Genetic

Principles
Jason Ryan, MD, MPH
Genetics
Terminology

• Genome
• DNA contained in nucleus of cells
• “Hereditary material”
• Passed to successive generations of cells
• Genes
• Portions of DNA/genome
• Code for proteins that carry out specific functions
Genetics
Terminology

• Chromosome
• Rod-shaped, cellular organelles
• Single, continuous DNA double helix strand
• Contains a collection of genes (DNA)
• 46 chromosomes arranged in 23 pairs
• Chromosomes 1 through 22 plus X/Y (sex)
• Two copies each chromosome 1 through 22 (homologous)
• Key point: Two copies of any gene of a chromosome
Chromosomes
Cell Types
• Somatic cells (most body cells)
• Diploid: two sets of chromosomes (23 pairs)
• Gametes (reproductive cells)
• “Haploid”: one set of chromosomes
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Somatic Cell Replication

Mitosis

• S phase of cell cycle

• Chromosomes replicate → two sister chromatids
• M phase (mitosis): Cell divides
• Daughter cells will contain copies of chromosomes
Chromosome Daughter
Pair Chromosomes

Daughter
Chromosomes with Chromosomes
sister chromatids
Meiosis
• Gametes (reproductive cells)
• “Haploid”: one set of chromosomes
• Produced by meiosis of germ line cells
• Male and female gametes merge in fertilization
• New “diploid” organism formed
• Key point: one gene from mother, one from father
Genetics
Terminology

• Allele
• Alternative forms of gene
• Many genes have several forms
• Often represented by letter (A, a)
• Genetic polymorphism
• Genes exist in multiple forms (alleles)
• Locus (plural loci)
• Location of allele on chromosome
• DNA → gene → allele → locus → chromosome
Genetics
Terminology

• Genotype
• Genetic makeup of a cell or individual
• Often refers to names of two copies of a gene
• Example: Gene A from father, Gene B from mother
• Genotype: AB
• Or two alleles of gene A (A and a): AA, Aa, aa
• Phenotype
• Physical characteristics that result from genotype
• Example: AB = blue eyes; BB = green eyes
 AfraTafreeh.com for more

Genetics
Terminology

• Wild type gene/allele

• Common in most individuals
• Example: A = wild type
• Mutant gene/allele
• Different from wild type
• Caused by a mutation
• Example: a = mutant
• Individual: AA, Aa, aa
Genetics
Terminology

• Homozygous
• Two identical copies of a gene (i.e. AA)
• Heterozygous
• Two different copies of a gene (i.e. Aa)
Genetics
Terminology

• Germ line mutations

• DNA of sperm/eggs
• Transmitted to offspring
• Found in every cell in body
• Somatic mutations
• Acquired during lifespan of cell
• Not transmitted to offspring
Genetics
Terminology

• Dominant gene/allele
• Determines phenotype even in individuals with single copy
• Often denoted with capital letters
• Example: Gene has two alleles: A, a
• Aa, AA all have A phenotype
• Recessive gene/allele
• Requires two copies to produce phenotype
• Often denoted with lower case letters
• Example: aa = a phenotype; Aa and AA = A phenotype
Codominance
• Both alleles contribute to phenotype
• Classic example: ABO Blood Groups
• A gene = A antigen on blood cells
• B gene = B antigen
• O gene = No A or B antigen
• AB individuals
• Express A and B antigens
 AfraTafreeh.com for more

α-1 Antitrypsin Deficiency

• May cause early COPD and liver disease
• Mutations in AAT gene (produces α1 antitrypsin)
• M = normal allele
• S = moderately low levels protein
• Z = severely reduced protein levels
• Combination of alleles determines protein levels
• MM = normal
• ZZ = severe deficiency
• Other combinations = variable risk of disease
Penetrance
• Proportion with allele that express phenotype
• Incomplete penetrance
• Not all individuals with disease mutation develop disease
• Commonly applied to autosomal dominant disorders
• Not all patients with AD disease gene develop disease
• Example BRCA1 and BRCA2 gene mutations
BRCA1 and BRCA2
• Genetic mutations that lead to cancer
• Germline gene mutations
• Autosomal dominant
• Not all women with mutations develop cancer
• Implications:
• Variable cancer risk reduction from prophylactic surgery
Expressivity
• Variations in phenotype of gene
• Different from penetrance
• Classic case: Neurofibromatosis type (NF1)
• Neurocutaneous disorder
• Brain tumors, skin findings
• Autosomal dominant disorder
• 100% penetrance (all individuals have disease)
• Variable disease severity (tumors, skin findings)
Pleiotropy
• One gene = multiple phenotypic effects and traits
• Example: single gene mutation affects skin, brain, eyes
• Clinical examples:
• Phenylketonuria (PKU): skin, body odor, mental disability
• Marfan syndrome: Limbs, eyes, blood vessels
• Cystic fibrosis: Lungs, pancreas
• Osteogenesis imperfecta: Bones, eyes, hearing
Two-Hit Origin of Cancer
• Mutations in tumor suppressor genes
• Genes with many roles
• Gatekeepers that regulate cell cycle progression
• DNA repair genes
• Heterozygous mutation = no disease
• Mutation of both alleles → cancer
• Cancer requires “two hits”
• “Loss of heterozygosity”
Two-Hit Origin of Cancer

Wpeissner/Wikipedia
Two-Hit Origin of Cancer
• Classic example: Retinoblastoma
• Rare childhood eye malignancy
• Hereditary form (40% of cases)
• One gene mutated in all cells at birth (germline mutation)
• Second somatic mutation “hit”
• Cancer requires only one somatic mutation
• Frequent, multiple tumors
• Tumors at younger age

Wikipedia/Public Domain
Two-Hit Origin of Cancer
• Retinoblastoma: Sporadic form (non-familial)
• Requires two somatic “hits”
• Two mutations in same cell = rare
• Often a single tumor
• Occurs at a later age
Two-Hit Origin of Cancer
Other Examples

• HNPCC (Lynch syndrome)

• Hereditary nonpolyposis colorectal cancer
• Inherited colorectal cancer syndrome
• Germline mutation in DNA mismatch repair genes
• Second allele is inactivated by mutation
 AfraTafreeh.com for more

Two-Hit Origin of Cancer

Other Examples

• Familial Adenomatous Polyposis (FAP)

• Germline mutation of APC gene (tumor suppressor gene)
• Always (100%) progresses to colon cancer
• Treatment: Colon removal (colectomy)
Two-Hit Origin of Cancer
Other Examples

• Li-Fraumeni syndrome
• Syndrome of multiple malignancies at an early age
• Sarcoma, Breast, Leukemia, Adrenal Gland (SBLA) cancer
syndrome
• Germline mutation in tumor suppressor gene TP53
• Codes for tumor protein p53
• Delays cell cycle progression to allow for DNA repair
Mosaicism
• Gene differences in cells of same individual
• Mutations in cells → genetic changes
• Individual will be a mixture of cells
Mosaicism
• Germline mosaicism
• Can be passed to offspring
• Pure germline mosaicism difficult to detect
• Not present is blood/tissue samples used for analysis
• Offspring disease may appear sporadic
• Can present as recurrent “sporadic” disease in offspring
Mosaicism
• Somatic mosaicism
• Gene differences in tissues/organs
• 45X/46XX mosaic Turner syndrome (milder form)
• Rare forms of Down syndrome
McCune-Albright Syndrome
• Rare disorder
• Affects many endocrine organs
• Precocious puberty
• Menstruation may occur 2 years old
• Fibrous growth in bones
• Fractures, deformity
• Skin pigmentation
• Café-au-lait spots
• Irregular borders (“Coast of Maine”)
 Claudia E Dumitrescu, Michael T Collins

Alexrk2
McCune-Albright Syndrome
• Caused by sporadic mutation in development
• Not inherited
• Somatic mutation of GNAS gene
• Codes for alpha subunit of G3 protein
• Activates adenylyl cyclase
• Continued stimulation of cAMP signalling
McCune-Albright Syndrome
• “Postzygotic” mutation
• Occurs after fertilization
• Only some tissues/organs affected (mosaicism)
• Clinical phenotype varies depending on which tissues affected
• Germline occurrences of mutation are lethal
• Entire body effected
• Cells with mutation survive only if mixed with normal cells
Genetic Heterogeneity
• Same phenotype from different genes/mutations
• Different mutations of same allele → same disease
• Different gene (loci) mutations → same disease
• Multiple gene mutations often cause same disease
• Many diseases have multiple genotypes
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Allelic heterogeneity
• Allele = Alternative form of gene
• Allele 1 = mutation X
• Allele 2 = mutation Y
• Both X and Y cause same disease
• X and Y found at same chromosomal locus (position)
• Many alleles possess multiple mutant forms
• One disease = multiple genes = single location
Allelic heterogeneity
• Beta Thalassemia
• Mutation in beta globin gene
• Wide spectrum of disease depending on mutation
• βo = no function; β1 = some function
• Cystic Fibrosis
• Mutation in CFTR gene
• Over 1400 different mutations described
Locus heterogeneity
• Mutations in different loci cause same phenotype
• Example: Retinitis Pigmentosa
• Causes visual impairment
• Autosomal dominant, recessive, and X-linked forms
• Mutations at 43 different loci can lead to disease
• One disease = multiple genes = multiple locations
Genetic Mapping
Jason Ryan, MD, MPH
Genetic Recombination
• During meiosis chromosomes exchange segments
• Child inherits “patchwork” of parental chromosomes
• Never exact copy of parental chromosomes
Father Mother

Child 1 Child 2
Independent Assortment
• Suppose father has two alleles of F and M genes
• F and f
• M and m
• F and M found on different chromosomes
• Independent assortment
• Occurs if F and M genes can independently recombine
• 25% chance of each combination in gamete
Independent Assortment
Father
Chromosome 1 Chromosome 2
F f
M m

Gamete 1 2 3 4
F F f f
M m M m

25% 25% 25% 25%

Independent Assortment
• What if genes on same chromosome?
• If very far apart, crossover may occur in meiosis
• Result: Same combinations as separate chromosomes
Chromosome 1
F f

M m

Gamete 1 2 3 4
F F f f

M m m M
25% 25% 25% 25%
Independent Assortment
• What if genes on same chromosome?
• If very far apart, crossover may occur in meiosis
• Result: Same combinations as separate chromosomes
Chromosome 1
F f

M m

Parental

Gamete 1 2 3 4
F F f f

M m m M
25% 25% 25% 25%
Independent Assortment
• What if genes on same chromosome?
• If very far apart, crossover may occur in meiosis
• Result: Same combinations as separate chromosomes
Chromosome 1
F f

M m

Recombinant
Gamete 1 2 3 4
F F f f

M m m M
25% 25% 25% 25%
Independent Assortment
• If alleles close together: little crossover
• Low occurrence of recombination (Fm or fM)
Chromosome 1
F f

M m

Gamete 1 2 3 4
F F f f

M m m M
50% 0% 50% 0%
Recombination
Any break
here allows A a
A and B B b
to recombine
Any break
here allows
B and C
to recombine

C c

Two copies of
parental chromosome
Recombination Frequency
• Frequency of recombined genes (Fm or fM)
• Denoted by Greek letter theta (θ)
• Ranges from zero to 0.5
• Key point: recombination frequency α distance
• Close together: θ = 0
• Far apart: θ = 0.5
• Used for genetic mapping of genes
Genetic Mapping
Linkage Mapping

• Done by studying families

• Track frequency of genetic recombination
• Use frequency to determine relative gene location
Linkage
• Tendency of alleles to transmit together
• More linkage = less independent assortment
• Close together (θ = 0) = tightly linked
• Far apart (θ = 0.5) = unlinked
Linkage Disequilibrium
• Used to study genes that are very close together
• Recombination very rare
• Family studies impractical
• Done by studying large populations
Linkage Equilibrium A = 0.5
a = 0.5
B = 0.9
B = 0.1
• Gene A has two polymorphisms: A and a
• A found in 50% of individuals
• a in 50%
• Gene B has two polymorphisms: B and b
• B found in 90% of individuals
• b in 10%
Linkage Equilibrium A = 0.5
a = 0.5
B = 0.9
B = 0.1
• Population frequencies should be:
• AB = (0.5) x (0.9) = 0.45
• aB = (0.5) x (0.9) = 0.45
• Ab = (0.5) x (0.1) = 0.05
• ab = (0.5) x (0.1) = 0.05
• This is linkage equilibrium
Linkage Disequilibrium
• Population frequencies higher/lower than expected
• AB = 0.75 (higher than expected 0.45)
• This haplotype (AB) is in linkage disequilibrium
Linkage Disequilibrium
• Consider new gene mutation A
• Initially close to gene B
• AB transmitted together in a population
• Eventually A and B genes may recombine
• Depends on distance apart and size of population
• LD greatest when gene first enters population (i.e. mutation)
• Fades with successive generations (i.e. population size)
• Fades if distance between genes is greater
Linkage Disequilibrium
• Linkage disequilibrium affected by:
• Genetic distance
• Time alleles have been present in population
• Different populations: different degrees of linkage
disequilibrium
Meiosis
Jason Ryan, MD, MPH
Meiosis
• Diploid cells give rise to haploid cells (gametes)
• Unique to “germ cells”
• Spermatocytes
• Oocytes
• Two steps: Meiosis I and Meiosis II
 Meiosis I
• Diploid → Haploid (“reductive division”)
• Separates homologous chromosomes
Replicated
Chromosomes

Interphase
Cell Division
Haploid Cells (1n)

Diploid Cell (2n) Crossover/

Paired Chromosome Recombination
“Homologous”

Blue = Paternal Meiosis I

Red = Maternal
Meiosis II
• Chromatids separate
• Four daughter cells
 Meiosis
Blue = Paternal
Red = Maternal

Meiosis I

Meiosis II
Spermatogenesis
Begins at puberty
Oogenesis
• “Primary oocytes” form in utero
• Diploid cells
• Just beginning meiosis I
• Arrested in prophase of meiosis I until puberty
• At puberty
• A few primary oocytes complete meiosis 1 each cycle
• Some form polar bodies → degenerate
• Some form secondary oocytes (haploid)
• Meiosis II begins → arrests in metaphase
• Fertilization → completion of meiosis II
Aneuploidy
• Abnormal chromosome number
• Extra or missing chromosome
• Disomy = two copies of a chromosome (normal)
• Monosomy = one copy
• Trisomy = three copies
Meiotic Nondisjunction
• Failure of chromosome pairs to separate
• Most common mechanism of aneuploidy
• Can occur in meiosis I or II
Meiosis I Nondisjunction
Meiosis II Nondisjunction
Nondisjunction
Monosomy
• Fertilization of 1n (normal) and 0n gamete
• Usually not viable
• Turner syndrome (45,X)
• Only one sex chromosome
Trisomy
• Fertilization of 1n (normal) and 2n gametes
• Not compatible with life for most chromosomes
• Exceptions:
• Trisomy 21 = Down syndrome (95% cases due to NDJ)
• Trisomy 18 = Edward syndrome
• Trisomy 13 = Patau syndrome
Trisomy
• Maternal meiosis I NDJ errors are a common cause
• Meiosis I protracted in females
• Begins prenatally, completed at ovulation years later
• Advanced maternal age → ↑ risk trisomy
Trisomy
• Cause of NJD suggested by trisomy genotype
• Father = 21A and 21B; Mother = 21C and 21D
• Trisomy 21 ACD = Meiosis I nondisjunction in mother
• Trisomy 21 ACC = Meiosis II nondisjunction in mother
Uniparental Disomy
• Child has two copies of one parent’s chromosomes
• No copies of other parent’s chromosomes
• Father = 21A and 21B; Mother = 21C and 21D
• Child AA (isodisomy) = Meiosis II error (father)
• Child CD (heterodisomy) = Meiosis I error (mother)
Uniparental Disomy
• Child is euploid
• Normal number of chromosomes
• No aneuploidy
• Usually normal phenotype
• Can lead to phenotype of recessive disease
• Father = Aa (recessive gene for disease)
• Child = aa (two copies of a from father)
Robertsonian Translocation
• Fusion of long arms of two chromosomes
• Occurs in acrocentric chromosomes
• Chromosomes with centromere near end (13, 14, 21, 22)

14;21 Lost

14

21
Robertsonian Translocation
Robertsonian Translocation
• Carrier has only 45 chromosomes (one translocated)
• Loss of short arms → normal phenotype (no disease)
• 13-14 and 14-21 are most common
• Main clinical consequences
• Many monosomy and trisomy gametes
• Frequent spontaneous abortions
• Carrier may have child with Down syndrome (trisomy 21)
Karyotype
• Can be done in couples with recurrent fetal losses
• Used to diagnose chromosomal imbalances

Wikipedia/public domain
Hardy-Weinberg
Law
Jason Ryan, MD, MPH
Hardy-Weinberg Law
• Used in studies of populations
• Used to derive genotypes from allele frequencies
• Allelle: one of two or more alternative forms of the same gene
• Key point: Used to study single genes with multiple forms
• Not used for different genes at different loci/chromosomes
Hardy-Weinberg Law
Example

• Given gene has two possible alleles: A and a

• Allele A found in 40% of genes (p=0.40)
• Allele a found in 60% of genes (q=0.60)
• What is frequency of genotypes AA, Aa, and aa?

p+ q = 1
Hardy-Weinberg Law
p = 0.4
• Frequency of AA = = 0.16
p2 q = 0.6
• Frequency Aa = 2pq = 0.48
• Frequency aa = q2 = 0.36
1.00

p2 + 2pq + q2 = 1 p+ q = 1
Hardy-Weinberg Law p = 0.4
q = 0.6
p2 = 0.16
• p+q=1 2pq = 0.48
• p = 0.4 → 40% of GENES in population are A q2 = 0.36
• q = 0.6 → 60% of genes in population are a
• p2 + 2pq + q2 = 1
• p2 = 0.16 → 16% of INDIVIDUALS in population are AA
• 2pq = 0.48 → 48% of individuals in population are Aa
• q2 = 0.36 → 36% of individuals in population are aa
Hardy-Weinberg Law
Assumptions

• Large population
• Completely random mating
• No mutations
• No migration in/out of population
• No natural selection
Hardy-Weinberg Law
• If assumptions met, allele frequencies do not change
from one generation to the next
• “Hardy-Weinberg equilibrium”
 AfraTafreeh.com for more

Hardy-Weinberg Law
• Very useful in autosomal recessive diseases
• Disease (aa) frequency often known
• Example: 1/5000 individuals have disease
• Carrier (Aa) frequency often unknown
Hardy-Weinberg Law
• Disease X caused by recessive gene
• Disease X occurs in 1/4500 children
• q2 = 1/4500 = 0.0002
• q = SQRT (0.0002) = 0.015
• p+q=1
• p = 1 – 0.015 = 0.985
• Carrier frequency = 2pq
• 2 (0.985) (0.015) = 0.029 = 3%
• Very rare diseases p close to 1.0
• Carrier frequency ≈ 2q
Hardy-Weinberg Law
• Special case: X linked disease
• Two male genotypes (XdY or XY)
• Three female genotypes (XX or XdXd or XdX)
Hardy-Weinberg Law
X-linked Disease

• Consider males and females separately

• Among males
• p + q = 1 (all males are either Xd or X)
• p = frequency healthy males (XY)
• q = frequency diseased males (XdY)
• Males/females have same allele frequencies
• p males = p females
• q males = q females
Hardy-Weinberg Law
X-linked Disease

• Among females
• p2 = frequency healthy females (XX)
• 2pq = frequency carrier females (XdX)
• q2 = frequency diseased females (XdXd)
Pedigrees
Jason Ryan, MD, MPH
Pedigree
• Visual representation of a family
• Often used to study single gene disorders
• Gene passed down through generations
• Some members have disease
• Some members are carriers
• Several typical patterns
• Autosomal recessive genes
• Autosomal dominant genes
• X-linked genes
Pedigree Symbols
Unaffected Affected
Male Male

Unaffected Affected
Female Female

Marriage

Children
Autosomal Recessive
• Two alleles for a gene (i.e. A = normal; a = disease)
• Only homozygotes (aa) have disease
Autosomal Recessive

• If both parents are carriers (Aa)

• Child can have disease (aa)
• Only 1 in 4 chance of child with disease
• 2 of 4 children will be carriers (Aa)
• 1 of 4 children NOT carriers (AA)
Autosomal Recessive

• If both parents are carriers (Aa)

• 50% chance mother gives a to child
• 50% chance father gives a to child
• (0.5) x (0.5) = 0.25 chance child has disease
Autosomal Recessive

• Mother 1/50 chance of being carrier

• Father 1/100 chance of being carrier
• Chance BOTH carriers = (1/100) * (1/50) = 1/5,000
• Chance child affected = (1/4) * (1/5000) = 1/20,000
Autosomal Recessive
• Males and females affected equally
• Few family members with disease
• Often many generations without disease
• Increased risk: Consanguinity
• Parents are related
• Share common ancestors
Autosomal Recessive
• Cystic fibrosis
• Sickle cell anemia
• Hemochromatosis
• Wilson’s disease
• Many others
Autosomal Dominant
• Two alleles for a gene (i.e. A = disease; a = no disease)
• Heterozygotes(Aa) and homozygotes(AA) have disease
 AfraTafreeh.com for more

Autosomal Dominant
• Males and females affected equally
• One affected parent → 50% offspring with disease
• Male-to-male transmission occurs
Autosomal Dominant
• Familial hypercholesterolemia
• Huntington’s disease
• Marfan syndrome
• Hereditary spherocytosis
• Achondroplasia
• Many others
Incomplete Dominance
Semidominant

• Heterozygote phenotype different from homozygote

• Heterozygotes: less severe form of disease
• Homozygotes: more severe
Incomplete Dominance
Semidominant

• Classic example: Achondroplasia

• Autosomal dominant disorder of bone growth
• Heterozygotes (Dd): Dwarfism
• Homozygotes (dd): Fatal
• Familial hypercholesterolemia
• Heterozygotes: total cholesterol 350–550mg/dL
• Homozygotes: 650–1000mg/dL
X-linked Disorders
• Disease gene on X chromosome (Xd)
• Always affects males (XdY)
• Females (XdX) variable
• X-linked recessive = females usually NOT affected
• X-linked dominant = females can be affected
X-linked Recessive
• All males with disease gene have disease
• Most females with disease gene are carriers
X-linked Recessive
• No male-to-male transmission
• All fathers pass Y chromosome to sons
• Sons of heterozygous mothers: 50% affected
• Classic examples: Hemophilia A and B
X-linked Recessive
• Females very rarely develop disease
• Usually only occurs if homozygous for gene
• Father must have disease and mother must be carrier
• Females can develop disease with skewed lyonization
Lyonization
• Results in inactivated X chromosome in females
• One X chromosome undergoes “Lyonization”
• Condensed into heterochromatin with methylated DNA
• Creates a Barr body in female cells

Barr Body
Lyonization
• Random process
• Different inactive X chromosomes in different cells
• Occurs early in development (embryo <100 cells)
• Results in X mosaicism in females
• May cause symptoms in females X-recessive disorders
• “Skewed lyonization”
X-linked Dominant
• Occur in both sexes
• Every daughter of affected male has disease
• All daughters get an X chromosome from father
• Affected father MUST give disease X chromosome to daughter
X-linked Dominant
• Can mimic autosomal dominant pattern
• Key difference: No male-to-male transmission
• Fathers always pass Y chromosome to sons
X-linked Dominant
• More severe among males (absence of normal X)
• Classic example: Fragile X syndrome
• 2nd most common genetic cause intellectual disability (Down)
• More severe in males
• Often features of autism
• Long, narrow face, large ears and jaw

Peter Saxon/Wikipedia
Mitochondrial Genes
• Each mitochondria contains DNA (mtDNA)
• Code for mitochondrial proteins
• Organs most affected by gene mutations:
• CNS
• Skeletal muscle
• Rely heavily on aerobic metabolism
Mitochondrial Genes
• Heteroplasmy
• Multiple copies of mtDNA in each mitochondria
• Multiple mitochondria in each cell
• All normal or abnormal: Homoplasmy
• Mixture: Heteroplasmy
• Mutant gene expression highly variable
• Depends on amount of normal versus abnormal genes
• Also number of mutant mitochondria in each cell/tissue
Mitochondrial Disorders
• Mitochondrial DNA inherited from mother
• Sperm mitochondria eliminated from embryos
• Homoplasmic mothers → all children have mutation
• Heteroplasmic mothers → variable
Mitochondrial Myopathies
• Rare disorders
• Weakness (myopathy), confusion, lactic acidosis
• Wide range of clinical disease expression
• Classic hallmark: Red, ragged fibers
• Seen on muscle biopsy with special stains
• Caused by compensatory proliferation of mitochondria
• Accumulation of mitochondria in muscle fibers visualized
• Mitochondria appear bright red against blue background
Ragged Red Fibers

Nephron/Wikipedia
Polygenic Inheritance
• Many traits/diseases depend on multiple genes
• Height
• Heart disease
• Cancer
• “Run in families”
• Do not follow a classic Mendelian pattern
Polygenic Inheritance

Wikipedia
Multifactorial Inheritance
• Genes , lifestyle, environment → disease
• Seen in many diseases
• Diabetes
• Coronary artery disease
• Hypertension
Imprinting
Jason Ryan, MD, MPH
Imprinting
• Epigenetic phenomenon
• Alteration in gene expression
• Different expression in maternal/paternal genes
Imprinting
• Occurs during gametogenesis (before fertilization)
• Genes “marked” as being parental/maternal in origin
• Often by methylation of cytosine in DNA

Cytosine Methylcytosine
Imprinting
• After conception, imprinting controls gene expression
• “Imprinted genes”: Only one allele expressed
• Non-imprinted genes: Both alleles expressed
Imprinting Syndromes
• Prader-Willi and Angelman syndromes
• Both involve abnormal chromosome 15q11-q13
• “PWS/AS region”
• Paternal copy abnormal: Prader-Willi
• Maternal copy abnormal: Angelman
• Differences due to imprinting

Wikipedia/Public Domain
Imprinting Syndromes
• PWS genes
• Normally expressed on paternal chromosome 15
• NOT normally expressed on maternal copy
• UBE3A
• Normally expressed on maternal chromosome 15
• NOT normally expressed on paternal copy

F-15 M-15

PWS

UBE3A
Prader-Willi Syndrome
PWS

• Loss of function of paternal copy of PWS gene

F-15 M-15

PWS

UBE3A
Prader-Willi Syndrome
PWS

• ~75% cases from deletion of paternal gene

• Most cases due to sporadic mutation
• ~25% from maternal uniparental disomy
• Two copies of maternal gene inherited
• No copies of paternal gene
Prader-Willi Syndrome
PWS

• Most common “syndromic” cause of obesity

• Hypotonia
• Newborn feeding problems
• Poor suck reflex
• Delayed milestones
• Hyperphagia and obesity
• Begins in early childhood
• Intellectual disability (mild)
• Contrast with AS (severe)
• Hypogonadism
• Delayed puberty Fanny Cortés et al. Rev. méd.
Chile v.133 n.1 Santiago ene. 2005
Angelman Syndrome
• Abnormal maternal chromosome 15q11-q13
• Lack of expression of UBE3A

F-15 M-15

PWS

UBE3A
Angelman Syndrome
• Majority of cases caused by deletions
• Only about 3-5% from uniparental disomy
• Paternal disomy much less common than maternal
• Non-disjunction less common

F-15 M-15

PWS

UBE3A
Angelman Syndrome
• Frequent laughter/smiling
• “Happy puppet”
• Seizures (80% patients)
• Ataxia
• Severe intellectual disability
Down Syndrome
Jason Ryan, MD, MPH
Trisomy Disorders
• Down syndrome (21)
• Edward syndrome (18)
• Patau syndrome (13)
Down Syndrome
• Most common liveborn chromosome abnormality
• Most common form intellectual disability
• Other key features
• “Dysmorphic” features (face, hands, stature)
• Congenital malformations (heart, GI tract)
• Early Alzheimer’s disease
• Increased risk of malignancy
• Clinical phenotype variable
• Range of features from mild to severe
Dysmorphic Features
• “Flat” facial profile
• Flat nasal bridge
• Low-set small ears
• Short neck
• Brachycephaly
• Posterior skull is flat (not rounded)

Wikipedia/Public Domain
Dysmorphic Features
• Prominent epicanthal folds
• Skin of the upper eyelid
• Covers the inner corner of the eye
• Upslanting palpebral fissures
• Separation upper/lower eyelids
• Outer corners higher than inner

Wikipedia/Public Domain
Brushfield Spots
• White spots on iris

Erin Ryan/Wikipedia/Public Domain

Dysmorphic Features
• Short, broad hands
• Transverse palmar crease
• “Sandal gap”
• Space between 1st/2nd toes

Wikipedia/Public Domain
Other Physical Features
• Hypotonia
• Often identified at birth
• Short stature
Intellectual Disability
• Almost all patients affected
• Wide range of cognitive impairment
• Normal IQ ~100
• Mild Down syndrome: 50 to 70
• Severe Down syndrome: 20 to 35
Congenital Heart Disease
• Occurs in 50% of patients
• Most commonly endocardial cushion defects
• Involves atrioventricular septum
• Forms base of interatrial septum
• Forms upper interventricular septum
Congenital Heart Disease
• Common defects:
• Primum ASD
• VSD (holosystolic murmur)
Gastrointestinal Anomalies
• Occur in 5% of patients
• Duodenal atresia or stenosis (most common)
• Hirschsprung disease
• More common than in general population

Olek Remesz/Wikipedia
Alzheimer’s Disease
• Occurs early
• Average age of onset in 50s
• Amyloid Precursor Protein (APP)
• Found on chromosome 21
• Breakdown forms beta amyloid
• Amyloid plaques form in AD
Malignancy
• Lifetime risk of leukemia about 1 to 1.5%
• Often occurs in childhood
• Acute lymphoblastic leukemia
• Risk 10 to 20 times higher in DS
• Acute myeloid leukemia
• M7 subtype
• Megakaryoblastic leukemia

VashiDonsk /Wikipedia
Down Syndrome
Genetics

• Meiotic nondisjunction
• Two chromosomes from one parent; one from other
• Most common cause of Down syndrome (95% cases)
• Usually meiosis I (90% of cases)
• Extra chromosome from mother in 90% cases
• Increased risk with advanced maternal age
Down Syndrome
Genetics

• Rarely caused by Robertsonian translocation

• 2-3% of cases
• Chromosome 21 fused with another chromosome
• Most commonly chromosome 14 or 10
• Two copies 21 passed to fetus from one parent
• No increased risk with advanced maternal age
• High recurrence risk within families
Down Syndrome
Genetics

• Rarely (<2% cases) caused by mitotic error

• Error in mitosis of somatic cells after fertilization
• May result in somatic mosaicism
• Some cells trisomy 21, others normal
• Can lead to milder features of DS
• No association with advanced maternal age
Down Syndrome
Prenatal Screening

• Definitive test: Fetal karyotype

• Chorionic villus sampling (placental tissue)
• Amniocentesis (amniotic fluid)
Karyogram
Normal

Wikipedia/public domain
Karyogram
Trisomy

Wikipedia/public domain
Down Syndrome
Prenatal Screening

• Noninvasive tests
• Ultrasound
• Maternal serum testing
Down Syndrome
First Trimester Screening

• Fetal ultrasound
• Small, poorly-formed nasal bones
• Nuchal translucency
• Fluid under at back of neck

Wolfgang Moroder/Wikipedia
Down Syndrome
First Trimester Screening

• Maternal blood testing

• Pregnancy-associated plasma protein-A (PAPP-A)
• Glycoprotein produced by placenta
• Lower levels in pregnancies with fetal Down syndrome
• Free or total β-hCG
• Hormone produced by placenta
• Levels are higher in pregnancies with fetal Down syndrome
Down Syndrome
Second Trimester Screening

• α-fetoprotein and estriol (uE3)

• Reduced in pregnancies with fetal Down syndrome
• AFP: protein produced by yolk sac and liver
• NOTE: Increased AFP associated with neural tube defects
• β-hCG and inhibin A
• Increased in pregnancies with fetal Down syndrome
• Inhibin A synthesized by placenta
• “Quad screen”
Trisomy
Jason Ryan, MD, MPH
Trisomy Disorders
• Down syndrome (21)
• Edward syndrome (18)
• Patau syndrome (13)
Trisomy Disorders
• All associated with advanced maternal age
• All most commonly due to meiotic nondisjunction
• Common features
• Intellectual disability
• Physical deformities
• Congenital heart defects
Edward Syndrome
Trisomy 18

• 2nd most common trisomy in live births

• Severe intellectual disability
• Often female (3:1 female to male ratio)
Edward Syndrome
Trisomy 18

• Poor intrauterine growth – low birth weight

• Abnormally shaped head
• Very small
• Prominent back of skull (occiput)
• Low set ears
• Small jaw and mouth
• Clenched fists with overlapping fingers
• “Rockerbottom” (curved) feet
Bobjgalindo/Wikipedia
Edward Syndrome
Trisomy 18

• Congenital heart disease (50% babies)

• Ventricular septal defects
• Patent ductus arteriosus
• Gastrointestinal defects (75% cases)
• Meckel's diverticulum
• Malrotation
• Omphalocele
Edward Syndrome
Trisomy 18

• Many cases die in utero

• 50% affected infants die in first two weeks
• Only 5 to 10% survive first year
Edward Syndrome
Screening

• Physical features often diagnosed by fetal ultrasound

• Limb deformities, congenital heart defects
Edward Syndrome
Screening
Patau Syndrome
Trisomy 13

• Rare
• Severe intellectual disability
• Severe structural malformations
• Detected by fetal ultrasound >90% of cases
Patau Syndrome
Trisomy 13

• Eye abnormalities
• Microphthalmia: abnormally small eyes
• Anophthalmia: absence of one or both eyes
• Cleft lip and palate
Pre-axial
• Post-axial polydactyly
• Polydactyly: extra finger or toe
• Extra digit away from midline (ulnar)

Post-axial
Patau Syndrome
Trisomy 13

• Holoprosencephaly
• CNS malformation
• Failure of cleavage of prosencephalon
• Left/right hemispheres fail to separate
• May result in “alobar” brain
Patau Syndrome
Trisomy 13

• Congenital heart disease (80% cases)

• Ventricular septal defect (VSD)
• Patent ductus arteriosus (PDA)
• Atrial septal defect (ASD)
Patau Syndrome
Trisomy 13

• Most cases die in utero

• Median survival 7 days
• 91% die within 1st year of life
Patau Syndrome
Trisomy 13

• Usually diagnosed by fetal ultrasound

Muscular Dystrophy
Jason Ryan, MD, MPH
Muscular Dystrophies
• Group of genetic disorders
• More than 30 types
• All result from defects in genes for muscle function
• Main symptom: Progressive muscle weakness
Muscular Dystrophies
• Duchenne: Most common
• Becker: Milder variant of Duchenne
• Myotonic: Trinucleotide repeat disorder
Duchenne and Becker
• Both X-linked
• “X-linked muscular dystrophies”
• Both involve DMD gene and dystrophin protein
• Myotonic dystrophy
• Different gene
• Different protein
• Not X-linked (autosomal dominant)
DMD
Duchenne Muscular Dystrophy

• X-linked recessive disorder

• All male carriers affected
• 1/3 cases new mutations in fertilized egg (no parental carrier)
• 2/3 inherited from carrier mothers
DMD
Duchenne Muscular Dystrophy

• Abnormal DMD gene

• Massive gene (2300kb)
• 1.5% of the X chromosome
• Among largest known genes
• High mutation rate
• Codes for dystrophin
Dystrophin
• Maintains muscle membranes
• Connects intracellular actin to transmembrane proteins
• Binds α- and β-dystroglycan in membrane
• Connected to the extracellular matrix (laminin)

α Dystroglycan

Actin Dystrophin
Dystrophin
• Also found in cardiac and smooth muscle
• Also found in some brain neurons

α Dystroglycan

Actin Dystrophin
Dystrophin Gene Mutations
• Most mutations are deletions
• Duchenne: Frameshift mutation
• Deletion disrupts reading frame
• Early stop codon
• Truncated or absent dystrophin protein
• Becker: Non-frameshift mutation
• Some functioning protein
• Less severe disease
Dystrophin Gene Mutations
Normal Duchenne Becker
1 2 3 4 5 1 2 3 4 5 1 2 3 4 5
Dystrophin Gene Dystrophin Gene Dystrophin Gene

1 2
1 2 4 5
Frameshift Mutation Non-Frameshift Mutation

``

Normal Protein Absent or Abnormal Protein

Truncated
Protein
DMD
Duchenne Muscular Dystrophy

• Loss of dystrophin → myonecrosis

• Creatine kinase elevation
• Common in early stages
• Released from diseased muscle
• Other muscle enzymes also elevated
• Aldolase
• Aspartate transaminase (AST)
• Alanine transaminase (ALT)
DMD
Duchenne Muscular Dystrophy

• Affected boys normal first few years

• Weakness develops age 3-5
• Wheelchair usually by age 12
• Death usually by age 20
• Usually due to respiratory failure
• Sometimes heart failure
DMD
Duchenne Muscular Dystrophy

• Proximal muscles affected before distal limb muscles

• Lower limbs affected before upper extremities
• Affected children:
• Difficulty running, jumping, climbing stairs
• Use hands to push themselves up from chair (Gower's sign)
• Waddling gait
• Muscle replaced with fat/connective tissue
• Calf enlargement
• “Pseudohypertrophy”
DMD
Duchenne Muscular Dystrophy

• Cardiomyopathy
• Depressed LVEF
• Systolic heart failure
• Myocardial fibrosis
• Conduction abnormalities
• AV block
• Arrhythmias
DMD
Duchenne Muscular Dystrophy

• Muscle biopsy (rarely done in modern era)

• Degeneration of fibers
• Replacement of muscle by fat and connective tissue

Wikipedia/Public Domain
DMD
Duchenne Muscular Dystrophy
Normal
• Western blot Becker Duchenne
• Absence of dystrophin in Duchenne
• Altered dystrophin in Becker
DMD
Duchenne Muscular Dystrophy

• Diagnosis: Genetic testing

• Usually with variations of polymerase chain reaction
• Identify most common DMD gene abnormalities
BMD
Becker Muscular Dystrophy

• Also X-linked recessive disorder

• 90% cases inherited from carrier mothers
• Less severe disease
• More males pass gene on to female offspring
BMD
Becker Muscular Dystrophy

• Milder form of muscular dystrophy

• Late age of onset
• Some patients remain ambulatory
• Often survive into 30s
Trinucleotide
Repeat Disorders
Jason Ryan, MD, MPH
Trinucleotide Repeat Disorders
• Occur in genes with repeat trinucleotide units
• Example: CAGCAGCAGCAG
• Most disorders involve nervous system
• Key examples
• Fragile X syndrome
• Friedreich’s ataxia
• Huntington’s disease
• Myotonic dystrophy
Trinucleotide Repeat Disorders
• Wild-type (normal) allele
• Found in most individuals
• Polymorphic
• Variable number of repeats from person to person
• Overall number of repeats relatively low
• Disease (abnormal) allele
• Found in affected individuals
• Increased (“expanded”) number of repeats
• Beyond the normal range
• Likely due to slipped DNA mispairing
Trinucleotide Repeat Disorders
• Disease gene: “Unstable repeat expansions”
• Number of repeats may increase in offspring
• One generation to next: more repeats
• Key point: genetic abnormality changes over time
• Anticipation
• Disease severity worse in subsequent generations
• Earlier onset in subsequent generations
• Associated with more repeats in abnormal gene
Fragile X Syndrome
• X-linked dominant disorder
• Abnormal FMR1 gene
• Fragile X mental retardation 1 gene
• Found on long arm of X chromosome
• Most commonly an increase in CGG repeats
• Normal <55 repeats
• Full mutation: >200 repeats
• Leads to DNA methylation of FMR1 gene
• Gene silenced by methylation
Fragile X Syndrome
• More severe among males (absence of normal X)
• 2nd most common genetic cause intellectual disability
• Down syndrome most common
• Anxiety, ADHD
• Often has features of autism
• Long, narrow face, large ears and jaw
• Macroorchidism (large testicles)
• Classic feature

Peter Saxon/Wikipedia
Friedreich’s Ataxia
• Hereditary ataxia disorder
• Autosomal recessive
• Mutation of frataxin gene on chromosome 9
• Needed for normal mitochondrial function
• Increased number GAA repeats
• Leads to decreased frataxin levels
• Frataxin: mitochondrial protein
• High levels in brain, heart, and pancreas
• Abnormal frataxin → mitochondrial dysfunction
Friedreich’s Ataxia
• Begins in adolescence with progressive symptoms
• Cerebellar and spinal cord degeneration
• Loss of balance
• Weakness
• Associated with hypertrophic cardiomyopathy
• Physical deformities:
• Kyphoscoliosis
• Foot abnormalities
Huntington’s Disease
• Movement (CNS) disorder
• Autosomal dominant
• Mutation in the HTT gene
• Codes for protein huntingtin
• Mutation → Increased CAG repeat
• CAG codes for glutamine
• “Polyglutamine disorders:” Huntington’s, other rare CNS diseases
• Normal 10-35 repeats
• Huntington’s 36 to 120 repeats
 AfraTafreeh.com for more

Huntington’s Disease
• Degeneration in basal ganglia (striatum)
• Leads to chorea, dementia
• Onset of symptoms 30s-40s
• Death after 10-20 years
Myotonic Dystrophy
• Muscle disorder
• Autosomal dominant
Myotonic Dystrophy
• Type I (most common)
• Abnormal DMPK gene (chromosome 19)
• Dystrophia myotonica protein kinase
• CTG expansion
• Codes for myotonic dystrophy protein kinase
• Abnormal gene transcribed to mRNA but not translated
• Type 2: abnormal CNBP gene
• Rare type
• Usually less severe than type I
• CCTG (tetranucleotide) repeat (not a trinucleotide disorder)
Myotonic Dystrophy
• Most common MD that begins in adulthood
• Often starts in 20s or 30s
• Progressive muscle wasting and weakness
• Prolonged muscle contractions (myotonia)
• Unable to relax muscles after use
• Cannot release grip
• Locking of jaw
Myotonic Dystrophy
• Facial muscles often affected
• Characteristic facial appearance
• Caused by muscle weakness and wasting
• Long and narrow face
• Hollowed cheeks

Herbert L. Fred, MD, Hendrik A. van Dijk

Myotonic Dystrophy
• Multisystem disorder
• Many non-muscle features
• Hypogonadism
• Cataracts
• Cardiac arrhythmia
• Frontal balding

Herbert L. Fred, MD, Hendrik A. van Dijk

Myotonic Dystrophy
Endocrine Involvement

• Primary hypogonadism
• Low testosterone
• Elevated FSH
• Oligospermia
• Infertility
• Testicular atrophy
• Insulin resistance
Myotonic Dystrophy
Cardiac Involvement

• Arrhythmias and conduction disease common

• First degree atrioventricular block (20 to 30%)
• Bundle branch block (10 to 15%)
• Atrial flutter and atrial fibrillation
Myotonic Dystrophy
Cataracts

• High prevalence
• Occur at younger age
• Regular slit-lamp exams for screening

Image courtesy of Rakesh Ahuja, MD

Myotonic Dystrophy
Lung Involvement

• Respiratory complications common

• Weakness/myotonia of respiratory muscles
• Decreased vital capacity
• Alveolar hypoventilation
• Respiratory failure may occur
Myotonic Dystrophy
Intellectual Disability

• Common in myotonic dystrophy

• Severity worse with younger age of onset
• Childhood disease → severe cognitive impairment
Deletion
Syndromes
Jason Ryan, MD, MPH
Deletion Syndromes
• Partial deletion of chromosome
• Long or short arm
• Portion of long/short arm
Deletion Syndromes
• Usually an error in crossover in meiosis
• Unbalanced exchange of genes
• One chromosome with duplication; other with deletion

Meiosis
Replication/Crossover

Interphase
Deletion Syndromes
• Most cases sporadic (congenital)
• Key syndromes:
• Cri-du-chat
• Williams
• Thymic aplasia
Cri-du-chat Syndrome
• Deletion of part of short arm (p) of chromosome 5
• “5p- syndrome”

Wikipedia/Public Domain
Cri-du-chat Syndrome
• Severe intellectual disability
• Cognitive, speech, motor delays
• Infants cry like a cat
• Classically described as “mewing”: high-pitched cry
• Occurs soon after birth then resolves
Cri-du-chat Syndrome
• Microcephaly (small head)
• Characteristic facial features
• Widely set eyes (hypertelorism)
• Low-set ears
• Small jaw
• Rounded face

Paola Cerruti Mainardi.

Cri-du-chat Syndrome
• Congenital heart defects
• Ventricular septal defect (VSD)
• Patent ductus arteriosus (PDA)
• Tetralogy of Fallot (TOF)
• Others
Williams Syndrome
Williams-Beuren syndrome

• Partial deletion on long arm of chromosome 7

• Deleted portion includes gene for elastin
• Elastic protein in connective tissue
• Results in elastin “haploinsufficency”

Wikipedia/Public Domain
Williams Syndrome
Williams-Beuren syndrome

• Classically an “elfin” facial appearance

• Small nose
• Small chin
• Wide mouth
• Long philtrum (upper lip length)
Williams Syndrome
Williams-Beuren syndrome

• Intellectual disability
• Delayed developmental milestones
• Well-developed verbal skills
• Extremely friendly with strangers
• Unafraid of strangers
• Great interest in talking with adults
Williams Syndrome
Vascular Manifestations

• Supravalvular aortic stenosis

• Constriction of ascending aorta above aortic valve
• High prevalance among children with WS
• Pulmonary artery stenosis
• Renal artery stenosis
Williams Syndrome
Hypercalcemia

• Higher calcium than general pediatric population

• Evidence of ↑ vitamin D levels and ↑ vitamin D sensitivity
• Usually mild to moderate
• Does not usually cause symptoms
• May lead to constipation
Thymic Aplasia
DiGeorge Syndrome

• Many different names

• 22q11 deletion syndrome
• Velocardiofacial syndrome
• Shprintzen syndrome Wikipedia/Public Domain

• Conotruncal anomaly face syndrome

• Partial deletion of long arm (q) chromosome 22
• Immune deficiency
• Hypocalcemia
• Congenital heart defects
Klinefelter and
Turner Syndromes
Jason Ryan, MD, MPH
Klinefelter and Turner
• Sex chromosome aneuploidy disorders
• Klinefelter: Male with extra X (XXY)
• Turner: Female with missing X (XO)
Karyotype
• Diagnosis of both syndromes
• Often multiple cells to look for mosaicism

Wikipedia/public domain
Klinefelter Syndrome
• Usually 47 XXY (~80% of cases)
• Usually meiotic nondisjunction of either parent
• Rarely 48,XXXY (more severe)
• Or 46,XY/47,XXY mosaicism (less severe)
• Nondisjunction during mitosis after conception
Klinefelter Syndrome

Wikipedia/Public Domian
Klinefelter Syndrome
• Male with primary hypogonadism
• Small, firm testes
• Atrophy of seminiferous tubules
• Low testosterone
• Ratio of estrogens:testosterone determines severity
Klinefelter Syndrome
• Increased gonadotropins
• Loss of inhibin B → ↑FSH
• ↓ testosterone → ↑ LH
FSH and LH
-

- -

LH FSH

Leydig Sertoli
Cells Cells
Testosterone Inhibin
Testes
Klinefelter Syndrome
Low Testosterone Features

• Delayed puberty
• Reduced facial/body hair
• Female pubic hair pattern
• Gynecomastia
• Infertility/reduced sperm count

Wikipedia
Klinefelter Syndrome
Genital Abnormalities

• Cryptorchidism (undescended testes)

• Hypospadia
• Micropenis

Wikipedia/Public Domian
Klinefelter Syndrome
Physical Appearance

• Long legs and arms

• Extra copy of SHOX gene (X-chromosome)
• Important for long bone growth
• “Eunuchoid body shape”

Malcolm Gin/Wikipedia
Klinefelter Syndrome
Cognitive Findings

• Learning disabilities
• Delayed speech/language development
• Quiet personality
• Quiet, unassertive
Barr Body
• Inactivated X chromosome
• Normally found in cells of females (XX)
• One X chromosome undergoes “Lyonization”
• Condensed into heterochromatin with methylated DNA
• Seen in cells of patients with Klinefelter’s
• Not normally seen in males

Barr Body
Turner Syndrome
• Often 45, XO (45% cases)
• Most cases caused by sperm lacking X chromosome
• Mosaic Turner syndrome (often milder)
• 45,X/46,XX
• Mitotic nondisjunction during post-zygotic cell division
Turner Syndrome
General Features

• Female with short stature

• Loss of one copy of SHOX gene on X-chromosome
• Growth hormone treatment: given in childhood
• Broad chest (shield chest)
• Widely spaced nipples
Turner Syndrome
General Features

• Lymphatic obstruction in fetal development

• Webbed neck
• Swollen hands/feet (especially at birth)

Wikipedia

Johannes Nielsen/Wikipedia
Cystic Hygroma
• Congenital lymphatic defect
• Large collection of lymph/cysts
• Often found in head/neck
• Often seen in utero on US

Vardhan Kothapalli
Turner Syndrome
Ovarian Function

• Hallmark: female with primary hypogonadism

• Loss of ovarian function
• “Gonadal dysgenesis”
• May have “streak ovaries”
• Streaks of fibrous tissue seen in expected location of ovaries
• No or very few follicles

Wikipedia/Public Domain
Turner Syndrome
Ovarian Function

• Decreased inhibin B
• Decreased estrogens
• Increased LH/FSH
• Levels can vary during childhood
• Sometimes within normal range
• Often abnormal in early childhood (<5) and pre-puberty (>10)
Turner Syndrome
Ovarian Function

• Delayed puberty
• Absence of breast development
• Failure to menstruate
• Can be treated with estrogen to induce puberty
• Primary amenorrhea (most common cause)
• “Menopause before menarche”
• Some girls menstruate with menopause in teens/20s
• More common in cases with mosaicism
Turner Syndrome
Ovarian Function

• Most women infertile

• Some can become pregnant with donated oocytes

Øyvind Holmstad/Wikipedia
Turner Syndrome
Cardiovascular

• ~30% of children born with bicuspid aortic valve

• 5-10% of children have coarctation of the aorta
• High blood pressure may occur in in childhood
• Sometimes due to coarctiaton or renal disease
• Often primary

Patrick J. Lynch, medical illustrator

Turner Syndrome
Renal Manifestations

• Kidney malformations affect ~ 1/3 patients

• Abnormal collecting ducts
• Often a horseshoe kidney

Wikipedia/Public Domain
Turner Syndrome
Osteoporosis

• High incidence of osteoporosis

• Low circulating estrogens
• Estrogen treatments often prescribed

Open Stax College

Turner Syndrome
Endocrine

• Type II Diabetes
• Turner syndrome 2x risk of general population
• Thyroid disease
• ~ 1/3 have a thyroid disorder
• Usually hypothyroidism from Hashimoto's thyroiditis