GENE MAPPING AND
IDENTIFICATION: CASE STUDIES
SARAH OSSLER
SARAH.OSSLER@CCHMC.ORG
LEARNING OBJECTIVES
• Understand inheritance patterns, such as autosomal
recessive inheritance and autosomal dominant
inheritance
• Be able to interpret and create a family history
using appropriate symbols
• Identify when more information is needed to make
a differential diagnosis for a patient
• Recall important details about genetic conditions
that may be applicable to the patient
• Apply knowledge of genetic conditions to the
patients’ medical and family history to make a
diagnosis
MENDEL’S PRINCIPLES
• Principle of Dominance
• One allele masked another, one allele is dominant over the
other
• Principle of Segregation
• When gametes are formed, the pairs of hereditary factors
(genes) become separated, so that each sex cell
(egg/sperm) receives only one kind of gene
• Principle of Independent Assortment
• “Members of one gene pair segregate independently from
other gene pairs during gamete formation”
FAMILY HISTORY
• You can learn a lot from taking a family history
• May make it clear to you if a certain mode of
inheritance is present in a family
• Three common modes of inheritance
• Autosomal recessive
• Autosomal dominant
• X-linked
AUTOSOMAL RECESSIVE EXAMPLE
• Examples:
Hearing loss
Hemochromatosis
PKU
Spinal muscular
atrophy
• Tay Sachs
•
•
•
•
AUTOSOMAL DOMINANT EXAMPLE
What are
some
common
autosomal
dominant
conditions?
X-LINKED EXAMPLE
• Fragile X Syndrome
• Caused by
trinucleotide repeats
• What is the normal
range of CGG
repeats, premutation,
and mutation range?
• Hemophilia
ACTIVITY
• Now you will draw your own family tree!
• Do not have to include any medical information
• Do three generations (you/cousins, your
parents/aunts/uncles, grandparents)
• Please let me know if you have questions drawing
something!
WHY DO WE CARE ABOUT GENE
MAPPING?
• Diagnosing patients
• Allows us to:
•
•
•
•
Perform prenatal diagnoses
Personalize medicine with pharmacogenomics
Direct psychosocial counseling
May aid in prevention of disease
CASE STUDIES
• 3 case studies
•
•
•
•
Clinical description for each
Ask questions about the patient
Create a differential diagnosis
Think of testing you could offer the patient
PATIENT 1
• Patient is a 14 year old female. She went to the
hospital complaining of a cold that was worsening.
Her BMI was in the underweight range. The
physicians gave her a chest radiograph and
sputum culture, CBC panel, RPR, and Chem 16.
They then diagnosed her with pneumonia.
ABNORMAL LABS
Abnormal
Lab
Normal value
Her value
Transferrin
250-380
219
Magnesium
1.8-3
1.6
HbA1C
3.9-5.2
6.3
WBC
4.8-11.8
13
HGB
12-15
11.5
HCT
37-47
33
Ferritin
20-120
19
Activity:
Research what
each of these
levels mean
WHAT OTHER INFORMATION DO YOU
WANT ABOUT THE PATIENT IN ORDER
TO MAKE A DIFFERENTIAL DIAGNOSIS?
DIFFERENTIAL DIAGNOSIS
• Alpha-1 antitrypsin deficiency
• Activated P13K-δ Syndrome (APDS)
• http://www.cam.ac.uk/research/news/scientists-discovergenetic-disease-which-causes-recurrent-respiratoryinfections
•
•
•
•
Cystic Fibrosis
Asthma
Primary immunodeficiency
This is not an exhaustive list!
CYSTIC FIBROSIS
• Thick mucous secretions from the epithelial surfaces of
several organ systems including the respiratory tract,
gastrointestinal tract, liver, genitourinary system, and
sweat glands
• Autosomal recessive
• Delta F508 is the most common mutation
WHAT TESTS WOULD YOU ORDER ON
THE BASIS OF COST/BENEFIT?
• Options:
• Sweat chloride test
• Positive test= ≥60 mEq/L
• Pancreatic function tests
• Pulmonary function tests
• Gene testing
• Most common approach- screening for the two most common
mutations
• If not found, can sequence the CFTR gene
• Newborn Screening
• Can also detect carriers, may cause extra stress in families
• Activity: in groups, find costs and their diagnostic
ability for the above tests
MATH.
PATIENT 2
• Patient is a 2 year old male. His mother is concerned
that he is not meeting his developmental
milestones, and wanted a consultation with her
pediatrician. The pediatrician noticed several
brown patches on the patients’ skin, and referred
the family to genetics.
WHAT OTHER INFORMATION DO YOU
WANT ABOUT THE PATIENT TO MAKE
A DIFFERENTIAL DIAGNOSIS?
DIFFERENTIAL DIAGNOSIS
•
•
•
•
•
•
NF1
NF2
McCune-Albright syndrome
Tuberous sclerosis
Fanconi Anemia
Again, not an exhaustive list!
NEUROFIBROMATOSIS TYPE 1
• Characterized by multiple café au
lait spots
• Axillary and inguinal freckling
• Multiple cutaneous neurofibromas
• Lisch nodules
• 50% of individuals have learning
disabilities
• Other manifestations:
• plexiform neurofibromas
• optic nerve and other central nervous
system gliomas
• malignant peripheral nerve sheath
tumors
• scoliosis
• tibial dysplasia
• Vasculopathy
• Autosomal dominant, about 50% of
cases are de novo
•
http://www.ncbi.nlm.nih.gov/books/NBK1109/
DIAGNOSTIC CRITERIA
• individual who has two or more of the following
features:
Six or more café au lait spots
Two or more neurofibromas
Freckling in the axillary or inguinal regions
Optic glioma
Two or more Lisch nodules (iris hamartomas)
A distinctive osseous lesion such as sphenoid dysplasia or
tibial pseudarthrosis
• A first degree relative (parent, sibling, or offspring) with NF1
•
•
•
•
•
•
WHAT TESTS WOULD YOU ORDER?
• Generally, mutation analysis is not needed to
confirm a diagnosis in a patient.
• When would you need to have a confirmed diagnosis by
mutation analysis?
• Mutation analysis of NF1can be useful
• Sequence variants= ~90% mutation detection
• Deletion/duplication analysis= ~5%
• Large scale rearrangements= ~1%
PATIENT 3 (THIS IS A TOUGH ONE!)
• A 5 year old Caucasian female, who is previously
healthy, presents to the ED with a 3 day history of
vomiting and diarrhea such that she is only able to
keep down a small amount of water. On exam she
is clearly dehydrated, with rapid pulse and
elevated respiratory rate. Initial labs show glucose
of 40 (normal 45-120), as well as evidence of
dehydration. Urine demonstrates a large amount of
ketones. Of note, all previous medical exams and
studies were normal.
WHAT OTHER INFORMATION DO YOU
WANT ABOUT THE PATIENT TO MAKE
A DIFFERENTIAL DIAGNOSIS?
DIFFERENTIAL DIAGNOSIS
•
•
•
•
•
•
Pyloric stenosis
Hyperthyroidism
Organic acidemias
Aminoacidemia
Urea Cycle Disorder
Other
• Since this one is so tough, look up these conditions
and see if any of them fit!
DIAGNOSIS
• Nongenetic!
• The baby was sick with the flu
LESSON
• We are trained as geneticists when we hear hoof
steps, we think of the Zebra instead of the horse
• ALWAYS keep in mind the possibility a patient is
presenting with a non-genetic illness
SUMMARY
• Discussed inheritance patterns, such as autosomal
recessive inheritance and autosomal dominant
inheritance
• interpreted and created family histories using
appropriate symbols
• Identified when more information was needed to
make a differential diagnosis for a patient
• Recalled important details about genetic
conditions that may be applicable to the patient
• Applied knowledge of genetic conditions to the
patients’ medical and family history to make a
diagnosis
ASSIGNMENT
• Keep a food journal for about one week
• Can write down the information, or use an app like my fitness pal
• Keep track of calories and protein
• Write a one page reflection about how you felt doing this exercise
and what you learned
• Full assignment is posted on Blackboard
• See how many calories you can buy with $5
• You can go anywhere (grocery store, fast food restaurant, etc.)
• It has to be a food that would normally be eaten (you cannot buy a
ton of olive oil!)
• Full assignment posted on Blackboard
• Both are due for the Fetal Programming and Obesity lecture
(March 11th)
• Required reading: Chapter 12, Multifactorial Inheritance and
Common Diseases
• If you are having issues or have questions, please feel free to
email me at sarah.ossler@cchmc.org!!
QUESTIONS?