Ichthyosis Panel

Last modified: Oct 16, 2018

Summary

  • Is a 31 gene panel that includes assessment of non-coding variants
  • Is ideal for patients with a clinical suspicion of congenital ichthyosis or lamellar ichthyosis.

Analysis methods

  • FLEX
  • PLUS
  • SEQ
  • DEL/DUP

Availability

4 weeks

Number of genes

31

Test code

DE0601

Panel size

Small

CPT codes

SEQ 81252
SEQ 81401
DEL/DUP 81479
SEQ 81479

Summary

The Blueprint Genetics Ichthyosis Panel (test code DE0601):

  • Is a 31 gene panel that includes assessment of selected non-coding disease-causing variants
  • Is available as PLUS analysis (sequencing analysis and deletion/duplication analysis), sequencing analysis only or deletion/duplication analysis only

ICD codes

Commonly used ICD-10 code(s) when ordering the Ichthyosis Panel

ICD-10 Disease
Q80.9 Congenital ichthyosis
Q80.2 Lamellar ichthyosis

Sample Requirements

  • EDTA blood, min. 1 ml
  • Purified DNA, min. 3μg
  • Saliva (Oragene DNA OG-500 kit)

Label the sample tube with your patient’s name, date of birth and the date of sample collection.

Note that we do not accept DNA samples isolated from formalin-fixed paraffin-embedded (FFPE) tissue.

Vast majority of ichthyoses are inherited, but this condition may also develop in the setting of malignancy, autoimmune or infectious disease and nutritional deficiency. Generally severe ichthyosis is inherited in autosomal recessive manner and less severe ichthyosis and related disorders have X-linked recessive or autosomal dominant heritance. Ichthyosis is characterized by dry, scaling skin that may be thickened or very thin. The disease onset is usually at birth, or within the first year, and continues to affect the patient throughout their lifetime. Autosomal recessive congenital ichthyosis (ARCI) includes several forms of non-syndromic ichthyosis: lamellar ichthyosis, congenital ichthyosiform erythroderma and harlequin ichthyosis. Although most neonates with ARCI are collodion babies, severity of ARCI vary significantly from harlequin ichthyosis, the most severe and usually fatal form, to lamellar ichthyosis and congenital nonbullous ichthyosiform erythroderma. Infants with harlequin ichthyosis are often born prematurely and are encased in thick, hard, armor-like plates of cornified skin that severely restrict movement. The skin affision may lead to dehydration, infections, chronic blistering, overheating and rapid-calorie loss. Autosomal dominant ichthyosis, also called as bullous congenital ichthyosiform erythroderma or epidermolytic hyperkeratosis, is generally mild, later onset disease (no presentation as collodion baby) restricted to itching and psychological impact of having skin with an unusual appearance. Mutations in TGM1 explain 90% or more of severe lamellar ichthyosis and 34%-55% of all ARCI and ALOX12B and ALOXE3 genes are estimated to be involved in 17% of ARCI cases. Ichthyosis vulgaris (AD) and X-linked ichthyosis are the most common types of ichthyosis, with an estimated incidence of 1:250 births and 1:6,000 male births. ARCI including lamellar ichthyosis, congenital ichthyosiform erythroderma and harlequin ichthyosis has overall incidence of 1:200,000.

Genes in the Ichthyosis Panel and their clinical significance

Gene Associated phenotypes Inheritance ClinVar HGMD
ABCA12 Ichthyosis, harlequin, Ichthyosis, lamellar AR 35 118
ABHD5 Chanarin-Dorfman syndrome AR 8 36
ALDH3A2 Sjogren-Larsson syndrome AR 51 105
ALOX12B Ichthyosiform erythroderma, congenital, nonbullous AR 23 64
ALOXE3 Ichthyosiform erythroderma, congenital, nonbullous AR 14 22
CDSN Peeling skin syndrome, Hypotrichosis AD/AR 6 13
CERS3 Ichthyosis, congenital, autosomal recessive 9 AR 2 8
CYP4F22 Ichthyosis, congenital AR 12 21
EBP Chondrodysplasia punctata, Male EBP disorder with neurologic defects (MEND) XL 43 90
ERCC2 Xeroderma pigmentosum, Trichothiodystrophy, photosensitive, Cerebrooculofacioskeletal syndrome 2 AR 24 93
FLG* Icthyosis vulgaris AD/AR 77 92
GJA1* Oculodentodigital dysplasia mild type, Oculodentodigital dysplasia severe type, Syndactyly type 3 AD/AR 32 106
GJB2 Deafness, Bart-Pumphrey syndrome, Keratoderma, palmoplantar, with deafness, Vohwinkel syndrome, Hystrix-like ichthyosis with deafness, Keratitis-icthyosis-deafness syndrome AD/AR/Digenic 119 397
GJB3 Deafness, Erythrokeratodermia variabilis et progressiva 1, Deafness, autosomal dominant 2B AD/Digenic 10 39
GJB4 Erythrokeratodermia variabilis et progressiva, Erythrokeratodermia variabilis with erythema gyratum repens AD 7 21
KRT1 Palmoplantar keratoderma, nonepidermolytic, Ichthyosis, cyclic, with epidermolytic hyperkeratosis, Epidermolytic hyperkeratosis, Ichthyosis histrix, Curth-Macklin, Keratosis palmoplantaris striata, Palmoplantar keratoderma, epidermolytic AD 23 61
KRT2 Ichthyosis bullosa of Siemens, Ichthyosis exfoliativa AD 9 18
KRT9# Knuckle pads, Palmoplantar keratoderma, epidermolytic AD 12 30
KRT10 Erythroderma, ichthyosiform, congenital reticular, Aaru disease, Ichthyosis, cyclic, with epidermolytic hyperkeratosis, Epidermolytic hyperkeratosis, Ichthyosis with confetti AD/AR 25 62
LOR Vohwinkel syndrome, variant form AD 3 10
MBTPS2 Keratosis follicularis spinulosa decalvans, IFAP syndrome, Palmoplantar keratoderma, mutilating, with periorificial keratotic plaques XL 10 24
MPLKIP Trichothiodystrophy 4, nonphotosensitive AR 8 18
NIPAL4 Ichthyosis, congenital, autosomal recessive AR 6 18
PEX7 Refsum disease, Rhizomelic CDP type 1 AR 37 52
PHYH Refsum disease AR 11 36
PNPLA1 Ichthyosis, congenital, autosomal recessive 10 AR 10 44
SLC27A4 Ichthyosis prematurity syndrome AR 9 22
SPINK5 Netherton syndrome AR 23 83
STS Steroid sulfatase deficiency XL 10 67
SUMF1 Multiple sulfatase deficiency AR 21 52
TGM1 Ichthyosis, congenital AR 65 186

* Some, or all, of the gene is duplicated in the genome. Read more.

# The gene has suboptimal coverage (means <90% of the gene’s target nucleotides are covered at >20x with mapping quality score (MQ>20) reads).

The sensitivity to detect variants may be limited in genes marked with an asterisk (*) or number sign (#)

Gene refers to the HGNC approved gene symbol; Inheritance refers to inheritance patterns such as autosomal dominant (AD), autosomal recessive (AR), X-linked (XL), X-linked dominant (XLD) and X-linked recessive (XLR); ClinVar refers to the number of variants in the gene classified as pathogenic or likely pathogenic in this database (ClinVar); HGMD refers to the number of variants with possible disease association in the gene listed in Human Gene Mutation Database (HGMD). The list of associated, gene specific phenotypes are generated from CGD or Orphanet databases.

Non-coding variants covered by the panel

Gene Genomic location HG19 HGVS RefSeq RS-number
ALDH3A2 Chr17:19561044 c.681-14T>A/G NM_001031806.1
GJB2 Chr13:20763744 c.-22-2A>C NM_004004.5 rs201895089
GJB2 Chr13:20766921 c.-23+1G>A NM_004004.5 rs80338940
GJB2 Chr13:20766922 c.-23G>T NM_004004.5 rs786204734
GJB2 Chr13:20767158 c.-259C>T NM_004004.5
GJB2 Chr13:20767159 c.-260C>T NM_004004.5
PEX7 Chr6:137143759 c.-45C>T NM_000288.3 rs267608252
SPINK5 Chr5:147484503 c.1431-12G>A NM_006846.3 rs368134354
SPINK5 Chr5:147491511 c.1820+53G>A NM_006846.3 rs754599628
SPINK5 Chr5:147465956 c.283-12T>A NM_006846.3
TGM1 Chr14:24730233 c.509-329C>T NM_000359.2

Test strength

The strengths of this test include:
  • CAP and ISO-15189 accreditations covering all operations at Blueprint Genetics including all Whole Exome Sequencing, NGS panels and confirmatory testing
  • CLIA-certified personnel performing clinical testing in a CLIA-certified laboratory
  • Powerful sequencing technologies, advanced target enrichment methods and precision bioinformatics pipelines ensure superior analytical performance
  • Careful construction of clinically effective and scientifically justified gene panels
  • Our Nucleus online portal providing transparent and easy access to quality and performance data at the patient level
  • Our publically available analytic validation demonstrating complete details of test performance
  • ~1,500 non-coding disease causing variants in Blueprint WES assay (please see below ‘Non-coding disease causing variants covered by this panel’)
  • Our rigorous variant classification based on modified ACMG variant classification scheme
  • Our systematic clinical interpretation workflow using proprietary software enabling accurate and traceable processing of NGS data
  • Our comprehensive clinical statements

Test limitations

This test does not detect the following:
  • Complex inversions
  • Gene conversions
  • Balanced translocations
  • Mitochondrial DNA variants
  • Repeat expansion disorders unless specifically mentioned
  • Non-coding variants deeper than ±20 base pairs from exon-intron boundary unless otherwise indicated (please see above Panel Content / non-coding variants covered by the panel).

This test may not reliably detect the following:

  • Low level mosaicism (variant with a minor allele fraction of 14.6% is detected with 90% probability)
  • Stretches of mononucleotide repeats
  • Indels larger than 50bp
  • Single exon deletions or duplications
  • Variants within pseudogene regions/duplicated segments

The sensitivity of this test may be reduced if DNA is extracted by a laboratory other than Blueprint Genetics.

For additional information, please refer to the Test performance section and see our Analytic Validation.

The Blueprint Genetics ichthyosis panel covers classical genes associated with congenital ichthyosis, lamellar ichthyosis and multiple sulfatase deficiency. The genes on the panel have been carefully selected based on scientific literature, mutation databases and our experience.

Our panels are sliced from our high-quality whole exome sequencing data. Please see our sequencing and detection performance table for different types of alterations at the whole exome level (Table).

Assays have been validated for different starting materials including EDTA-blood, isolated DNA (no FFPE), saliva and dry blood spots (filter card) and all provide high-quality results. The diagnostic yield varies substantially depending on the assay used, referring healthcare professional, hospital and country. Blueprint Genetics’ Plus Analysis (Seq+Del/Dup) maximizes the chance to find a molecular genetic diagnosis for your patient although Sequence Analysis or Del/Dup Analysis may be a cost-effective first line test if your patient’s phenotype is suggestive of a specific mutation type.

Performance of Blueprint Genetics Whole Exome Sequencing (WES) assay. All individual panels are sliced from WES data.

Sensitivity % (TP/(TP+FN) Specificity %
Single nucleotide variants 99.65% (412,456/413,893) >99.99%
Insertions, deletions and indels by sequence analysis
1-10 bps 96.94% (17,070/17,608) >99.99%
11-50 bps 99.07% (957/966) >99.99%
Copy number variants (exon level dels/dups)
Clinical samples (small CNVs, n=52)
1 exon level deletion 92.3% (24/26) NA
2 exons level deletion/duplication 100.0% (11/11) NA
3-7 exons level deletion/duplication 93.3% (14/15) NA
Microdeletion/-duplication sdrs (large CNVs, n=37))
Size range (0.1-47 Mb) 100% (37/37)
Simulated CNV detection
2 exons level deletion/duplication 90.98% (7,357/8,086) 99.96%
5 exons level deletion/duplication 98.63% (7,975/8,086) 99.98%
     
The performance presented above reached by WES with the following coverage metrics
     
Mean sequencing depth at exome level 174x
Nucleotides with >20x sequencing coverage (%) 99.4%

Bioinformatics

The target region for each gene includes coding exons and ±20 base pairs from the exon-intron boundary. In addition, the panel includes non-coding variants if listed above (Non-coding variants covered by the panel). Some regions of the gene(s) may be removed from the panel if specifically mentioned in the ‘Test limitations” section above. The sequencing data generated in our laboratory is analyzed with our proprietary data analysis and annotation pipeline, integrating state-of-the art algorithms and industry-standard software solutions. Incorporation of rigorous quality control steps throughout the workflow of the pipeline ensures the consistency, validity and accuracy of results. Our pipeline is streamlined to maximize sensitivity without sacrificing specificity. We have incorporated a number of reference population databases and mutation databases such as, but not limited, to 1000 Genomes Project, gnomAD, ClinVar and HGMD into our clinical interpretation software to make the process effective and efficient. For missense variants, in silico variant prediction tools such as SIFT, PolyPhen, MutationTaster are used to assist with variant classification. Through our online ordering and statement reporting system, Nucleus, the customer has an access to details of the analysis, including patient specific sequencing metrics, a gene level coverage plot and a list of regions with inadequate coverage if present. This reflects our mission to build fully transparent diagnostics where customers have easy access to crucial details of the analysis process.

Clinical interpretation

We provide customers with the most comprehensive clinical report available on the market. Clinical interpretation requires a fundamental understanding of clinical genetics and genetic principles. At Blueprint Genetics, our PhD molecular geneticists, medical geneticists and clinical consultants prepare the clinical statement together by evaluating the identified variants in the context of the phenotypic information provided in the requisition form. Our goal is to provide clinically meaningful statements that are understandable for all medical professionals regardless of whether they have formal training in genetics.

Variant classification is the corner stone of clinical interpretation and resulting patient management decisions. Our classifications follow the Blueprint Genetics Variant Classification Schemes based on the ACMG guideline 2015. Minor modifications were made to increase reproducibility of the variant classification and improve the clinical validity of the report. Our experience with tens of thousands of clinical cases analyzed at our laboratory allowed us to further develop the industry standard.

The final step in the analysis of sequence variants is confirmation of variants classified as pathogenic or likely pathogenic using bi-directional Sanger sequencing. Variant(s) fulfilling all of the following criteria are not Sanger confirmed: 1) the variant quality score is above the internal threshold for a true positive call, 2) an unambiguous IGV in-line with the variant call and 3) previous Sanger confirmation of the same variant at least three times at Blueprint Genetics. Reported variants of uncertain significance are confirmed with bi-directional Sanger sequencing only if the quality score is below our internally defined quality score for true positive call. Reported copy number variations with a size <10 exons are confirmed by orthogonal methods such as qPCR if the specific CNV has been seen less than three times at Blueprint Genetics.

Our clinical statement includes tables for sequencing and copy number variants that include basic variant information (genomic coordinates, HGVS nomenclature, zygosity, allele frequencies, in silico predictions, OMIM phenotypes and classification of the variant). In addition, the statement includes detailed descriptions of the variant, gene and phenotype(s) including the role of the specific gene in human disease, the mutation profile, information about the gene’s variation in population cohorts and detailed information about related phenotypes. We also provide links to the references used, congress abstracts and mutation databases to help our customers further evaluate the reported findings if desired. The conclusion summarizes all of the existing information and provides our rationale for the classification of the variant.

Identification of pathogenic or likely pathogenic variants in dominant disorders or their combinations in different alleles in recessive disorders are considered molecular confirmation of the clinical diagnosis. In these cases, family member testing can be used for risk stratification within the family. In the case of variants of uncertain significance (VUS), we do not recommend family member risk stratification based on the VUS result. Furthermore, in the case of VUS, we do not recommend the use of genetic information in patient management or genetic counseling.

Our interpretation team analyzes millions of variants from thousands of individuals with rare diseases. Thus, our database, and our understanding of variants and related phenotypes, is growing by leaps and bounds. Our laboratory is therefore well positioned to re-classify previously reported variants as new information becomes available. If a variant previously reported by Blueprint Genetics is re-classified, our laboratory will issue a follow-up statement to the original ordering health care provider at no additional cost.