- Is a 39 gene panel that includes assessment of non-coding variants
Is ideal for patients with a clinical suspicion of congenital ichthyosis or lamellar ichthyosis.
The Blueprint Genetics Ichthyosis Panel (test code DE0601):
Commonly used ICD-10 code(s) when ordering the Ichthyosis Panel
|E75.29||Multiple sulfatase deficiency|
- Blood (min. 1ml) in an EDTA tube
- Extracted DNA, min. 2 μg in TE buffer or equivalent
- Saliva (Oragene DNA OG-500 kit/OGD-500 or OG-575 & OGD-575)
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. Read more about our sample requirements here.
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
|ABCA12||Ichthyosis, harlequin, Ichthyosis, lamellar||AR||37||125|
|ALOX12B||Ichthyosiform erythroderma, congenital, nonbullous||AR||23||64|
|ALOXE3||Ichthyosiform erythroderma, congenital, nonbullous||AR||14||22|
|CASP14||Ichthyosis, congenital, autosomal recessive 12||AR||1||1|
|CDSN||Peeling skin syndrome, Hypotrichosis||AD/AR||6||14|
|CERS3||Ichthyosis, congenital, autosomal recessive 9||AR||2||8|
|CSTA||Peeling skin syndrome 4||AR||5||6|
|EBP||Chondrodysplasia punctata, Male EBP disorder with neurologic defects (MEND)||XL||43||90|
|ERCC2||Xeroderma pigmentosum, Trichothiodystrophy, photosensitive, Cerebrooculofacioskeletal syndrome 2||AR||26||98|
|GJA1*||Oculodentodigital dysplasia mild type, Oculodentodigital dysplasia severe type, Syndactyly type 3||AD/AR||31||107|
|GJB2||Deafness, Bart-Pumphrey syndrome, Keratoderma, palmoplantar, with deafness, Vohwinkel syndrome, Hystrix-like ichthyosis with deafness, Keratitis-icthyosis-deafness syndrome||AD/AR/Digenic||133||405|
|GJB3||Deafness, Erythrokeratodermia variabilis et progressiva 1, Deafness, autosomal dominant 2B||AD/AR||11||40|
|GJB4||Erythrokeratodermia variabilis et progressiva, Erythrokeratodermia variabilis with erythema gyratum repens||AD||7||21|
|KDSR||Erythrokeratodermia variabilis et progressiva 4||AR||4||10|
|KRT1||Palmoplantar keratoderma, nonepidermolytic, Ichthyosis, cyclic, with epidermolytic hyperkeratosis, Epidermolytic hyperkeratosis, Ichthyosis histrix, Curth-Macklin, Keratosis palmoplantaris striata, Palmoplantar keratoderma, epidermolytic||AD||24||63|
|KRT10||Erythroderma, ichthyosiform, congenital reticular, Aaru disease, Ichthyosis, cyclic, with epidermolytic hyperkeratosis, Epidermolytic hyperkeratosis, Ichthyosis with confetti||AD/AR||25||65|
|KRT2||Ichthyosis bullosa of Siemens, Ichthyosis exfoliativa||AD||9||18|
|KRT9||Knuckle pads, Palmoplantar keratoderma, epidermolytic||AD||12||31|
|LIPN||Ichthyosis, congenital, autosomal recessive 8||AR||1||1|
|LOR||Vohwinkel syndrome, variant form||AD||3||10|
|MBTPS2||Keratosis follicularis spinulosa decalvans, IFAP syndrome, Palmoplantar keratoderma, mutilating, with periorificial keratotic plaques||XL||12||25|
|MPLKIP||Trichothiodystrophy 4, nonphotosensitive||AR||8||19|
|NIPAL4||Ichthyosis, congenital, autosomal recessive||AR||6||18|
|OSMR||Amyloidosis, primary localized cutaneous, 1||AD||5||14|
|PEX7||Refsum disease, Rhizomelic CDP type 1||AR||44||53|
|PNPLA1||Ichthyosis, congenital, autosomal recessive 10||AR||11||46|
|SDR9C7||Ichthyosis, congenital, autosomal recessive 13||AR||4||9|
|SLC27A4||Ichthyosis prematurity syndrome||AR||9||22|
|ST14||Ichthyosis, congenital, autosomal recessive 11||AR||4||9|
|STS||Steroid sulfatase deficiency||XL||11||67|
|SUMF1||Multiple sulfatase deficiency||AR||21||53|
|TGM5||Peeling skin syndrome||AR||10||25|
* 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), and/or the gene has exons listed under Test limitations section that are not included in the panel as they are not sufficiently covered with high quality sequence 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 Ichthyosis Panel
|Gene||Genomic location HG19||HGVS||RefSeq||RS-number|
Added and removed genes from the panel
|Genes added||Genes removed|
|CASP14 CSTA KDSR LIPN OSMR SDR9C7 ST14 TGM5|
- CAP accredited laboratory
- 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 publicly available analytic validation demonstrating complete details of test performance
- ~2,000 non-coding disease causing variants in our clinical grade NGS assay for panels (please see ‘Non-coding disease causing variants covered by this panel’ in the Panel Content section)
- Our rigorous variant classification scheme
- Our systematic clinical interpretation workflow using proprietary software enabling accurate and traceable processing of NGS data
- Our comprehensive clinical statements
Genes with partial, or whole gene, segmental duplications in the human genome are marked with an asterisk (*) if they overlap with the UCSC pseudogene regions. The technology may have limited sensitivity to detect variants in genes marked with these symbols (please see the Panel content table above).
- 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).
- 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 genes on the panel have been carefully selected based on scientific literature, mutation databases and our experience.
Our panels are sectioned from our high-quality, clinical grade NGS assay. Please see our sequencing and detection performance table for details regarding our ability to detect different types of alterations (Table).
Assays have been validated for various sample types including EDTA-blood, isolated DNA (excluding from formalin fixed paraffin embedded tissue), saliva and dry blood spots (filter cards). These sample types were selected in order to maximize the likelihood for high-quality DNA yield. The diagnostic yield varies depending on the assay used, referring healthcare professional, hospital and country. Plus analysis increases the likelihood of finding a genetic diagnosis for your patient, as large deletions and duplications cannot be detected using sequence analysis alone. Blueprint Genetics’ Plus Analysis is a combination of both sequencing and deletion/duplication (copy number variant (CNV)) analysis.
Performance of Blueprint Genetics high-quality, clinical grade NGS sequencing assay for panels.
|Sensitivity % (TP/(TP+FN)||Specificity %|
|Single nucleotide variants||99.89% (99,153/99,266)||>99.9999%|
|Insertions, deletions and indels by sequence analysis|
|1-10 bps||96.9% (7,563/7,806)||>99.9999%|
|11-50 bps||99.13% (2,524/2,546)||>99.9999%|
|Copy number variants (exon level dels/dups)|
|1 exon level deletion (heterozygous)||100% (20/20)||NA|
|1 exon level deletion (homozygous)||100% (5/5)||NA|
|1 exon level deletion (het or homo)||100% (25/25)||NA|
|2-7 exon level deletion (het or homo)||100% (44/44)||NA|
|1-9 exon level duplication (het or homo)||75% (6/8)||NA|
|Simulated CNV detection|
|5 exons level deletion/duplication||98.7%||100.00%|
|Microdeletion/-duplication sdrs (large CNVs, n=37))|
|Size range (0.1-47 Mb)||100% (37/37)|
|The performance presented above reached by Blueprint Genetics high-quality, clinical grade NGS sequencing assay with the following coverage metrics|
|Mean sequencing depth||143X|
|Nucleotides with >20x sequencing coverage (%)||99.86%|
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 and regulatory 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 including, 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, ordering providers have access to the details of the analysis, including patient specific sequencing metrics, a gene level coverage plot and a list of regions with <20X sequencing depth if applicable. This reflects our mission to build fully transparent diagnostics where ordering providers can easily visualize the crucial details of the analysis process.
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 is orthogonal confirmation. Sequence variants classified as pathogenic, likely pathogenic and variants of uncertain significance (VUS) are confirmed using bi-directional Sanger sequencing when they do not meet our stringent NGS quality metrics for a true positive call. Reported heterozygous and homo/hemizygous copy number variations with a size <10 and <3 target exons are confirmed by orthogonal methods such as qPCR if the specific CNV has been seen and confirmed 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, abstracts and variant databases used to help ordering providers 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. We do not recommend using variants of uncertain significance (VUS) for family member risk stratification or patient management. Genetic counseling is recommended.
Our interpretation team analyzes millions of variants from thousands of individuals with rare diseases. Our internal database and our understanding of variants and related phenotypes increases with every case analyzed. 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.