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Blueprint Genetics Cleft Lip/Palate and Associated Syndromes Panel

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Blueprint Genetics Cleft Lip/Palate and Associated Syndromes Panel Cleft Lip/Palate and Associated Syndromes Panel Test code: MA3701 Is a 22 gene panel that includes assessment of non-coding variants. Is ideal for patients with cleft lip and/or cleft palate, particularly those who have a positive family history for clefts or who are suspected to have an associated genetic syndrome. About Cleft Lip/Palate and Associated Syndromes Clefts of the lip and/or palate are common birth defects. Cleft lip (CL) with or without cleft palate is found in 1/700 – 1/1,000 births and cleft palate (CP) is found in about 1/1,500 births. In most cases CL and/or CP occur as an isolated malformation but they can be part of several genetic syndromes or chromosomal anomalies. The etiology of the non-syndromic clefts remains poorly understood and multifactorial inheritance is suspected but in some families predisposition to clefts may follow autosomal dominant inheritance with varying penetrance. There are many syndromes that can have clefts as a feature. Van der Woude syndrome (VWS) is caused by a pathogenic mutation in IRF6 or GRHL3 and is characterized by cleft lip with or without cleft palate or isolated cleft palate and lower-lip paramedian pits. It follows autosomal dominant inheritance, but penetrance is incomplete. Cleft palate can be a feature of Stickler syndrome, also known as hereditary arthro- ophthalmopathy, an inherited vitreoretinopathy characterized by the association of ocular signs with abnormalities affecting head and face, bone disorders, and sensorineural deafness. Stickler syndrome caused by mutations in COL2A1, COL11A1 or COL11A2 is inherited in an autosomal dominant manner. Autosomal recessive Stickler syndrome is rare and is caused by biallelic mutations in COL9A1, COL9A2 and COL9A3. Kabuki syndrome (KS) is a multiple congenital anomaly syndrome characterized by typical facial features, skeletal anomalies, mild to moderate intellectual disability and postnatal growth deficiency. Other findings may include cleft lip and/or palate. Kabuki syndrome is caused by mutations in KMT2D or KDM6A. Availability 4 weeks Gene Set Description Genes in the Cleft Lip/Palate and Associated Syndromes Panel and their clinical significance Gene Associated phenotypes Inheritance ClinVar HGMD ARHGAP29 AD 3 19 COL11A1 Marshall syndrome, Fibrochondrogenesis, Stickler syndrome type 2 AD/AR 34 94 COL11A2 Weissenbacher-Zweymuller syndrome, Deafness, AD/AR 29 57 Otospondylomegaepiphyseal dysplasia, Fibrochondrogenesis, Stickler syndrome type 3 (non-ocular) COL2A1 Avascular necrosis of femoral head, Rhegmatogenous retinal detachment, AD 180 561 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 COL9A1 Stickler syndrome recessive type, Multiple epiphyseal dysplasia type 6 AD/AR 9 6 (EDM6) COL9A2 Stickler syndrome, Multiple epiphyseal dysplasia type 2 (EDM2) AD/AR 7 12 https://blueprintgenetics.com/ COL9A3 Multiple epihyseal dysplasia type 3 (EDM3), Stickler syndrome recessive AD/AR 10 14 type CTNND1 Blepharocheilodontic syndrome 2, Cleft lip AD 4 16 FOXE1 Thyroid cancer, nonmedullary 4, Hypothyroidism, thyroidal, with spiky AD/AR 4 23 hair and cleft palate (Bamforth-Lazarus syndrome), Congenital hypothyroidism GRHL3 van der Woude syndrome 2 AD 12 27 IRF6 Orofacial cleft, Popliteal pterygium syndrome, van der Woude syndrome AD 45 338 KDM6A Kabuki syndrome XL 40 69 KMT2D Kabuki syndrome AD 350 670 MSX1 Orofacial cleft 5, Tooth agenesis, selective, 1, with/without orofacial cleft, AD 11 48 Witkop syndrome SATB2 Glass syndrome AD 62 106 SPECC1L Facial clefting, oblique, 1, Opitz GBBB syndrome, type II AD 7 8 TBX2 AD 1 12 TBX22 Cleft palate with or without ankyloglossia XL 12 29 TGDS Catel-Manzke syndrome AR 6 7 TP63 Rapp-Hodgkin syndrome, Orofacial cleft, ADULT syndrome, Ectrodactyly, AD 59 122 ectodermal dysplasia, and cleft lip/palate syndrome, Ankyloblepharon- ectodermal defects-cleft lip/palate, Split-hand/foot malformation, Limb- mammary syndrome TXNL4A Burn-McKeown syndrome AR 19 13 ZSWIM6 Acromelic frontonasal dysostosis AD 4 2 *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 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 COL11A1 Chr1:103386637 c.3744+437T>G NM_080629.2 https://blueprintgenetics.com/ COL11A1 Chr1:103488576 c.1027-24A>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 IRF6 Chr1:209975332 c.-19C>A NM_006147.3 IRF6 Chr1:209975361 c.-48A>T NM_006147.3 IRF6 Chr1:209979367 c.-151G>A NM_006147.3 IRF6 Chr1:209979435 c.-219C>T NM_006147.3 IRF6 Chr1:209989478 c.-10263dupT NM_006147.3 KMT2D Chr12:49428461 c.10356-12G>A NM_003482.3 TBX2 Chr17:59476302 c.-1236G>C NM_005994.3 TBX2 Chr17:59477201 c.-337C>T NM_005994.3 TBX2 Chr17:59477347 c.-191G>A NM_005994.3 TBX2 Chr17:59477352 c.-185delG NM_005994.3 TBX2 Chr17:59477371 c.-167G>A NM_005994.3 TBX22 ChrX:79270181 NM_001109878.1 rs1051260152 TBX22 ChrX:79278546 c.176-13C>A NM_016954.2 rs55760411 TXNL4A Chr18:77748580 c.-60-10913_-60-10880del34 NM_001305563.1 rs535089924 TXNL4A Chr18:77748603 c.-60-10936_-60-10903del34 NM_001305563.1 rs786205699 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 https://blueprintgenetics.com/ 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 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).
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