Genetics for the Dermatological Practice
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Transcript Genetics for the Dermatological Practice
The Genetics of
Ichthyosis
Sherri J. Bale, PhD, FACMG
Clinical Director, GeneDx
FIRST Family Conference
Orlando, FL - June 27, 2010
What we’re going to talk
about
A primer on how ichthyosis
genetically occurs, the chances of
passing it along and what genetic
tests are available and how they are
administered
How many different
ichthyoses are there?
> 20 disorders fit the definition of
ichthyosis
> 10 other related disorders with more
localized scaling/hyperkeratosis
How are ichthyoses
classified?
Clinical features
Non-syndromic ichthyoses
Syndromic ichthyoses
Related disorders
Inheritance pattern
Gene defects
Etiology
Enzyme deficiencies
Structural protein defects
Regulatory protein defects
Other
Genetics 101
Chromosomes – structures inside the nucleus
(command center) of the cell.
On the chromosomes, we carry genes
Genes are made up of a chemical called DNA
Chromosomes, and thus genes, are passed from
parent to child following “rules of inheritance”
[Mendel’s laws]
Genetics 101
Human Chromosomes
Types of Inheritance
X-linked
Recessive
Dominant (rare)
Autosomal
Recessive
Dominant
Steroid-Sulfatase
Deficiency
X-linked recessive
Incidence 1:6000 males
Primary features
Onset between 1 and 3 weeks of age
Dark scale, tightly adherent
Most prominent on flexure surfaces
(aka “Dirty neck” ichthyosis)
Asymptomatic corneal opacities (10-50%)
Cryptorchism (12-25%), increased risk of
testicular cancer
The disease does not improve with age
Steroid-Sulfatase Deficiency
• Diagnostic
• plasma cholesterol sulfate levels
• Assay to directly measure activity of steroid
sulfatase is rarely done
• Decreased placental sulfatase causes delayed
onset/progression of labor in affected male
fetuses
• Genetics
• STS gene on chromosome Xp22.32
• 90% of affected males have large intragenic
deletions, or contiguous gene deletions
Autosomal Dominant Ichthyoses
Ichthyosis
Gene
Epidermolytic hyperkeratosis
Epidermolysis Bullosa Siemens
Pachyonychia congenita I,II
KRT1; KRT10
KRT2e
KRT6a,b,
KRT16,
KRT17
KRT9
many genes
GJB2 (GJB6)
GJB3, GJB4
Epidermolytic PPK
Non-epidermolytic PPK
Keratitis-Ichth-Deafness (KID)
Erythrokeratoderma variabilis
Epidermolytic
Hyperkeratosis
Autosomal Dominant
(1/2 the cases are due to new mutations)
Incidence 1:200,000-1:300,000
Primary Features
Neonatal blistering, erosions and denuded skin
Progressive Hyperkeratosis, esp. of the flexures
Variable palm/sole involvement
Epidermolytic Hyperkeratosis
• Genetics
• Due to mutation in keratin-1 (KRT1) or keratin10 (KRT10) gene
• >40 different mutations, most are missense
changes
• >80% cluster at hot spots at the beginning or
end of the gene
•In 30% of all EHK patients mutations occur at
Arg156 in KRT10
How can you say its autosomal
dominant? I’m the only person in my
family with this disorder!
?
Germline Mutation
Ovaries
Testes
Sperm
Mutation
Egg cell
Mutation
Germline Mutation
Conception
Mutation
Disease
I have a been diagnosed with an
‘Epidermal Nevus’. What is it and how
does it come about?
?
‘Epidermal Nevus’
= Skin Mosaicism for Mutation
Gametes Zygote
Mutation
Post-zygotic
mutation
Two cell lineages
Cell Migration
Mosaic
Mosaicism
• Due to DNA Mutation that occurs during mitosis of a
single cell at early stages of fetal development
“post-zygotic mutation”
• All descendent cells will carry the mutation, other cells are
normal
• Gives rise to two (or more) genetically distinct cell lines
derived from a single zygote
• Mosaicism can affect somatic and/or germline tissues
• Generally only parts of the organism are affected
I have an ‘Epidermal Nevus’. Should I
be worried about my children?
?
• If germline is affected,
mutation can be
transmitted to the
offspring resulting in
full-blown disease
What is my risk of having an affected
child?
?
• Greater than the
population risk for a
new mutation
• Depends on what
percentage of germ cells
harbor mutation
• Rule of thumb:
• Small nevus-small risk
• Large nevus on both
sides of the body-high risk
Autosomal Recessive
Ichthyoses
Ichthyosis
Harlequin ichthyosis
Lamellar ichthyosis
CIE
Sjögren-Larsson syndrome
Neutral lipid storage disease
Netherton syndrome
Refsum disease
Trichothiodystrophy+Ichthyosis
Gene
ABCA12
TGM1, ABCA12
ALOXE3; ALOX12B
Ichthyin
Cytochrome P450
ALDH3A2
CGI-58 (ABHD5)
SPINK5
PAHX, PEX7
ERCC2; ERCC3
Lamellar Ichthyosis
Autosomal Recessive
Incidence 1:200,000
Primary
Features:
Collodion
baby phenotype
Plate-like, large, dark scale
Ectropion, Eclabium
Scarring alopecia
Lamellar Ichthyosis
Due to mutation in the TGM1 gene in
the vast majority of cases, coding for
Transglutaminase-1
A few common mutations exist (the
“German” splice-site mutation) and
R141 and R142 in exon 3.
Few
families with mutation in ABCA12,
Ichthyin, and cytochrome P450 genes
Congenital Ichthyosiform
Erythroderma
Autosomal Recessive
Incidence 1:200,000-300,000
Primary features
Collodion
baby presentation
Bright red (erythrodermic) skin
Fine, white scale
Congenital Ichthyosiform
Erythroderma
Due to mutation in many different genes, 5 of
which are known
ALOX12B and ALOXE3 (in about ~10%)
Ichthyin (in about ~10%)
A new cytochrome P450 gene
Enzymes encoded by these genes are
involved in lipid metabolism
Operate in common membrane arachidonic
acid pathway (lipoxygenase)
Harlequin Ichthyosis
Autosomal recessive
Mutation in ABCA12 gene
(ATP-binding cassette transporter protein)
Primary features:
Thick, armor-like plates of scale that fissure and
crack
Eclabium and Ectropion
Poor prognosis, although survivors have a
congenital ichthyosiform erythroderma phenotype
So what is a mutation,
anyway?
How do we detect a mutation?
• Chromosomes
• DNA
• Metabolic
Karyotype
arrayCGH
FISH
Sequence analysis
Mutation scanning
Targeted mutation
analysis
Analytes
Enzyme assay
What do we need for mutation
testing?
Material required
for testing:
Buccal swabs
Blood
Skin punch biopsy
How is DNA Sequencing Done?
Gly278Arg
What is the use of this
mutation information ?
Identification of disease-causing
mutation(s) allows answers to the
questions:
What do I have?
Why do I have it or how did it happen?
What is the chance it will happen again?
What’s wrong with my skin and how best
can it be treated?