Ciliopathy Panel

Last modified: Mar 01, 2019

Summary

  • Is a 100 gene panel that includes assessment of non-coding variants
  • Is ideal for patients with a clinical suspicion of Bardet-Biedl syndrome, Joubert syndrome, Meckel syndrome, nephronophthisis with or without retinal dystrophy, or complex ciliopathy phenotype.

    Isn’t ideal for a patient with primary ciliary dyskinesia or isomerism/heterotaxy. For patients with a suspicion of primary ciliary dyskinesia, Primary Ciliary Dyskinesia Panel is recommended. For patients with isomerism/heterotaxy, Heterotaxy and Situs Inversus Panel is recommended.

Analysis methods

  • PLUS
  • SEQ
  • DEL/DUP

Availability

4 weeks

Number of genes

100

Test code

KI0701

Panel size

Large

CPT codes

SEQ 81479
DEL/DUP 81479

Summary

The Blueprint Genetics Ciliopathy Panel (test code KI0701):

ICD codes

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

ICD-10 Disease
Q87.89 Bardet-Biedl syndrome
Q04.3 Joubert syndrome
Q61.9 Meckel syndrome
Q61.9 Cystic kidney disease
Q61.5 Nephronophthisis with retinal dystrophy

Sample Requirements

  • 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.

Ciliopathies are a group of disorders resulting from either abnormal formation or function of cilia. Mutations in ciliary gene are known to cause single organ phenotypes, as well as complex syndromes. Ciliopathies have a broad range of phenotypes encompassing a number of different autosomal recessive, dominant and X-linked syndromes. As cilia are a component of almost all cells, ciliary dysfunction can manifest as a collection of features that include retinal degeneration, renal disease and brain malformations. Additional features may include congenital fibrocystic diseases of the liver and pancreas, diabetes, obesity and skeletal dysplasias. Ciliopathies can result from a mutation at a single locus in one patient while mutations affecting a number of different loci can, at the same time, can result in a similar phenotype in other patients. Ciliopathies can be classified according to whether there is aberrant function in an intact cilium or complete absence/loss of the mature cilium. The latter is the case with severe multi-organ phenotypes.

Genes in the Ciliopathy Panel and their clinical significance

Gene Associated phenotypes Inheritance ClinVar HGMD
ACVR2B Heterotaxy, visceral, 4, autosomal AD 1 2
AHI1 Joubert syndrome AR 62 93
ALMS1* Alström syndrome AR 197 302
ANKS6 Nephronophthisis AR 9 12
ARL13B Joubert syndrome AR 11 10
ARL6 Bardet-Biedl syndrome, Retinitis pigmentosa AR 14 21
ARMC9 Joubert syndrome 30 AR 12 11
B9D1 Meckel syndrome AR 7 10
B9D2 Meckel syndrome AR 8 4
BBIP1# Bardet-Biedl syndrome 18 AR 1 1
BBS1 Bardet-Biedl syndrome AR 66 103
BBS10 Bardet-Biedl syndrome AR 90 107
BBS12 Bardet-Biedl syndrome AR 36 58
BBS2 Bardet-Biedl syndrome, Retinitis pigmentosa AR 58 91
BBS4 Bardet-Biedl syndrome AR 25 53
BBS5 Bardet-Biedl syndrome AR 18 31
BBS7 Bardet-Biedl syndrome AR 19 43
BBS9 Bardet-Biedl syndrome AR 27 52
C21ORF2 Retinal dystrophy with or without macular staphyloma (RDMS), Spondylometaphyseal dysplasia, axial (SMDAX) AR 13 22
C2CD3 Orofaciodigital syndrome XIV AR 9 10
C5ORF42 Orofaciodigital syndrome, Joubert syndrome AR 97 103
C8ORF37 Retinitis pigmentosa, Cone rod dystrophy AR 8 17
CC2D2A COACH syndrome, Joubert syndrome, Meckel syndrome AR 76 91
CENPF Ciliary dyskinesia -Lethal Ciliopathy AR 13 8
CEP104 Joubert syndrome AR 7 5
CEP120 Short-rib thoracic dysplasia 13 with or without polydactyly AR 9 9
CEP164 Nephronophthisis AR 11 9
CEP290* Bardet-Biedl syndrome, Leber congenital amaurosis, Joubert syndrome, Senior-Loken syndrome, Meckel syndrome AR 130 289
CEP41 Joubert syndrome AR/Digenic 7 11
CEP83 Nephronophthisis AR 10 10
CRB2 Focal segmental glomerulosclerosis, Ventriculomegaly with cystic kidney disease AR 12 22
CSPP1 Jeune asphyxiating thoracic dystrophy, Joubert syndrome AR 32 27
DCDC2 Deafness AR 13 9
DDX59 Orofaciodigital syndrome V AR 2 6
DHCR7 Smith-Lemli-Opitz syndrome AR 88 217
DYNC2H1 Short -rib thoracic dysplasia with or without polydactyly type 1, Short -rib thoracic dysplasia with or without polydactyly type 3, Asphyxiating thoracic dysplasia (ATD; Jeune), SRPS type 2 (Majewski) AR/Digenic 148 205
DYNC2LI1 Short-rib throacic dysplasia 15 with polydactyly AR 19 14
EVC Weyers acrofacial dysostosis, Ellis-van Creveld syndrome AD/AR 58 83
EVC2 Ellis-van Creveld syndrome, Weyers acrodental dysostosis AD/AR 78 75
FAM58A Toe syndactyly, telecanthus, and anogenital and renal malformations (STAR syndrome) XL 8 11
GLI2 Culler-Jones syndrome AD 29 82
GLI3 Acrocallosal syndrome, Pallister-Hall syndrome, Grieg cephalopolysndactyly syndrome, Postaxial polydactyly type A, Preaxial polydactyly type 3, Preaxial polydactyly type 4 AD 70 235
GLIS2 Nephronophthisis AR 3 3
HYLS1 Hydrolethalus syndrome AR 3 2
IFT122* Sensenbrenner syndrome, Cranioectodermal dysplasia (Levin-Sensenbrenner) type 1, Cranioectodermal dysplasia (Levin-Sensenbrenner) type 2 AR 13 23
IFT140 Short -rib thoracic dysplasia with or without polydactyly, Asphyxiating thoracic dysplasia (ATD; Jeune) AR 38 63
IFT172 Retinitis pigmentosa, Short -rib thoracic dysplasia with or without polydactyly, Asphyxiating thoracic dysplasia (ATD; Jeune) AR 22 25
IFT43 Cranioectodermal dysplasia 3 AR 4 7
IFT80 Short -rib thoracic dysplasia with or without polydactyly, Asphyxiating thoracic dysplasia (ATD; Jeune) AR 11 11
IFT81 Short rib thoracic dysplasia with polydactyly, Cone-Rod dystrophy, autosomal recessive AR 4 9
INPP5E Joubert syndrome, Mental retardation, truncal obesity, retinal dystrophy, and micropenis (MORM syndrome) AR 25 50
INVS Nephronophthisis AR 16 34
IQCB1 Senior-Loken syndrome AR 24 41
KIAA0556 Joubert syndrome 26 AR 2 2
KIAA0586 Short rib thoracic dysplasia with polydactyly, Joubert syndrome AR 29 31
KIAA0753 Orofaciodigital syndrome XV AR 6 7
KIF14 Meckel syndrome 12 AR 9 16
KIF7 Acrocallosal syndrome, Hydrolethalus syndrome, Al-Gazali-Bakalinova syndrome, Joubert syndrome AR/Digenic 24 44
LEFTY2* Left-right axis malformations AD 1 3
LZTFL1 Bardet-Biedl syndrome 17 AR 6 3
MAPKBP1 Nephronophthisis 20 AR 6 7
MKKS Bardet-Biedl syndrome, McKusick-Kaufman syndrome AR 21 59
MKS1 Bardet-Biedl syndrome, Meckel syndrome AR 50 52
NEK1 Short -rib thoracic dysplasia with or without polydactyly, SRPS type 2 (Majewski) AR/Digenic 22 23
NEK8 Nephronophthisis AR 16 18
NODAL Heterotaxy, visceral AD 4 15
NPHP1 Nephronophthisis, Joubert syndrome, Senior-Loken syndrome AR 19 76
NPHP3 Nephronophthisis, Renal-hepatic-pancreatic dysplasia, Meckel syndrome AR 38 75
NPHP4 Nephronophthisis, Senior-Loken syndrome AR 20 113
OFD1 Simpson-Golabi-Behmel syndrome, Retinitis pigmentosa, Orofaciodigital syndrome, Joubert syndrome XL 153 160
PDE6D Joubert syndrome 22 AR 3 1
PKD1* Polycystic kidney disease AD 237 1923
PKD2 Polycystic kidney disease AD 55 333
PKHD1 Polycystic kidney disease AR 249 557
PMM2 Congenital disorder of glycosylation AR 76 128
PNPLA6 Laurence-Moon syndrome, Boucher-Neuhauser syndrome, Spastic paraplegia 39 AR 26 58
POC1B Cone-rod dystrophy 20 AR 4 7
RPGRIP1L COACH syndrome, Joubert syndrome, Meckel syndrome, Retinal degeneration in ciliopathy, modifier AD/AR 39 49
SDCCAG8 Bardet-Biedl syndrome, Senior-Loken syndrome AR 14 18
TCTN1 Joubert syndrome AR 6 6
TCTN2 Joubert syndrome, Meckel syndrome AR 20 15
TCTN3 Orofaciodigital syndrome (Mohr-Majewski syndrome), Joubert syndrome AR 9 12
TMEM107 Joubert syndrome AD/AR 10 3
TMEM138 Joubert syndrome AR 6 8
TMEM216 Joubert syndrome, Meckel syndrome AR 17 8
TMEM231 Joubert syndrome, Meckel syndrome AR 12 19
TMEM237 Joubert syndrome AR 7 11
TMEM67 Nephronophthisis, COACH syndrome, Joubert syndrome, Meckel syndrome AR 87 170
TRAF3IP1 Senior-Loken syndrome 9 AR 11 15
TRIM32 Bardet-Biedl syndrome, Muscular dystrophy, limb-girdle AR 13 16
TTC21B Short-rib thoracic dysplasia, Nephronophthisis, Asphyxiating thoracic dysplasia (ATD; Jeune) AR 23 63
TTC8 Bardet-Biedl syndrome, Retinitis pigmentosa AR 5 16
USP9X Mental retardation, X-linked 99, Mental retardation, X-linked 99, syndromic, female restricted XL 30 27
WDPCP Meckel-Gruber syndrome, modifier, Bardet-Biedl syndrome, Congenital heart defects, hamartomas of tongue, and polysyndactyly AR 6 8
WDR19 Retinitis pigmentosa, Nephronophthisis, Short -rib thoracic dysplasia with or without polydactyly, Senior-Loken syndrome, Cranioectodermal dysplasia (Levin-Sensenbrenner) type 1, Cranioectodermal dysplasia (Levin-Sensenbrenner) type 2, Asphyxiating thoracic dysplasia (ATD; Jeune) AR 33 43
WDR34 Short -rib thoracic dysplasia with or without polydactyly, Asphyxiating thoracic dysplasia (ATD; Jeune) AR 18 21
WDR35 Cranioectodermal dysplasia (Levin-Sensenbrenner) type 1, Cranioectodermal dysplasia (Levin-Sensenbrenner) type 2, Short rib-polydactyly syndrome type 5 AR 28 31
WDR60 Short-rib thoracic dysplasia 8 with or without polydactyly AR 12 13
ZIC3 Heterotaxy, visceral, VACTERL association, Congenital heart defects, nonsyndromic XL 15 41
ZNF423 Nephronophthisis, Joubert syndrome AD/AR 10 7

* 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 Ciliopathy Panel

Gene Genomic location HG19 HGVS RefSeq RS-number
BBS1 Chr11:66291105 c.951+58C>T NM_024649.4
BBS1 Chr11:66291682 c.1110+329C>T NM_024649.4 rs571170303
BBS4 Chr15:73001820 c.77-216delA NM_033028.4 rs113994189
BBS5 Chr2:170354110 c.619-27T>G NM_152384.2
C21ORF2 Chr21:45750232 c.1000-23A>T NM_001271441.1
CEP290 Chr12:88462434 c.6012-12T>A NM_025114.3 rs752197734
CEP290 Chr12:88494960 c.2991+1655A>G NM_025114.3 rs281865192
DYNC2H1 Chr11:103019205 c.2819-14A>G NM_001080463.1 rs781091611
EVC Chr4:5749725 c.940-150T>G NM_153717.2
OFD1 ChrX:13768358 c.935+706A>G NM_003611.2 rs730880283
OFD1 ChrX:13773245 c.1130-22_1130-19delAATT NM_003611.2 rs312262865
PKD1 Chr16:2140209 c.12445-14T>C NM_001009944.2
PKHD1 Chr6:51747238 c.7350+653A>G NM_138694.3
PMM2 Chr16:8898599 c.179-25A>G NM_000303.2 rs760689221
PMM2 Chr16:8941558 c.640-23A>G NM_000303.2
TMEM231 Chr16:75575364 c.824-11T>C NM_001077416.2
WDR35 Chr2:20151929 c.1434-684G>T NM_001006657.1
WDR35 Chr2:20182313 c.143-18T>A NM_001006657.1

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 suboptimal coverage in our assay are marked with number sign (#) and 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. Gene is considered to have suboptimal coverage when >90% of the gene's target nucleotides are not covered at >20x with mapping quality score (MQ>20) reads. 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 ciliopathy panel covers classical genes associated with Bardet-Biedl syndrome, Joubert syndrome, Meckel syndrome, cystic kidney disease and nephronophthisis with retinal dystrophy. 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 the following criteria are not Sanger confirmed: the variant quality score is above the internal threshold for a true positive call, and visual check-up of the variant at IGV is in-line with the variant call. 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.