1. The Genetics of Ichthyosis
Sherri J. Bale, Ph.D., FACMG
Clinical Director, GeneDx

2. 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

3. How many different ichthyoses are there?
> 20 disorders fit the definition of ichthyosis
> 10 other related disorders with more localized scaling/hyperkeratosis

4. 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

5. 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]

6. Genetics 101

7. Human Chromosomes

8. Types of Inheritance X-linked Autosomal Recessive Dominant (rare)

9. 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

10. 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

13. Autosomal Dominant Ichthyoses
Ichthyosis Gene
Epidermolytic hyperkeratosis KRT1; KRT10
Epidermolysis Bullosa Siemens KRT2e
Pachyonychia congenita I,II KRT6a,b, KRT16, KRT17
Epidermolytic PPK KRT9
Non-epidermolytic PPK many genes
Keratitis-Ichth-Deafness (KID) GJB2 (GJB6)
Erythrokeratoderma variabilis GJB3, GJB4

14. 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

15. Epidermolytic Hyperkeratosis
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

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

19. Germline Mutation
Ovaries
Testes
Sperm
Egg cell
Mutation
Mutation

20. Germline Mutation
Conception
Disease
Mutation

21. I have a been diagnosed with an ‘Epidermal Nevus’
I have a been diagnosed with an ‘Epidermal Nevus’. What is it and how does it come about? ?

22. = Skin Mosaicism for Mutation
‘Epidermal Nevus’
= Skin Mosaicism for Mutation
Gametes
Zygote
Two cell lineages
Post-zygotic
mutation
Mutation
Cell Migration
Mosaic

23. 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

24. 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

25. 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 ?

26. Autosomal Recessive Ichthyoses
Ichthyosis Gene
Harlequin ichthyosis ABCA12
Lamellar ichthyosis TGM1, ABCA12
CIE ALOXE3; ALOX12B Ichthyin, Cytochrome P Sjögren-Larsson syndrome ALDH3A2
Neutral lipid storage disease CGI-58 (ABHD5)
Netherton syndrome SPINK5
Refsum disease PAHX, PEX7
Trichothiodystrophy+Ichthyosis ERCC2; ERCC3

29. Lamellar Ichthyosis Autosomal Recessive Incidence 1:200,000
Primary Features:
Collodion baby phenotype
Plate-like, large, dark scale
Ectropion, Eclabium
Scarring alopecia

30. 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

31. Congenital Ichthyosiform Erythroderma
Autosomal Recessive
Incidence 1:200, ,000
Primary features
Collodion baby presentation
Bright red (erythrodermic) skin
Fine, white scale

32. 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)

33. 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

34. So what is a mutation, anyway?

35. How do we detect a mutation?
Karyotype
arrayCGH
FISH
Chromosomes
DNA
Metabolic
Sequence analysis
Mutation scanning
Targeted mutation
analysis
Analytes
Enzyme assay

36. What do we need for mutation testing?
Material required for testing:
Buccal swabs
Blood
Skin punch biopsy

37. How is DNA Sequencing Done?
Gly278Arg

38. 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?