Cataract Panel

Last modified: Jun 12, 2018

Summary

  • Is a 69 gene panel that includes assessment of non-coding variants
  • Is ideal for patients with a clinical suspicion / diagnosis of congenital cataracts or a syndrome with cataracts as a feature.

Analysis methods

  • PLUS
  • SEQ
  • DEL/DUP

Availability

4 weeks

Number of genes

69

Test code

OP0201

Panel size

Large

CPT codes

SEQ 81404
SEQ 81406
SEQ 81408
DEL/DUP 81479

Summary

The Blueprint Genetics Cataract Panel (test code OP0201):

  • Is a 69 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 Cataract Panel

ICD-10 Disease
Q12.0 Cataract

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.

Cataract is defined as opacification of the normally transparent crystalline lens. Cataract can be classified as congenital, infantile, juvenile, presenile, and senile. Congenital cataract (CC) is present at birth or during early childhood and is one of the most common ocular diseases causing visual impairment or blindness in children worldwide. Nuclear cataract is the most common type of hereditary CC and is characterized by the opacification limited to the embryonic and/or fetal nuclei of the lens (PMID: 24384146). It can be inherited in an autosomal dominant, autosomal recessive, or X-linked manner, of which the autosomal dominant mode is the most common. Nuclear CC is genetically highly heterogeneous. Mutations in lens crystallins (CRYAACRYABCRYBB1CRYBB2CRYBB3CRYGCCRYGD) explain approximately half of the cases, followed by connexins (GJA3GJA8). Congenital nuclear cataract can be isolated (70%) or associated with other ocular disorders, such as microphthalmia or aniridia. It may also be part of multisystem genetic disorders such as Nance-Horan syndrome (NHS), Lowe syndrome (OCRL) or neurofibromatosis type 2 (NF2). The prevalence of cataract in children has been estimated between 1-15:10,000.

Genes in the Cataract Panel and their clinical significance

Gene Associated phenotypes Inheritance ClinVar HGMD
ABCB6 Blood group, Langereis system, Pseudohyperkalemia, Dyschromatosis universalis hereditaria, Microphthalmia, isolated, with coloboma 7 AD/BG 9 19
ADAMTS18 Knobloch syndrome 2, Microcornea, myopic chorioretinal atrophy, and telecanthus, Retinal dystrophy, early onset, autosomal recessive AR 4 11
ADAMTSL4 Ectopia lentis, isolated AR 11 26
AGK* Sengers syndrome, Cataract 38 AR 18 27
ALDH18A1 Spastic paraplegia, Cutis laxa AD/AR 21 28
BCOR Microphthalmia, syndromic, Oculofaciocardiodental syndrome XL 38 50
BFSP1 Cataract 33 AR 4 6
BFSP2 Cataract AD 2 7
CHMP4B Cataract 31, multiple types AD 2 2
COL2A1 Avascular necrosis of femoral head, Rhegmatogenous retinal detachment, Epiphyseal dysplasia, with myopia and deafness, Czech dysplasia, Achondrogenesis type 2, Platyspondylic dysplasia Torrance type, Hypochondrogenesis, Spondyloepiphyseal dysplasia congenital (SEDC), Spondyloepimetaphyseal dysplasia (SEMD) Strudwick type, Kniest dysplasia, Spondyloperipheral dysplasia, Mild SED with premature onset arthrosis, SED with metatarsal shortening, Stickler syndrome type 1 AD 166 544
COL4A1 Schizencephaly, Anterior segment dysgenesis with cerebral involvement, Retinal artery tortuosity, Porencephaly, Angiopathy, hereditary, with nephropathy, aneurysms, and muscle cramps, Brain small vessel disease AD 56 99
COL11A1 Marshall syndrome, Fibrochondrogenesis, Stickler syndrome type 2 AD/AR 30 86
COL18A1 Knobloch syndrome AR 24 29
CRYAA Cataract AD/AR 12 24
CRYAB Cataract, myofibrillar myopathy and cardiomyopathy, Congenital cataract and cardiomyopathy, Dilated cardiomyopathy (DCM), Myopathy, myofibrillar, Cataract 16, multiple types, Myopathy, myofibrillar, fatal infantile hypertonic, alpha-B crystallin-related AD 15 28
CRYBA1 Cataract 10, multiple types AD 7 12
CRYBA4 Cataract 23 AD 4 9
CRYBB1 Cataract AD/AR 6 17
CRYBB2* Cataract AD 10 27
CRYBB3 Cataract AR 3 7
CRYGC Cataract AD 9 27
CRYGD Cataract AD 10 26
CRYGS Cataract, progressive polymorphic cortical AD 2 8
CTDP1 Congenital cataracts, facial dysmorphism, and neuropathy AR 1 1
CYP27A1 Cerebrotendinous xanthomatosis AR 61 108
EPHA2 Cataract 6, multiple types AD 7 20
ERCC2 Xeroderma pigmentosum, Trichothiodystrophy, photosensitive, Cerebrooculofacioskeletal syndrome 2 AR 24 93
ERCC5 Xeroderma pigmentosum, Xeroderma pigmentosum/Cockayne syndrome AR 21 52
ERCC6* Xeroderma Pigmentosum-Cockayne Syndrome, De Sanctis-Cacchione syndrome AD/AR 52 93
ERCC8 UV-sensitive syndrome, Cockayne syndrome AR 17 48
EYA1 Otofaciocervical syndrome, Branchiootic syndrome, Branchiootorenal syndrome AD 44 203
FAM126A Leukodystrophy, hypomyelinating AR 8 12
FOXE3 Aphakia, congenital primary, Anterior segment mesenchymal dysgenesis, Cataract 34 AR/AD 9 23
FTL Hyperferritinemia-cataract syndrome, L-ferritin deficiency, Neurodegeneration with brain iron accumulation AD/AR 21 63
FYCO1 Cataract AR 10 16
FZD4 Retinopathy of prematurity, Exudative vitreoretinopathy AD/Digenic 12 89
GALE Galactose epimerase deficiency AR 13 25
GALK1 Galactokinase deficiency AR 5 44
GALT Galactosemia AR 248 327
GCNT2 Blood group, Ii, Adult i pheno without cataract, Cataract 13 with adult i pheno BG/AR 9 9
GJA1* Oculodentodigital dysplasia mild type, Oculodentodigital dysplasia severe type, Syndactyly type 3 AD/AR 32 106
GJA3 Cataract AD 14 41
GJA8 Cataract AD/AR 20 58
HSF4 Cataract AD 6 17
LIM2 Cataract AR 2 3
MAF Ayme-Gripp syndrome, Cataract 21, multiple types AD 20 18
MIP Cataract 15, multiple types AD 11 23
MYH9 Sebastian syndrome, May-Hegglin anomaly, Epstein syndrome, Fechtner syndrome, Macrothrombocytopenia and progressive sensorineural deafness, Deafness, autosomal dominant 17 AD 23 117
NDP Exudative vitreoretinopathy, Norrie disease XL 31 165
NF2 Schwannomatosis, Neurofibromatosis AD 47 428
NHS Nance-Horan syndrome, Cataract XL 28 48
OCRL Lowe syndrome, Dent disease XL 42 260
OPA3 Optic atrophy, 3-methylglutaconic aciduria AD/AR 9 15
P3H2 Myopia, high, with cataract and vitreoretinal degeneration AR 7 7
PAX6 Aniridia, cerebellar ataxia, and mental retardation (Gillespie syndrome), Keratitis, Coloboma, ocular, Cataract with late-onset corneal dystrophy, Morning glory disc anomaly, Foveal hypoplasia, Aniridia, Optic nerve hypoplasia, Peters anomaly AD 130 518
PITX3 Cataract, Anterior segment mesenchymal dysgenesis AD 5 9
PXDN Anterior segment dysgenesis 7 AR 6 11
RAB3GAP1 Warburg micro syndrome AR 23 62
RECQL4 Baller-Gerold syndrome, RAPADILINO syndrome, Rothmund-Thomson syndrome AR 53 100
SIL1 Marinesco-Sjogren syndrome AR 14 49
SLC16A12 Cataract 47 AD 2 18
SLC33A1* Congenital cataracts, hearing loss, and neurodegeneration, Spastic paraplegia 42, autosomal dominant AR 6 7
TDRD7 Cataract AR 3 5
TFAP2A Branchiooculofacial sydrome AD 12 41
TMEM70 Mitochondrial complex V (ATP synthase) deficiency AR 11 18
VIM Cataract 30, multiple types AD 3 3
VSX2 Microphthalmia, isolated 2, Microphthalmia, isolated, with coloboma 3 AR 8 13
WFS1 Wolfram syndrome, Deafness, Wolfram-like syndrome, autosomal dominant, Deafness, autosomal dominant 6/14/38, Cataract 41 AD/AR 68 351
WRN* Werner syndrome AR 36 103

* 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
COL11A1 Chr1:103488576 c.1027-24A>G NM_080629.2
COL11A1 Chr1:103386637 c.3744+437T>G NM_080629.2
COL11A1 Chr1:103491958 c.781-450T>G NM_080629.2 rs587782990
COL2A1 Chr12:48379984 c.1527+135G>A NM_001844.4
COL4A1 Chr13:110802679 c.*31G>T NM_001845.4
COL4A1 Chr13:110802678 c.*32G>T NM_001845.4
COL4A1 Chr13:110802675 c.*35C>A NM_001845.4
ERCC6 Chr10:50681659 c.2599-26A>G NM_000124.3 rs4253196
ERCC8 Chr5:60223645 c.173+1046A>G NM_000082.3
EYA1 Chr8:72156939 c.1051-12T>G NM_000503.4
EYA1 Chr8:72211483 c.640-15G>A NM_000503.4
FTL Chr19:49468655 c.-110C>T NM_000146.3
FTL Chr19:49468621 c.-144A>T NM_000146.3
FTL Chr19:49468617 c.-148G>C NM_000146.3
FTL Chr19:49468616 c.-149G>C NM_000146.3 rs398124638
FTL Chr19:49468615 c.-150C>A NM_000146.3
FTL Chr19:49468614 c.-151A>C NM_000146.3
FTL Chr19:49468612 c.-153G>A NM_000146.3
FTL Chr19:49468611 c.-154T>G NM_000146.3
FTL Chr19:49468608 c.-157G>A NM_000146.3
FTL Chr19:49468606 c.-159G>C NM_000146.3 rs398124634
FTL Chr19:49468605 c.-160A>G NM_000146.3 rs398124633
FTL Chr19:49468604 c.-161C>A/G NM_000146.3
FTL Chr19:49468604 c.-161C>T NM_000146.3 rs398124636
FTL Chr19:49468602 c.-163A>C/G/T NM_000146.3
FTL Chr19:49468601 c.-164C>A/T NM_000146.3 rs398124637
FTL Chr19:49468601 c.-164C>G NM_000146.3
FTL Chr19:49468599 c.-166T>C NM_000146.3
FTL Chr19:49468598 c.-167C>A/T NM_000146.3
FTL Chr19:49468597 c.-168G>A/C/T NM_000146.3 rs398124635
FTL Chr19:49468594 c.-171C>G NM_000146.3
FTL Chr19:49468586 c.-175_-170delGTCTCT NM_000146.3 rs398124639
FTL Chr19:49468589 c.-176T>C NM_000146.3
FTL Chr19:49468587 c.-178T>G NM_000146.3
FTL Chr19:49468583 c.-182C>T NM_000146.3
FTL Chr19:49468581 c.-184C>T NM_000146.3
FTL Chr19:49468579 c.-186C>G NM_000146.3
FTL Chr19:49468575 c.-190C>T NM_000146.3
FTL Chr19:49468350 c.-415C>A NM_000146.3
GALK1 Chr17:73761239 c.-22T>C NM_000154.1 rs545362817
GALT Chr9:34646606 c.-96T>G NM_000155.3
GALT Chr9:34649617 c.1059+56C>T NM_000155.3 rs111033821
GALT Chr9:34648519 c.687+66T>A NM_000155.3
GALT Chr9:34648904 c.820+13A>G NM_000155.3 rs111033768
GALT Chr9:34647075 c.83-11T>G NM_000155.3
HSF4 Chr16:67197914 c.-497-8C>G NM_001040667.2 rs573984716
NDP ChrX:43818099 c.-207-1G>A NM_000266.3
NDP ChrX:43832549 c.-208+1G>A NM_000266.3
NDP ChrX:43832548 c.-208+2T>G NM_000266.3
NDP ChrX:43832545 c.-208+5G>A NM_000266.3
NF2 Chr22:30050946 c.516+232G>A NM_000268.3
OCRL ChrX:128687279 c.239-4023A>G NM_000276.3
OCRL ChrX:128674707 c.40-14A>G NM_000276.3
OCRL ChrX:128696350 c.940-11G>A NM_000276.3
PAX6 Chr11:31685945 c.*125537G>T NM_000280.4 rs606231388
PAX6 Chr11:31828474 c.-128-1G>T NM_000280.4
PAX6 Chr11:31832374 c.-129+2T>A NM_000280.4
PAX6 Chr11:31828396 c.-52+1G>A NM_000280.4
PAX6 Chr11:31816377 c.524-41T>G NM_000280.4
SIL1 Chr5:138283180 c.1030-18G>A NM_022464.4 rs769052639
WFS1 Chr4:6271704 c.-43G>T NM_006005.3
WRN Chr8:30966107 c.2089-3024A>G NM_000553.4 rs281865157
WRN Chr8:30999982 c.3234-160A>G NM_000553.4

Added and removed genes from the panel

Genes added Genes removed
ADAMTS18
BFSP1
CHMP4B
CRYBA1
CRYBA4
CRYGS
CTDP1
EPHA2
GALE
MIP
P3H2
PXDN
SLC16A12
VIM
VSX2

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

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).

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 cataract panel covers classical genes associated with cataract, early-onset non-syndromic cataract, Oculocerebrorenal syndrome, Nance-Horan syndrome, Marinesco-Sjogren syndrome, COFS syndrome, Cataract-microcornea syndrome and hereditary hyperferritinemia with congenital cataracts. 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.