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Blueprint Genetics Joubert Syndrome Panel

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Blueprint Genetics Joubert Syndrome Panel Joubert Syndrome Panel Test code: KI1001 Is a 36 gene panel that includes assessment of non-coding variants. Is ideal for patients with a clinical suspicion of Joubert syndrome. The genes on this panel are included in the Ciliopathy Panel and the Retinal Dystriophy Panel. About Joubert Syndrome Classic Joubert syndrome (JS) is characterized by three primary findings: a distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS), hypotonia and developmental delay. MTS, seen on magnetic resonance imaging (MRI), results from hypoplasia of the cerebellar vermis and midbrain-hindbrain malformations. Additional features associated with Joubert syndrome include retinal anomalies, nystagmus, ataxia, polydactyly, hepatic fibrosis, and renal disease. Prevalence estimates range between 1:80,000 and 1:100,000 but this may represent an underestimate. Overall, about 50% of individuals with Joubert syndrome and related disorders have pathogenic variants identified in one of the identified genes. Defective ciliary biology underlies JS and it shares substantial allelism with other ciliopathies. Availability 4 weeks Gene Set Description Genes in the Joubert Syndrome Panel and their clinical significance Gene Associated phenotypes Inheritance ClinVar HGMD AHI1 Joubert syndrome AR 62 93 ARL13B Joubert syndrome AR 11 10 ARMC9 Joubert syndrome 30 AR 12 11 B9D1 Meckel syndrome AR 7 10 B9D2 Meckel syndrome AR 8 4 C21ORF2 Retinal dystrophy with or without macular staphyloma (RDMS), AR 13 22 Spondylometaphyseal dysplasia, axial (SMDAX) C5ORF42 Orofaciodigital syndrome, Joubert syndrome AR 97 103 CC2D2A COACH syndrome, Joubert syndrome, Meckel syndrome AR 76 91 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, AR 130 289 Senior-Loken syndrome, Meckel syndrome https://blueprintgenetics.com/ CEP41 Joubert syndrome AR/Digenic 7 11 CSPP1 Jeune asphyxiating thoracic dystrophy, Joubert syndrome AR 32 27 INPP5E Joubert syndrome, Mental retardation, truncal obesity, retinal dystrophy, AR 25 50 and micropenis (MORM syndrome) 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 KIF7 Acrocallosal syndrome, Hydrolethalus syndrome, Al-Gazali-Bakalinova AR/Digenic 24 44 syndrome, Joubert syndrome MKS1 Bardet-Biedl syndrome, Meckel syndrome AR 50 52 NPHP1 Nephronophthisis, Joubert syndrome, Senior-Loken syndrome AR 19 76 NPHP3 Nephronophthisis, Renal-hepatic-pancreatic dysplasia, Meckel syndrome AR 38 75 OFD1 Simpson-Golabi-Behmel syndrome, Retinitis pigmentosa, Orofaciodigital XL 153 160 syndrome, Joubert syndrome PDE6D Joubert syndrome 22 AR 3 1 RPGRIP1L COACH syndrome, Joubert syndrome, Meckel syndrome, Retinal AR 39 49 degeneration in ciliopathy, modifier 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 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 AR 87 170 syndrome TTC21B Short-rib thoracic dysplasia, Nephronophthisis, Asphyxiating thoracic AR 23 63 dysplasia (ATD; Jeune) ZNF423 Nephronophthisis, Joubert syndrome AD/AR 10 7 *Some regions of the gene are 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 (#). Due to possible https://blueprintgenetics.com/ limitations these genes may not be available as single gene tests. Gene refers to the HGNC approved gene symbol; Inheritance refers to inheritance patterns such as autosomal dominant (AD), autosomal recessive (AR), mitochondrial (mi), 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 Mitomap databases. Non-coding disease causing variants covered by the panel Gene Genomic location HG19 HGVS RefSeq RS-number 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 CEP290 Chr12:88508350 c.1910-11T>G NM_025114.3 CEP290 Chr12:88534822 c.103-18_103-13delGCTTTT NM_025114.3 OFD1 ChrX:13768358 c.935+706A>G NM_003611.2 rs730880283 OFD1 ChrX:13773245 c.1130-22_1130-19delAATT NM_003611.2 rs312262865 OFD1 ChrX:13773249 c.1130-20_1130-16delTTGGT NM_003611.2 TMEM231 Chr16:75575364 c.824-11T>C NM_001077416.2 Test Strengths The strengths of this test include: 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 Some of the panels include the whole mitochondrial genome (please see the Panel Content section) 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 Test Limitations The following exons are not included in the panel as they are not sufficiently covered with high quality sequence reads: CC2D2A (NM_020785:7), KIAA0586 (NM_001244189:6, 33), RPGRIP1L (NM_015272:23), TCTN1 (NM_001173976:2;NM_024549:6). Genes with suboptimal coverage in our assay are marked with number sign (#) and genes https://blueprintgenetics.com/ 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 d etect the following: Complex inversions Gene conversions Balanced translocations Some of the panels include the whole mitochondrial genome (please see the Panel Content section) 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 in nuclear genes (variant with a minor allele fraction of 14.6% is detected with 90% probability) Stretches of mononucleotide repeats Low level heteroplasmy in mtDNA (>90% are detected at 5% level) Indels larger than 50bp Single exon deletions or duplications Variants within pseudogene regions/duplicated segments Some disease causing variants present in mtDNA are not detectable from blood, thus post-mitotic tissue such as skeletal muscle may be required for establishing molecular diagnosis. 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. Test Performance 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. The performance metrics listed
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