Medical Genetics and Genetic

Counseling
Kelly Minks, MS, CGC
Departments of Neurology and Medicine
September 1, 2017
What is medical genetics?
 Any application of genetics to medical practice
 Study of inheritance of diseases in families
 Mapping of disease genes to specific locations on
chromosomes
 Analysis of molecular mechanisms through which genes cause
disease
 Diagnosis and treatment of disease
 Genetic counseling
Why is medical genetics important to
you?
 Genetic diseases make up a Genetic Approximate
large percentage of the total condition prevalence
disease burden in pediatric
populations Down syndrome 1/700 to 1/1000
 Increasing number of Cystic Fibrosis 1/2000 to 1/4000
pediatric deaths are due to (Caucasian)
genetic disease in developing
countries Fragile X syndrome 1/4000 males;
 Better understanding of 1/8000 females
disease process
 Prevention Neurofibromatosis 1/3000 to 1/5000
type 1
 Treatment
Types of genetic diseases
 Chromosome disorders
 Single-gene disorders
 Multifactorial disorders
 Mitochondrial disorders
Why is making an accurate diagnosis
important?
 Allows for discussion of natural history, prognosis,
management, treatment, earlier/more frequent disease
screening, recurrence risk and prenatal diagnostic options,
and referral to advocacy groups or clinical trials
 Involves recognition of phenotypic signs, dysmorphology
exam, family history and testing
Common indications for genetics
referral
 Evaluation of individual with developmental delay or
intellectual disability
 Individual with single or multiple malformations
 Individual with chromosome disorder
 Individual at risk for genetic condition
 Individual with questions about genetic aspect of disease
 Couples with history of recurrent miscarriage
 Consanguinity
 Teratogen counseling
 Preconception counseling
Principles of Dysmorphology
 Malformation/Anomaly (primary defect)
 Basic alteration in structure of a body part usually occurring
by 8 – 10 fetal weeks
 Example: Cleft lip, polydactyly
Major Anomaly
 Basic alteration in embryological development severe enough
to require intervention and which potentially has a long-term
impact medically and/or psychologically
 Ex: spina bifida, omphalocele, cleft lip/palate
Minor Anomaly
 Basic alteration in embrylogical and/or fetal development
which requires no treatment or can be, more or less,
corrected
 Ex: postaxial polydactyly, low-set ears, preauricular tag
Common multiple congenital anomaly
syndromes
 Down syndrome
 Minor anomalies: sandal gap, small ears, single palmar crease
 Major anomalies: Congenital heart defects, duodenal atresia, pyloric
stenosis
 Trisomy 18
 Minor anomalies: small ears with unraveled helics, small mouth, short
sternum, short halluces (first toes)
 Major anomalies: congenital heart defects, omphalocele, missing
radius bone, diaphragmatic hernia, spina bifida
 Van der Woude syndrome
 Major anomalies: cleft lip with or without cleft palate
 Minor anomalies: pits or fistulas of the lower lip
Minor/Normal variant feature
 Low frequency (1% - 5%) congenital feature found in the
normal population or as an integral part of a multiple
congenital anomaly syndrome

Ex: simian line, 5th finger clinodactyly, 2-3 toe syndactyly,

epicanthal fold, accessory nipple
Comment on Anomalies
 Most malformation syndromes have more minor / normal
variant type of anomalies than major anomalies
Ex. Down syndrome
Down syndrome

 Low nasal root

 Upslanting palpebral
fissures
 Overfolded, small ears
 Flattened maxillary and
malar region
Comment on Anomalies
 An anomaly is an anomaly whether it is major or minor;
which means they each carry equal diagnostic importance. In
fact, because minor anomalies are more numerous and often
overlooked, they, as a group, may be potentially powerful
diagnostically.
Syndrome
 Recurring pattern of structural defects and/or secondary
effects/defects that allow for secure recognition
 Combination of features most likely represents a specific
etiology
 Example: Roberts syndrome
Sequence
 A situation where a single event (usually undefined) leads to a
single anomaly (or situation) which has a cascading effect of
local and/or distant deformations and/or disruptions
 Ex: Potter, Pierre Robin, amniotic bands
 Sequences usually infrequently genetic, but can be
incorporated as part of the features of a syndrome
 Sequence Scenario
Potter/Oligo Pierre Robin Amn. Bands
seq
Oligohydramnios Micrognathia Bands

Pul. hypoplasia Glossoptosis Constrictions

Jt contractures Cleft palate Fusions

Abn. ear cartilage Low-set ears Amputations

Lower inner eye Cleft lip/palate

folds
Prom. Nasal tip Omphaloceles
Pedigree
 One of the most commonly used tools in medical genetics
Patterns of inheritance
Patterns of inheritance
Patterns of Inheritance
 Mendelian inheritance  Complexities in presentation
 Autosomal dominant  Reduced penetrance
 Autosomal recessive  Age-dependent penetrance
 X-linked recessive  Variable expressivity
 X-linked dominant  Anticipation
 Mitochondrial  Sex-limited
 Multifactorial  New mutation
 Non-Mendelian patterns  Germline mosaicism
 Mitochondrial  Consanguinity
 Imprinting  Skewed x-inactivation
 Multifactorial  Small families
 Sporadic
Evaluating a pedigree
 Transmission
 Vertical – phenotype seen in generation after
generation
 Horizontal – phenotype seen in siblings but not
previous generations
 Sex ratio
 Number of males and females displaying
phenotype – equal or unequal?
 Segregation - which parent passes on the trait and to whom?
 Do fathers appear to pass the trait or disease onto
sons and daughters?
 Do mothers appear to pass the trait on to sons and
daughters?
 % of children affected - Compare to expected
recurrence risk
Mendelian Inheritance
 The rules… not the exceptions.
Mendelian inheritance
 AUTOSOMAL DOMINANT
 Affected offspring usually have one affected
parent (heterozygote) and one unaffected
parent
 Transmission
 Vertical
 Sex ratio
 Equal number of males and females affected
 Segregation
 Either parent passes on the trait to sons and
daughters
 Expected recurrence risk 50%
Autosomal Dominant
Mendelian inheritance
 AUTOSOMAL RECESSIVE
 The parents of affected individuals are both
heterozygotes (carriers)
 Transmission
 Horizontal
 Sex ratio
 Equal number of males and females affected
 Segregation
 Either parent passes on the trait to sons and
daughters
 Expected recurrence risk 25%
Autosomal recessive
Mendelian inheritance
 X-LINKED
 Transmission
 Vertical with “skipped generations”
 Sex ratio
 Much more frequent in males than females
Mendelian inheritance
 X-LINKED
 Segregation
 Carrier mother
 Half of her sons (affected)
 Half of her sons (unaffected noncarriers)
 Half of her daughters (unaffected carriers)
 Half of her daughters (unaffected noncarriers)
 Affected father
 All sons (unaffected noncarriers)
 All daughters (unaffected carriers)
 Expected recurrence risk depends on the mating
type
X-linked
What is the mode of inheritance?
What is the mode of inheritance?
• “Skipped generations”
• Only males affected
• Affected males related
through carrier
females
• No male to male
transmission
What is the mode of inheritance?
 X- linked
What is the mode of inheritance?
What is the mode of inheritance?
• Vertical pattern
• # of males = # of
females
• See male to male
transmission
• Every affected child
has an affected parent
What is the mode of inheritance?
 Autosomal dominant
Non-Mendelian inheritance
 Mitochondrial
 A relatively small number of diseases are caused by mutations in
the mitochondrial DNA (ATP/energy producing cytoplasmic
organelles)
 Mitochondria have their own DNA
 Inherited exclusively through the maternal line (located in
cytoplasm).
 Heteroplasmy (within a single cell, there is a mixture of
mitochondria, some containing mutant DNA and some
containing normal DNA)
 Larger the % of mutant DNA, the more severe the expression disease
 % of mutant DNA can change over time, leading to variable expression
Non-Mendelian inheritance
 Imprinting
 Phenotype depends upon
which parent passed on the
gene.
 3-4 Mb deletion on
chromosome 15 inherited
from the mother results in
Angelman syndrome; if
inherited from the father it
results in Prader-Willi
syndrome.
Non-Mendelian inheritance
 Multifactorial
 A trait or disorder caused by a combination of genetic and
environmental factors.
 No characteristic pattern of inheritance.
 Empiric risk
 Based on direct observation of data
 Average – may not apply to all families
Non-Mendelian inheritance
 Multifactorial
 Recurrence risk is higher if:
 Closer relationship of relative
 More than one family member affected
 If phenotype is common in one sex and the opposite sex is affected in
family
Factors that affect expression of
disease-causing genes
 Reduced penetrance
 Individual with a disease-causing mutation may not have the
disease phenotype.
 Offspring are at risk.
 Example
 Retinoblastoma
Factors that affect expression of
disease-causing genes
 Age-dependent penetrance
 Delay of onset of symptoms of a genetic disease.
 Individuals may have children before they know that they are affected.
 Carriers of the disease-causing gene may pass away before the onset of
symptoms.
 Examples
 Huntington disease
 Hereditary breast and ovarian cancer
Factors that affect expression of
disease-causing genes
 Variable expression / expressivity
 Different than penetrance
 Severity of the phenotype varies widely, even within a family.
 An individual’s presentation may be so mild that they are not
aware that they are affected and can pass on the condition to
their children.
Factors that affect expression of
disease-causing genes
 Variable expression / expressivity
 Factors that may influence variable expression within a family:
 Environmental exposures
 Modifier genes
 Example
 Neurofibromatosis type I
Factors that affect expression of
disease-causing genes
 Anticipation
 More severe expression and/or earlier age of onset in more
recent generations.
 Sometimes caused by expansion of DNA repeats
Factors that affect expression of
disease-causing genes
 Anticipation
 Expansion may be more likely to occur when inherited through
mother or father, depending on the condition
 Examples
 Huntington disease
 Myotonic dystrophy
Factors that affect expression of
disease-causing genes
 New mutation
 Affected proband with no history of the disease in the family
 Especially in an autosomal dominant condition
 Example NF1
 Recurrence risks:
 Low (possible germline mosaicism)
 The risk to offspring depends on the inheritance pattern of the
condition
Factors that affect expression of
disease-causing genes
 Germline mosaicism
 Relatively rare phenomenon
 Two or more offspring affected with no family history
 Especially dominant conditions
 More than one genetically distinct germ cell line
 Increased risk to siblings of an affected proband
Factors that affect expression of
disease-causing genes
 Germline mosaicism
 Examples:
 Duchenne muscular dystrophy
 Hemophilia A
 Achondroplasia
 Neurofibromatosis type I
 Osteogenesis imperfecta type II
Factors that affect expression of
disease-causing genes
 Skewed X-inactivation (in X-linked conditions)
 The majority of the active X-chromosomes carry the mutation
 Manifesting heterozyogotes – females with the disease
phenotype, usually mildly affected
 Example
 Duchenne muscular dystrophy
Other factors
 Consanguinity
 Relatives share genes, including disease-causing genes, inherited
from a common ancestor
 With consanguinity, offspring are more likely to be affected
with a recessive disorder
 More rare recessive disorder, more likely consanguinity
Other factors
 Small families
 Pattern of inheritance may not be evident in small families.
What is the mode of inheritance?
What is the mode of inheritance?
• Horizontal pattern
• # of Males = # of
Females
• Consanguinity
What is the mode of inheritance?
 Autosomal recessive
Genetic testing
 Covers an array of techniques including analysis of human
DNA, RNA, or protein
 Diagnose a disease in an individual with symptoms
 Measure risk of developing a disease
 Preconception testing or prenatal testing
 Non-clinical uses such as paternity testing and forensics
Karyotype
 A photographic representation of the chromosomes of a
single cell, cut and arranged in pairs based on their banding
pattern and size according to a standard classification
 The karyotype is used to look for abnormal numbers or
structures of chromosomes
Chromosome Functions
 To transmit genetic information from one generation of cells
to the next (mitosis)

 To transmit genetic information from one generation of

organisms to the next (meiosis)
Chromosome Structure

Acrocentric chromosomes: 13-15, 21, 22

Karyotype
 Aneuploidy
Aneuploidy is the presence of an abnormal number of chromosomes in a
cell, such as having 45 or 47 chromosomes when 46 is expected.
 Aneuoploidy
 An estimated 10 - 30% of all fertilized eggs have a
chromosome abnormality

 Aneuploidy is the leading known cause of pregnancy

loss > 25% of all miscarriages

 Aneuploidy is the leading genetic cause of intellectual

disability

 0.3% of liveborns are aneuploid

 Among oocytes studied 20 - 25% are aneuploid

 Among sperm studied 1 - 2% are aneuploid

Limitations of karyotype
 Does not detect small rearrangements.
 Does not detect low level mosaicism
Microarray-based Comparative
Genomic Hybridization (aCGH)
 Chromosomal microarray (CMA)
 Genome wide screening for copy number variants
 For CMA to have higher resolution than a G-banded
karyotype, CMA must detect CNVs smaller than 5 Mb and
must have whole-genome coverage
 What is array CGH, cont.
Patient (test) and control (reference) DNAs are labeled
with different fluorescent molecules, then co-hybridized in
equal amounts to the array of DNA probes
green red

test DNA reference DNA

What is array CGH, cont.
Given a normal karyotype, each probe on the array should
hybridize equally to test (“green”) and reference (“red”)
DNA. This will produce a “yellow” signal. The slide is
scanned and images analyzed by computer.
green red

test DNA reference DNA

patient has a deletion of these two loci

Limitations of array CGH
 Does not provide information
on balanced rearrangements
 Ability to detect mosaicism is
limited (down to 20% -
possibly lower)
• Interpretation of array
findings can be challenging
• confounding factors include
variable expressivity of some
CNV’s, penetrance, and lack of
sufficient data to classify some
rare CNV’s as benign or
disease-causing
Making a diagnosis in an a child with
DD/ID
 The term “developmental delay” is usually reserved for
younger children (typically younger than 5 years), and the
term “intellectual disability” is usually applied to older
children when IQ testing is valid and reliable
 Diagnostic yield with karyotyping with DD/ID is 3.7%
 Diagnostic yield of 12.2% in individuals with developmental
delay, intellectual disability, autism spectrum disorders, or
multiple congenital abnormalities
Making a diagnosis in a child with
DD/ID
Making a diagnosis in an a child with
DD/ID
 CMA should not be ordered when a rapid turnaround time is
needed (ex: STAT newborn analysis)
 Not always appropriate as a first-tier test. For example,
karyotyping may be more appropriate when a common
aneuploidy (Trisomy 21) is suspected or when individual has
family history of chromosome abnormality
 Karyotyping will help clarify recurrence risk for family in
case of aneuploidy
Making a diagnosis in a child with
Autism Spectrum Disorders

 Advances in clinical testing

technology have increased
the diagnostic yield from
6–10% a few years ago to
30–40%. Therefore,
genetic testing should be
discussed with all patients
and families with ASDs.
Diagnostic yield in ASDs
Making a diagnosis in a child with
Autism Spectrum Disorders
Single gene testing
 DNA sequencing is the process of reading nucleotide bases in
a DNA molecule
 Molecular genetic tests (or gene tests) study single genes or
short lengths of DNA to identify variations or mutations that
lead to a genetic disorder
Fragile X syndrome
 Developmental problems including learning disabilities and
cognitive impairment
 Usually, males are more severely affected by this disorder than
females
 Most males and about half of females with fragile X
syndrome have characteristic physical features that become
more apparent with age
 long and narrow face, large ears, a prominent jaw and forehead,
unusually flexible fingers, flat feet, and in males, enlarged
testicles (macroorchidism) after puberty
Fragile X syndrome
 Mutations in the FMR1 gene located on the X-chromosome
 Caused (most cases) by a mutation in which a DNA segment, known
as the CGG triplet repeat, is expanded within the FMR1 gene
 Normally, this DNA segment is repeated from 5 to about 40 times. In people
with fragile X syndrome, however, the CGG segment is repeated more than
200 times.
 The abnormally expanded CGG segment turns off (silences) the
FMR1 gene, which prevents the gene from producing FMRP
(protein)

 Males and females with 55 to 200 repeats of the CGG segment are
said to have an FMR1 gene premutation.
 increased risk of disorders called fragile X-associated primary ovarian
insufficiency (FXPOI) and fragile X-associated tremor/ataxia
syndrome (FXTAS).
Panels
 Sequencing for 2 or more genes related to genetic disease

 Panel related to phenotype

 Example: Epilepsy panel

 Whole exome sequencing (WES)

 Sequencing of all exons (coding regions) of thousands of genes (20,000+) simultaneously

 When should panels be considered?

 When phenotype doesn’t correspond to a single disorder
 When disorder in question has high degree of genetic heterogeneity
 Other specific tests for the phenotype have not been diagnostic
Interpreting results of genetic tests
 Pathogenic variant: variant is a recognized cause of some or all
of the patient’s phenotype
 Likely pathogenic variant: previously unreported variant, but
based on its gene location and the predicted effect on protein
function, it is likely to be the cause of some or all of the patients
phenotype
 Benign variant: not responsible for the patient’s phenotype
 Likely benign variant: previously unreported variant, but
based on its gene location and predicted lack of effect on protein
function, it is likely to be benign and not responsible for the
patient’s phenotype
 Variant of unknown or uncertain significance (VUS)
Questions?

Feel free to contact me!

kelly_minks@urmc.rochester.edu