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Blueprint Genetics Congenital Hepatic Fibrosis Panel

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Congenital Hepatic Fibrosis Panel Test code: GA0101 Is a 52 gene panel that includes assessment of non-coding variants. Is ideal for patients presenting with congenital or early onset hepatic fibrosis including those with a clinical suspicion of autosomal recessive polycystic kidney and liver disease, Bardet-Biedl syndrome or Joubert syndrome. About Congenital Hepatic Fibrosis Congenital hepatic fibrosis (CHF) is a rare, mostly autosomal recessive condition that presents at birth and affects the liver. CHF rarely occurs as an isolated problem and is typically associated with ciliopathy syndromes that affect the kidneys. In many cases gross malformations are phenotypically pathognomonic such such as anencephaly in Meckel syndrome and the liver fibrosis is only a minor feature. The ciliopathy syndromes with hepatic fibrosis include Bardet-Biedl syndrome and Joubert syndrome. In contrast to ciliopathies, polycystic kidney disease affects relatively few organ systems other than liver cysts and hepatic fibrosis which present regularly. Typical liver abnormalities include an enlarged liver, portal hypertension and hepatic fibrosis. Gastrointestinal bleeding, splenomegaly and hypersplenism along with low platelet count may be present in the early stages of the disease. The prevalence of Bardet-Biedl syndrome is 1:13,500-140,000, Joubert syndrome 1:80,000-100,000 and autosomal recessive polycystic kidney and liver disease 1:10,000-40,000. Availability 4 weeks Gene Set Description Genes in the Congenital Hepatic Fibrosis Panel and their clinical significance Gene Associated phenotypes Inheritance ClinVar HGMD AHI1 Joubert syndrome AR 62 93 ANKS6 Nephronophthisis AR 9 12 ARL13B Joubert syndrome AR 11 10 ARL6 Bardet-Biedl syndrome, Retinitis pigmentosa AR 14 21 B9D1 Meckel syndrome AR 7 10 B9D2 Meckel syndrome AR 8 4 BAAT Hypercholanemia, familial AR 3 7 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 https://blueprintgenetics.com/ BBS7 Bardet-Biedl syndrome AR 19 43 BBS9 Bardet-Biedl syndrome AR 27 52 C5ORF42 Orofaciodigital syndrome, Joubert syndrome AR 97 103 CC2D2A COACH syndrome, Joubert syndrome, Meckel syndrome AR 76 91 CEP164 Nephronophthisis AR 11 9 CEP290* Bardet-Biedl syndrome, Leber congenital amaurosis, Joubert syndrome, AR 130 289 Senior-Loken syndrome, Meckel syndrome CEP41 Joubert syndrome AR/Digenic 7 11 DCDC2 Deafness, Nephronophthisis, Sclerosing cholangitis, neonatal AR 13 9 GLIS2 Nephronophthisis AR 3 3 INPP5E Joubert syndrome, Mental retardation, truncal obesity, retinal dystrophy, AR 25 50 and micropenis (MORM syndrome) INVS Nephronophthisis AR 16 34 IQCB1 Senior-Loken syndrome AR 24 41 KIF7 Acrocallosal syndrome, Hydrolethalus syndrome, Al-Gazali-Bakalinova AR/Digenic 24 44 syndrome, Joubert syndrome LIPA Wolman disease, Cholesterol ester storage disease AR 27 93 MKKS Bardet-Biedl syndrome, McKusick-Kaufman syndrome AR 21 59 MKS1 Bardet-Biedl syndrome, Meckel syndrome AR 50 52 NEK8 Nephronophthisis AR 16 18 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 NR1H4 Cholestasis, progressive familial intrahepatic 5 AR 6 5 OFD1 Simpson-Golabi-Behmel syndrome, Retinitis pigmentosa, Orofaciodigital XL 153 160 syndrome, Joubert syndrome PKD2 Polycystic kidney disease AD 55 333 PKHD1 Polycystic kidney disease AR 249 557 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 https://blueprintgenetics.com/ 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 TRIM32 Bardet-Biedl syndrome, Muscular dystrophy, limb-girdle AR 13 16 TTC21B Short-rib thoracic dysplasia, Nephronophthisis, Asphyxiating thoracic AR 23 63 dysplasia (ATD; Jeune) TTC8 Bardet-Biedl syndrome, Retinitis pigmentosa AR 5 16 WDR19 Retinitis pigmentosa, Nephronophthisis, Short -rib thoracic dysplasia with AR 33 43 or without polydactyly, Senior-Loken syndrome, Cranioectodermal dysplasia (Levin-Sensenbrenner) type 1, Cranioectodermal dysplasia (Levin- Sensenbrenner) type 2, Asphyxiating thoracic dysplasia (ATD; Jeune) WDR35 Cranioectodermal dysplasia (Levin-Sensenbrenner) type 1, AR 28 31 Cranioectodermal dysplasia (Levin-Sensenbrenner) type 2, Short rib- polydactyly syndrome type 5 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 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 BBS1 Chr11:66291105 c.951+58C>T NM_024649.4 BBS4 Chr15:73001820 c.77-216delA NM_033028.4 rs113994189 BBS5 Chr2:170354110 c.619-27T>G NM_152384.2 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 https://blueprintgenetics.com/ 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 PKD2 Chr4:88940551 c.596-59A>G NM_000297.3 rs750504141 PKHD1 Chr6:51618610 c.8798-459C>A NM_138694.3 PKHD1 Chr6:51747238 c.7350+653A>G NM_138694.3 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 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), 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 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) https://blueprintgenetics.com/ 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
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  • Molar Tooth Sign with Deranged Liver Function Tests: an Indian Case with COACH Syndrome

    Molar Tooth Sign with Deranged Liver Function Tests: an Indian Case with COACH Syndrome

    Hindawi Publishing Corporation Case Reports in Pediatrics Volume 2015, Article ID 385910, 3 pages http://dx.doi.org/10.1155/2015/385910 Case Report Molar Tooth Sign with Deranged Liver Function Tests: An Indian Case with COACH Syndrome Rama Krishna Sanjeev,1 Seema Kapoor,2 Manisha Goyal,3 Rajiv Kapur,4 and Joseph Gerard Gleeson5,6,7 1 Department of Pediatrics, ACMS, India 2DivisionofGenetics,LokNayak&MaulanaAzadMedicalCollege,NewDelhi,India 3Department of Paediatrics, Maulana Azad Medical College, New Delhi, India 4Department of Radiology, ACMS, New Delhi, India 5Neurogenetics Laboratory, Department of Neurosciences and Paediatrics, USA 6Rady Children’s Hospital, USA 7Howard Hughes Medical Institute, CA, USA Correspondence should be addressed to Rama Krishna Sanjeev; [email protected] Received 18 October 2014; Revised 18 March 2015; Accepted 30 March 2015 Academic Editor: Ozgur Cogulu Copyright © 2015 Rama Krishna Sanjeev et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. We report the first genetically proven case of COACH syndrome from the Indian subcontinent in a 6-year-old girl who presented with typical features of Joubert syndrome along with hepatic involvement. Mutation analysis revealed compound heterozygous missense mutation in the known gene TMEM67 (also called MKS3). 1. Introduction born to nonconsanguineous couple at term after LSCS with birth weight of 3.5 kg. Her motor developmental milestones COACH syndrome (cerebellar vermis hypo/aplasia, oligo- and speech were grossly delayed. phrenia, congenital ataxia, coloboma, and hepatic fibrosis; On examination, her weight was 18.2 kg (50th centile), OMIM# 216360) is a rare autosomal recessive multisystemic height 107 cm (50th centile), and head circumference 53 cm disorder first proposed by Verloes and Lambotte [1].