The Genetics of The Genetics of
IchthyosisIchthyosis
Sherri J. Bale, PhD, FACMGSherri J. Bale, PhD, FACMGClinical Director, GeneDxClinical Director, GeneDx
FIRST Family ConferenceFIRST Family Conference
Orlando, FL - June 27, 2010Orlando, 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 How many different ichthyoses are there?ichthyoses are there?
> 20 disorders fit the definition of > 20 disorders fit the definition of ichthyosisichthyosis
> 10 other related disorders with > 10 other related disorders with more localized scaling/hyperkeratosismore localized scaling/hyperkeratosis
How are ichthyoses How are ichthyoses classified?classified?
Clinical featuresClinical features Non-syndromic ichthyosesNon-syndromic ichthyoses Syndromic ichthyosesSyndromic ichthyoses Related disordersRelated disorders
Inheritance patternInheritance pattern
Gene defectsGene defects
EtiologyEtiology Enzyme deficienciesEnzyme deficiencies Structural protein defectsStructural protein defects Regulatory protein defectsRegulatory protein defects OtherOther
Genetics 101Genetics 101 Chromosomes – structures inside the Chromosomes – structures inside the
nucleus (command center) of the cell.nucleus (command center) of the cell.
On the chromosomes, we carry genesOn the chromosomes, we carry genes
Genes are made up of a chemical called Genes are made up of a chemical called
DNADNA
Chromosomes, and thus genes, are passed Chromosomes, and thus genes, are passed
from parent to child following “rules of from parent to child following “rules of
inheritance” [Mendel’s lawsinheritance” [Mendel’s laws]]
Genetics 101Genetics 101
Human Chromosomes
Types of InheritanceTypes of Inheritance X-linkedX-linked
RecessiveRecessive Dominant (rare)Dominant (rare)
AutosomalAutosomal RecessiveRecessive DominantDominant
Steroid-Sulfatase Steroid-Sulfatase DeficiencyDeficiency
X-linked recessiveX-linked recessive Incidence 1:6000 malesIncidence 1:6000 males
Primary featuresPrimary features Onset between 1 and 3 weeks of ageOnset between 1 and 3 weeks of age Dark scale, tightly adherentDark scale, tightly adherent Most prominent on flexure surfacesMost prominent on flexure surfaces
(aka “Dirty neck” ichthyosis)(aka “Dirty neck” ichthyosis) Asymptomatic corneal opacities (10-50%)Asymptomatic corneal opacities (10-50%) Cryptorchism (12-25%), increased risk of Cryptorchism (12-25%), increased risk of
testicular cancertesticular cancer The disease does not improve with ageThe disease does not improve with age
• 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
Steroid-Sulfatase DeficiencySteroid-Sulfatase DeficiencySteroid-Sulfatase DeficiencySteroid-Sulfatase Deficiency
Ichthyosis Gene Epidermolytic hyperkeratosis KRT1; KRT10 Epidermolysis Bullosa Siemens KRT2ePachyonychia congenita I,II KRT6a,b,
KRT16, KRT17
Epidermolytic PPK KRT9Non-epidermolytic PPK many genesKeratitis-Ichth-Deafness (KID) GJB2 (GJB6)Erythrokeratoderma variabilis GJB3, GJB4
Autosomal Dominant IchthyosesAutosomal Dominant IchthyosesAutosomal Dominant IchthyosesAutosomal Dominant Ichthyoses
Epidermolytic Epidermolytic HyperkeratosisHyperkeratosis
Autosomal DominantAutosomal Dominant (1/2 the cases are due to (1/2 the cases are due to newnew mutations) mutations)
Incidence 1:200,000-1:300,000Incidence 1:200,000-1:300,000 Primary FeaturesPrimary Features
Neonatal blistering, erosions and denuded skinNeonatal blistering, erosions and denuded skin Progressive Hyperkeratosis, esp. of the flexuresProgressive Hyperkeratosis, esp. of the flexures Variable palm/sole involvementVariable palm/sole involvement
• Genetics•Due to mutation in keratin-1 (KRT1) or keratin-10 (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
Epidermolytic HyperkeratosisEpidermolytic HyperkeratosisEpidermolytic HyperkeratosisEpidermolytic Hyperkeratosis
?
How can you say its autosomal How can you say its autosomal dominant? I’m the only person in my dominant? I’m the only person in my
family with this disorder!family with this disorder!
How can you say its autosomal How can you say its autosomal dominant? I’m the only person in my dominant? I’m the only person in my
family with this disorder!family with this disorder!
Germline Mutation
Mutation
Ovaries
Testes
Sperm Egg cell
Mutation
Germline Mutation
Mutation
Conception
Disease
?
I have a been diagnosed with an I have a been diagnosed with an ‘Epidermal Nevus’. What is it and how ‘Epidermal Nevus’. What is it and how
does it come about?does it come about?
I have a been diagnosed with an I have a been diagnosed with an ‘Epidermal Nevus’. What is it and how ‘Epidermal Nevus’. What is it and how
does it come about?does it come about?
GametesZygote
Two cell lineages
Cell Migration
Mosaic
Post-zygoticmutation
Mutation
‘Epidermal Nevus’ = Skin Mosaicism for Mutation
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 I have an ‘Epidermal Nevus’. Should I be worried about my children?be worried about my children?
I have an ‘Epidermal Nevus’. Should I I have an ‘Epidermal Nevus’. Should I be worried about my children?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 What is my risk of having an affected child?child?
What is my risk of having an affected What is my risk of having an affected child?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
?
Ichthyosis Gene
Harlequin ichthyosis ABCA12Lamellar ichthyosis TGM1, ABCA12CIE ALOXE3; ALOX12B
IchthyinCytochrome P450
Sjögren-Larsson syndrome ALDH3A2Neutral lipid storage disease CGI-58
(ABHD5)Netherton syndrome SPINK5Refsum disease PAHX, PEX7Trichothiodystrophy+Ichthyosis ERCC2; ERCC3
Autosomal Recessive Autosomal Recessive IchthyosesIchthyoses
Autosomal Recessive Autosomal Recessive IchthyosesIchthyoses
Lamellar IchthyosisLamellar Ichthyosis Autosomal RecessiveAutosomal Recessive Incidence 1:200,000Incidence 1:200,000
Primary Features:Primary Features: Collodion baby phenotypeCollodion baby phenotype Plate-like, large, dark scalePlate-like, large, dark scale Ectropion, EclabiumEctropion, Eclabium Scarring alopeciaScarring alopecia
Lamellar IchthyosisLamellar Ichthyosis Due to mutation in the TGM1 gene Due to mutation in the TGM1 gene
in the vast majority of cases, coding in the vast majority of cases, coding for Transglutaminase-1for Transglutaminase-1
A few common mutations exist (the A few common mutations exist (the “German” splice-site mutation) and “German” splice-site mutation) and R141 and R142 in exon 3.R141 and R142 in exon 3.
Few families with mutation in Few families with mutation in ABCA12, Ichthyin, and cytochrome ABCA12, Ichthyin, and cytochrome P450 genesP450 genes
Congenital Ichthyosiform Congenital Ichthyosiform ErythrodermaErythroderma
Autosomal RecessiveAutosomal Recessive Incidence 1:200,000-300,000Incidence 1:200,000-300,000 Primary featuresPrimary features
Collodion baby presentationCollodion baby presentation Bright red (erythrodermic) skinBright red (erythrodermic) skin Fine, white scaleFine, white scale
Due to mutation in many different Due to mutation in many different genes, 5 of which are knowngenes, 5 of which are known ALOX12B and ALOXE3 (in about ~10%)ALOX12B and ALOXE3 (in about ~10%) Ichthyin (in about ~10%)Ichthyin (in about ~10%) A new cytochrome P450 geneA new cytochrome P450 gene
Enzymes encoded by these genesEnzymes encoded by these genes are are involved in lipid metabolisminvolved in lipid metabolism
Operate in common membrane Operate in common membrane arachidonic acid pathway arachidonic acid pathway (lipoxygenase)(lipoxygenase)
Congenital Ichthyosiform Congenital Ichthyosiform ErythrodermaErythroderma
Congenital Ichthyosiform Congenital Ichthyosiform ErythrodermaErythroderma
Harlequin IchthyosisHarlequin Ichthyosis Autosomal recessiveAutosomal recessive Mutation in ABCA12 geneMutation in ABCA12 gene
(ATP-binding cassette transporter protein)(ATP-binding cassette transporter protein) Primary features:Primary features:
Thick, armor-like plates of scale that fissure Thick, armor-like plates of scale that fissure and crackand crack
Eclabium and EctropionEclabium and Ectropion Poor prognosis, although survivors have a Poor prognosis, although survivors have a
congenital ichthyosiform erythroderma congenital ichthyosiform erythroderma phenotypephenotype
So what is a mutation, So what is a mutation, anyway?anyway?
How do we detect a mutation?
• Chromosomes
• DNA
• Metabolic
KaryotypeKaryotype arrayCGHarrayCGH FISHFISH
Sequence analysisSequence analysis Mutation scanningMutation scanning Targeted mutation Targeted mutation
analysisanalysis
AnalytesAnalytes Enzyme assayEnzyme assay
What do we need for mutation What do we need for mutation testing?testing?
Material Material required for required for testing:testing: Buccal swabsBuccal swabs
BloodBlood
Skin punch Skin punch biopsybiopsy
How is DNA Sequencing Done?How is DNA Sequencing Done?Gly278Arg
What is the use of this What is the use of this mutation information ?mutation information ?
Identification of disease-causing Identification of disease-causing mutation(s) allows answers to the mutation(s) allows answers to the questions: questions:
What do I have?What do I have? Why do I have it or how did it happen?Why do I have it or how did it happen? What is the chance it will happen What is the chance it will happen
again?again? What’s wrong with my skin and how What’s wrong with my skin and how
best can it be treated?best can it be treated?