment of hypertension. The
  30-year-old man should have imaging studies to
  confirm the diagnosis followed by imaging studies
  of his two apparently normal sons and siblings.