The Genetics of Ichthyosis

The Genetics of Ichthyosis

Sherri J. Bale, Ph.D., FACMGClinical Director, GeneDx

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?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?

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 101Genetics 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 101Genetics 101

Human Chromosomes

Types of Inheritance

Types of Inheritance

• X-linked• Recessive• Dominant (rare)

• Autosomal• Recessive• Dominant

Steroid-Sulfatase Deficiency

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

• 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 Deficiency

Steroid-Sulfatase Deficiency

Ichthyosis Gene Epidermolytic hyperkeratosis KRT1; KRT10 Epidermolysis Bullosa Siemens KRT2ePachyonychia congenita I,II KRT6a,b, KRT16, KRT17Epidermolytic PPK KRT9Non-epidermolytic PPK many genesKeratitis-Ichth-Deafness (KID) GJB2 (GJB6)Erythrokeratoderma variabilis GJB3, GJB4

Autosomal Dominant Ichthyoses

Autosomal Dominant Ichthyoses

Epidermolytic HyperkeratosisEpidermolytic

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

• 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

Hyperkeratosis

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How can you say its autosomal dominant? I’m the only person in my family with this disorder!

How can you say its autosomal dominant? I’m the only person in my family with this disorder!

Germline Mutation

Mutation

Ovaries

Testes

Sperm Egg cell

Mutation

Germline Mutation

Mutation

Conception

Disease

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I have a been diagnosed with an ‘Epidermal Nevus’. What is it

and how does it come about?

I have a been diagnosed with an ‘Epidermal Nevus’. What is it

and how does it come about?

Gametes Zygote

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 be worried about my

children?

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

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What is my risk of having an affected child?

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

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Ichthyosis Gene

Harlequin ichthyosis ABCA12 Lamellar ichthyosis TGM1, ABCA12 CIE ALOXE3; ALOX12B Ichthyin, Cytochrome P450 Sjögren-Larsson syndrome ALDH3A2

Neutral lipid storage disease CGI-58 (ABHD5)Netherton syndrome SPINK5Refsum disease PAHX, PEX7Trichothiodystrophy+Ichthyosis ERCC2; ERCC3

Autosomal Recessive Ichthyoses

Autosomal Recessive Ichthyoses

Lamellar IchthyosisLamellar

Ichthyosis• Autosomal Recessive• Incidence 1:200,000

• Primary Features:• Collodion baby phenotype• Plate-like, large, dark scale• Ectropion, Eclabium• Scarring alopecia

Lamellar IchthyosisLamellar 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

Congenital Ichthyosiform Erythroderma

• Autosomal Recessive• Incidence 1:200,000-300,000• Primary features

• Collodion baby presentation• Bright red (erythrodermic) skin• Fine, white scale

• 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)

Congenital Ichthyosiform Erythroderma

Congenital Ichthyosiform Erythroderma

Harlequin IchthyosisHarlequin 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?

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?

What do we need for mutation testing?

• Material required for testing:• Buccal swabs

• Blood

• Skin punch biopsy

How is DNA Sequencing Done?How is DNA Sequencing Done?Gly278Arg

What is the use of this mutation information ?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?