Leber Congenital Amaurosis Panel

PLUSbpg-method Plus Analysis combines Sequence + Del/Dup (CNV) Analysis providing increased diagnostic yield in certain clinical conditions, where the underlying genetic defect may be detectable by either of the analysis methods. Results in 3–4 weeks. SEQbpg-method Our Sequence Analysis is based on a proprietary targeted sequencing method OS-Seq™ and offers panels targeted for genes associated with certain phenotypes. A standard way to analyze NGS data for finding the genetic cause for Mendelian disorders. Results in 3–4 weeks. DEL/DUPbpg-method Targeted Del/Dup (CNV) analysis is used to detect bigger disease causing deletions or duplications from the disease-associated genes. Results in 3–4 weeks.

Test code: OP1701

The Blueprint Genetics Leber Congenital Amaurosis Panel is a 25 gene test for genetic diagnostics of patients with clinical suspicion of Leber congenital amaurosis.

The panel covers genes associated with autosomal recessive and dominant Leber congenital amaurosis (LCA) and is estimated to provide molecular diagnosis for 70% of patients with LCA. This panel is included in the Retinal Dystrophy Panel.

About Leber Congenital Amaurosis

Leber congenital amaurosis (LCA) is a severe retinal dystrophy causing blindness or severe visual impairment before the age of 1 year. It accounts for 10-18% of congenital blindness and 5% of all retinal dystrophies. LCA is clinically characterized by poor visual function often accompanied by nystagmus, abnormal pupillary responses, photophobia, high hyperopia, markedly diminished electroretinogram and keratoconus. A characteristic finding is Franceschetti’s oculo-digital sign, comprising eye poking, pressing, and rubbing. LCA is a genetically heterogeneous disorder and is typically inherited in an autosomal recessive manner. Rare dominant cases have been reported. Recent clinical trials with RPE65 replacement therapy have been shown to be promising in improving vision in patients with RPE65-associated LCA (PMID: 23341635). The prevalence of LCA is 1:50,000 to 1:33,000.

Availability

Results in 3-4 weeks. We do not offer a maternal cell contamination (MCC) test at the moment. We offer prenatal testing only for cases where the maternal cell contamination studies (MCC) are done by a local genetic laboratory. Read more: http://blueprintgenetics.com/faqs/#prenatal

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Genes in the Leber Congenital Amaurosis Panel and their clinical significance
Gene Associated phenotypes Inheritance ClinVar HGMD
AIPL1 Retinitis pigmentosa, Cone rod dystrophy, Leber congenital amaurosis AD/AR 8 73
ALMS1* Alström syndrome AR 31 281
BBS4 Bardet-Biedl syndrome AR 13 45
CABP4 Night blindness, congenital stationary AR 4 10
CEP290* Bardet-Biedl syndrome, Leber congenital amaurosis, Joubert syndrome, Senior-Loken syndrome, Meckel syndrome AR 79 252
CNGA3 Leber congenital amaurosis, Achromatopsia AR 16 141
CRB1 Retinitis pigmentosa, Pigmented paravenous chorioretinal atrophy, Leber congenital amaurosis AD/AR 31 291
CRX Cone rod dystrophy, Leber congenital amaurosis AD/AR 22 87
DTHD1 Leber congenital amaurosis with muscle dystrophy AR 1
GUCY2D Cone rod dystrophy, Leber congenital amaurosis AD/AR 18 214
IMPDH1 Retinitis pigmentosa, Leber congenital amaurosis AD 6 20
IQCB1 Senior-Loken syndrome AR 15 35
KCNJ13 Snowflake vitreoretinal degeneration, Leber congenital amaurosis AD/AR 6 10
LCA5 Leber congenital amaurosis AR 7 45
LRAT Retinitis pigmentosa, juvenile, Leber congenital amaurosis, Retinitis punctata albescens, Retinal-dystrophy, early-onset severe AR 7 18
MERTK Retinitis pigmentosa AR 18 59
MYO7A Deafness, Usher syndrome AR 125 402
NMNAT1 Leber congenital amaurosis AR 11 64
RD3 Leber congenital amaurosis AR 5 13
RDH5 Fundus albipunctatus AR 11 50
RDH12 Retinitis pigmentosa, Leber congenital amaurosis AD/AR 20 95
RPE65 Retinitis pigmentosa, Leber congenital amaurosis AR 16 170
RPGRIP1 Cone rod dystrophy, Leber congenital amaurosis AR 23 117
SPATA7 Leber congenital amaurosis, Retitinitis pigmentosa AR 10 29
TULP1 Retinitis pigmentosa, Leber congenital amaurosis AR 19 66

*Some regions of the gene are duplicated in the genome leading to limited sensitivity within the regions. Thus, low-quality variants are filtered out from the duplicated regions and only high-quality variants confirmed by other methods are reported out. Read more.

Gene, refers to HGNC approved gene symbol; Inheritance to inheritance patterns such as autosomal dominant (AD), autosomal recessive (AR) and X-linked (XL); ClinVar, refers to a number of variants in the gene classified as pathogenic or likely pathogenic in ClinVar (http://www.ncbi.nlm.nih.gov/clinvar/); HGMD, refers to a number of variants with possible disease association in the gene listed in Human Gene Mutation Database (HGMD, http://www.hgmd.cf.ac.uk/ac/). The list of associated (gene specific) phenotypes are generated from CDG (http://research.nhgri.nih.gov/CGD/) or Orphanet (http://www.orpha.net/) databases.

Gene Genomic location HG19 HGVS RefSeq RS-number Comment Reference
BBS4 Chr15:73001820 c.77-216delA NM_033028.4 rs113994189
CEP290 Chr12:88494960 c.2991+1655A>G NM_025114.3 rs281865192
NMNAT1 Chr1:10003561 c.-69C>T NM_022787.3
NMNAT1 Chr1:10003560 c.-70A>T NM_022787.3

Blueprint Genetics offers a comprehensive Leber Congenital Amaurosis Panel that covers classical genes associated with Leber congenital amaurosis. The genes are carefully selected based on the existing scientific evidence, our experience and most current mutation databases. Candidate genes are excluded from this first-line diagnostic test. The test does not recognise balanced translocations or complex inversions, and it may not detect low-level mosaicism. The test should not be used for analysis of sequence repeats or for diagnosis of disorders caused by mutations in the mitochondrial DNA.

Analytical validation is a continuous process at Blueprint Genetics. Our mission is to improve the quality of the sequencing process and each modification is followed by our standardized validation process. Average sensitivity and specificity in Blueprint NGS Panels is 99.3% and 99.9% for detecting SNPs. Sensitivity to for indels vary depending on the size of the alteration: 1-10bps (96.0%), 11-20 bps (88.4%) and 21-30 bps (66.7%). The longest detected indel was 46 bps by sequence analysis. Detection limit for Del/Dup (CNV) analysis varies through the genome depending on exon size, sequencing coverage and sequence content. The sensitivity is 71.5% for single exon deletions and duplications and 99% for three exons’ deletions and duplications. We have validated the assays for different starting materials including EDTA-blood, isolated DNA (no FFPE) and saliva that all provide high-quality results. The diagnostic yield varies substantially depending on the used assay, referring healthcare professional, hospital and country. Blueprint Genetics’ Plus Analysis (Seq+Del/Dup) maximizes the chance to find molecular genetic diagnosis for your patient although Sequence Analysis or Del/Dup Analysis may be cost-effective first line test if your patient’s phenotype is suggestive for a specific mutation profile.

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. The highest relevance in the reported variants is achieved through elimination of false positive findings based on variability data for thousands of publicly available human reference sequences and validation against our in-house curated mutation database as well as the most current and relevant human mutation databases. Reference databases currently used are the 1000 Genomes Project (http://www.1000genomes.org), the NHLBI GO Exome Sequencing Project (ESP; http://evs.gs.washington.edu/EVS), the Exome Aggregation Consortium (ExAC; http://exac.broadinstitute.org), ClinVar database of genotype-phenotype associations (http://www.ncbi.nlm.nih.gov/clinvar) and the Human Gene Mutation Database (http://www.hgmd.cf.ac.uk). The consequence of variants in coding and splice regions are estimated using the following in silico variant prediction tools: SIFT (http://sift.jcvi.org), Polyphen (http://genetics.bwh.harvard.edu/pph2/), and Mutation Taster (http://www.mutationtaster.org).

Through our online ordering and statement reporting system, Nucleus, the customer can access specific details of the analysis of the patient. This includes coverage and quality specifications and other relevant information on the analysis. This represents our mission to build fully transparent diagnostics where the customer gains easy access to crucial details of the analysis process.

In addition to our cutting-edge patented sequencing technology and proprietary bioinformatics pipeline, we also provide the customers with the best-informed clinical report on the market. Clinical interpretation requires fundamental clinical and genetic understanding. At Blueprint Genetics our geneticists and clinicians, who together evaluate the results from the sequence analysis pipeline in the context of phenotype information provided in the requisition form, prepare the clinical statement. Our goal is to provide clinically meaningful statements that are understandable for all medical professionals, even without training in genetics.

Variants reported in the statement are always classified using the Blueprint Genetics Variant Classification Scheme modified from the ACMG guidelines (Richards et al. 2015), which has been developed by evaluating existing literature, databases and with thousands of clinical cases analyzed in our laboratory. Variant classification forms the corner stone of clinical interpretation and following patient management decisions. Our statement also includes allele frequencies in reference populations and in silico predictions. We also provide PubMed IDs to the articles or submission numbers to public databases that have been used in the interpretation of the detected variants. In our conclusion, we summarize all the existing information and provide our rationale for the classification of the variant.

A final component of the analysis is the Sanger confirmation of the variants classified as likely pathogenic or pathogenic. This does not only bring confidence to the results obtained by our NGS solution but establishes the mutation specific test for family members. Sanger sequencing is also used occasionally with other variants reported in the statement. In the case of variant of uncertain significance (VUS) we do not recommend risk stratification based on the genetic finding. Furthermore, in the case VUS we do not recommend use of genetic information in patient management or genetic counseling. For some cases Blueprint Genetics offers a special free of charge service to investigate the role of identified VUS.

We constantly follow genetic literature adapting new relevant information and findings to our diagnostics. Relevant novel discoveries can be rapidly translated and adopted into our diagnostics without delay. These processes ensure that our diagnostic panels and clinical statements remain the most up-to-date on the market.

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ICD & CPT codes

CPT codes

SEQ81479
DEL/DUP81479


ICD codes

Commonly used ICD-10 codes when ordering the Leber Congenital Amaurosis Panel

ICD-10 Disease
H35.50 Leber congenital amaurosis

Accepted sample types

  • EDTA blood, min. 1 ml
  • Purified DNA, min. 5μg
  • 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.

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