UKGTN Testing Criteria

Transcription

1 Test name: Osteopetrosis 21 Gene Panel UKGTN Testing Criteria Approved name and symbol of disorder/condition(s): Panel Test see Appendix 1 Approved name and symbol of gene(s): Panel Test see Appendix 1 OMIM number(s): OMIM number(s): Patient name: Patient postcode: Date of birth: NHS number: Name of referrer: Title/Position: Lab ID: Referrals will only be accepted from one of the following: Referrer Consultant paediatricians specialising in bone marrow transplantation, haematology, metabolic disease, or orthopaedics Consultant Clinical Geneticists Adult Orthopaedic Consultants (O only) Tick if this refers to you. Minimum criteria required for testing to be appropriate as stated in the Gene Dossier: Criteria ARO Clinical phenotype of ARO osteopetrosis. Characterised by generalised increase in bone density, propensity to fracture, macrocephaly, hepatosplenomegaly ± thrombocytopaenia ± anaemia ± progressive deafness and blindness. AND Isolated Case or Autosomal Recessive inheritance O Clinical phenotype of O Type I (OPTA1) characterized by generalized osteosclerosis most pronounced in the cranial vault. Patients are often asymptomatic, but some suffer from pain and hearing loss, low risk of fractures Type II (OPTA2) characterized by sclerosis, predominantly involving spine, the pelvis, and skull base. Fragility of bones and dental abscess. AND isolated case or dominant inheritance Tick if this patient meets criteria Additional Information: At risk family members where familial mutation is known do not require a full panel test but should be offered analysis of the known mutation If the sample does not fulfil the clinical criteria or you are not one of the specified types of referrer and you still feel that testing should be performed please contact the laboratory to discuss testing of the sample.

2 Appendix 1 Genes in panel test and associated conditions. Rows that are highlighted in yellow show where the gene is currently being fully analysed in the context of a single separate UKGTN test. HGNC standard name and symbol of the gene ANKH HGNC number OMIM number OMIM standard name of condition and symbol Craniometaphyseal dysplasia Chondrocalcinosis 2 Mode of inherita nce OMIM number Evidence of association between gene(s) and condition Reichenberger, E., Autosomal Dominant Craniometaphyseal dysplasia is caused by mutations in the transmembrane protein ANK Am.J. Hum. Genet 68: % of horizontal coverage of gene MLPA Comments CA Osteopetrosis recessive 3 OPTB3 Richette, P., An update on the epidemiology of calcium pyrophosphate dehydrate crystal deposition disease. Rheumatology, 48: AR Sly, W., Carbonic anhydrase II deficiency identified as the primary defect in the recessive syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification Proc. Natl. Acad. Sci 80: Borthwick, K., A phenocopy of CAII N/A deficiency: a novel genetic explanation for inherited infantile osteopetrosis with distal renal tubular acidosis. J. Med. Genet 40: Stark, Z., et al Osteopetrosis,

3 CLCN7 * CTSK Osteopetrosis recessive 4 OPTB4 Osteopetrosis dominant OPTA2 AR Orphanet Journal of Rare Diseases 4: Frattini, A., et al Chloride Channel CICN7 Mutations are responsible for severe recessive, dominant and intermediate osteopetrosis Journal of Bone and mineral research 18: Pycnodysostosis AR Hou, W., et al Characterization of novel cathepsin K mutations in the pro and mature polypeptide regions causing pycnodysostosis J. Clin. Invest N/A FAM123B FAM20C FERMT Osteopathia striata with cranial sclerosis Raine syndrome (RNS) Leukocyte adhesion deficiency Type III Pangrazio e XD Jenkins, Z., et al Germline mutations in WTX cause a sclerosing skeletal dysplasia but do not predispose to tumourigenesis Nature Genetics AR Fradin, M., et al Osteosclerotic bone dysplasia in siblings with a FAM20C mutation Clinical Genetics 80: AR Malinin, N., et al A point mutation in KINDLIN3 ablates activation of three integrin subfamilies in humans Nat Med. 15: N/A 88.9 N/A

4 IKBKG LEMD3 LRP5 OSTM1 * Ectodermal dysplasia, anhidrotic with immunodeficiency, osteopetrosis and lymphedema Buschke-Ollendorff syndrome, osteopoikilosis Osteopetrosis dominant Osteopetrosis recessive 5 OPT5 XD Schimd, J., et al Transient hemophagocytosis with deficient cellular cytotoxicity, monoclonal immunoglobulin M Gammopathy, Increased T cell numbers and hypomorphic NEMO mutation Pediatrics 117: e Hellemans, J.,et al Loss-offunction mutations in LEMD3 result in osteopoikilosis, Buschke-Ollendorff syndrome and melorheostosis Nature Genet Van Wesenbeek, L., et al Six novel missense Mutations in the LDL Receptor Protein 5 (LRP5) gene in different conditions with an increased bone density Am. J. Hum Gene. 72: AR Pangrazio, A., Mutations in OSTM1 (Grey Lethal) Define a particularly severe form of Autosomal Recessive Osteopetrosis with Neural involvement, Journal of Bone and mineral research 21: Ramirez, A., Identification of a novel mutation in the coding region of the Grey-Lethal Gene OSTM1 in Human Malignant Infantile Osteopetrosis. Human Mutation 23: N/A 99.5 N/A 98.2 N/A 97.4 N/A

5 PLEKHM1 PTH1R Osteopetrosis recessive Metaphyseal chondrodysplasia, Murk Jansen type AR Van Wesenbeeck, L., et al Involvement of PLECKHM1 in osteoclastic vesicular transport and osteopetrosis in incisors absent rats and humans J. Clin. Invest AR Silve, C., et al Jansen s metaphyseal chondrodysplasia Orphanet Journal of Rare Diseases Encyclopedia, N/A Blomstrand s Lethal chondrodysplasia AR Silve, C., et al Blomstrand s Lethal chondrodysplasia Orphanet Journal Of Rare Diseases Encyclopedia 2005 RASGRP Ollier disease/enchondro matosis Eiken Familial skeletal dysplasia Leukocyte adhesion deficiency Type III AR Silve, C., et al Ollier Disease Orphanet Journal Of Rare Diseases Encyclopedia 2006 Recessive mutations in PTHR1 cause contrasting skeletal dysplasia in Eiken and Blomstrand AR Bergmeier, W., et al Mice lacking the signalling molecular CalDAG-GEFI represent a model for leukocyte deficiency type III J. Clin. Invest 117: N/A

6 SNX10 * SOST TCIRG1 * Osteopetrosis recessive 8 OPT8 AR Aker et al An SNX10 mutation causes malignant osteopetrosis of infancy. J Med. Genet. 49: Sclerosteosis AR Balmans, W., et al Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST) Hum. Mol. Genet. 10: Osteopetrosis, recessive 1, OPTB1 AR Susani, L., et al TCIRG1- dependent recessive osteopetrosis:mutation analysis functional identification of the splicing defects, and in vitro rescue by U1 snrna Hum. Mut. 24: Pangrazio, A., et al Autosomal recessive osteopetrosis: a report of 41 novel mutations in the TCIRG1 gene and diagnostic implications Osteoporos Int, 23: N/A 99.1 N/A TGFB Camurati Engelmann Disease Wada K., et al (2013) A case of autosomeal dominant osteopetrosis type II with a novel TCIRG1 gene mutation. J Pediatr Endocrin Metab 2013;26(5-6): Janssens, K., et al Camurati- Engelmann disease: review of the clinical, radiological, and molecular data of 24 families and implications for diagnosis and treatment J. Med.Gene. 43: N/A

7 TNFRSF11 A (RANK) * TNFSF11 (RANKL) * TYROBP Osteopetrosis recessive 7 OPT Osteopetrosis recessive 2 OPT Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopat hy (PLOSL) (Nasu- Hakola disease) AR Guerrini, M., et al Human Osteoclast- Poor Osteopetrosis with hy[pgammaglobulinemia due to TNFRS11A (RANK) mutations A.J.Hum. Genet 83: AR Sobacchi C., et al Osteoclastpoor human osteopetrosis due to mutations in the gene encoding RANKL Nature Genetics, 39: AR Paloneva, J., et al Mutations in two genes encoding different subunits of a receptor signalling complex result in an identical disease phenotype Am. J. Hum. Genet 71: N/A 95.8 N/A