Clinical Utility Gene Card for: autosomal recessive cone-rod dystrophy

European Journal of Human Genetics (2015) 23, doi:10.1038/ejhg.2015.67 & 2015 Macmillan Publishers Limited All rights reserved 1018-4813/15 www.nature.com/ejhg CLINICAL UTILITY GENE CARD Clinical Utility Gene Card for: autosomal recessive cone-rod dystrophy Maria Pia Manitto*,1, Susanne Roosing2,3,7, Camiel JF Boon4,5, Eric H Souied6, Francesco Bandello1 and Giuseppe Querques1,6 European Journal of Human Genetics (2015) 23, doi:10.1038/ejhg.2015.67; published online 15 April 2015 1. DISEASE CHARACTERISTICS 1.1 Name of the Disease (Synonyms) Autosomal recessive (ar) cone-rod dystrophy (CORD/CRD), ar conerod degeneration. 1.2 OMIM# of the Disease CORD1 600624, CORD3 604116, CORD8 605549, CORD9 612775, CORD12 612657, CORD13 608194, CORD15 613660, CORD16 614500, ESCS 268100, RCD3A 610024, RCD3B 610356. 1.3 Name of the Analysed Genes or DNA/Chromosome Segments Gene Name Locus ABCA4 ATP-binding cassette, sub-family A (ABC1), member 4 1p21-23 ADAM9 A disintegrin and metalloproteinase domain 9 8p11.23 C8orf37 Chromosome 8 open reading frame 37 8q22.1 CDHR1 Cadherin-related family, member 1 10q23.1 CERKL Ceramide kinase-like 2q31.3 CNGB3 Cyclic nucleotide-gated channel, beta-3 18q21.3 CORD1 Locus 18q21.1-q21.3 CORD8 Locus 1q12-q24 CORD17 Locus 10q26.1 CRX Cone-rod homeobox-containing gene 19q13.33 EYS Eyes shuthomolog (Drosophila) 6q12 FSCN2 Fascin homolog 2, actin-bundling protein, retinal 17q25.3 GUCY2D Guanylatecyclase 2D, membrane 17p13.1 KCNV2 Potassium channel, voltage-gated, subfamily v, member 2 9p24.2 PDE6C Phosphodiesterase 6C, cGMP-specific, cone, alpha prime 10q24 POC1B POC1 centriolar protein homolog B 12q21.33 PROM1 Prominin 1 4p15.32 RAB28 RAS-associated protein 28 4p15.33 RPE65 Retinal pigment epithelium-specific protein 65kDa 1p31 RPGRIP1 Retinitis pigmentosa GTPase regulator-interacting protein 14q11.2 TULP1 6p21.31 Tubby-like protein 1 1.4 OMIM# of the Gene(s) ABCA4 (CORD3) 601691, ADAM9 (CORD9) 602713, C8orf37 (CORD16) 614477, CDHR1 (CORD15) 609502, CERKL (RP26) 608381, CNGB3 (ACHM3) 605080, CORD1 600624, CORD8 605549, CORD17 615163, CRX (CORD2) 602225, EYS (RP25) 612424, FSCN2 (RP30) 607643, GUCY2D (CORD6) 600179, KCNV2 (RCD3B) 607604, PDE6C (COD4) 600827, POC1B 614784, PROM1 604365, RAB28 (CORD18) 612994, RPE65 (RP20) 180069, RPGRIP1 (CORD13) 605446, TULP1 (RP14) 602280. 1.5 Mutational Spectrum All types of mutations have been reported: nonsense mutations, missense mutations, splice-site mutations, frameshift mutations, and also small deletions, duplications and insertions. Large gene rearrangements are rare; three deletions in ABCA4 have been identified spanning exon 5, 18 and exon 20–22, respectively.1–3 In the KCNV2 gene, several deletions are described ranging from single basepairs deletions to complete gene deletions.4,5 1.6 Analytical Methods Several strategies can be used. (1) Genotyping microarrays with the known cone-rod and cone dystrophy causing mutations (includes recessive, dominant and X-linked causative genes).6 This approach is relatively inexpensive, although one should consider this chip only contains a subset of the known pathogenic variants. (2) Direct sequencing of the coding regions and their intron–exon boundaries of known CRD genes. (3) When only one mutation in a CRD gene is identified, or no mutations at all, MLPA/quantitative multiplex PCR enables the detection of heterozygous copy number variants (deletions or duplications) affecting one exon or more. (4) Next-generation sequencing (NGS) provides a large-scale sequencing of the exome in a single experiment for an individual and will likely be privileged in diagnostic screening. In the future, whole genome sequencing could become available for diagnostic analysis provided that the functional relevance of variants in non-coding regions is established. 1.7 Analytical Validation Sequence variants have to be confirmed using bidirectional sequencing. In addition, a segregation analysis in the parents and affected and/or unaffected siblings has to be performed to demonstrate ‘biallelism’ or ‘biparental transmission’ following a recessive pattern 1 Department of Ophthalmology, University Vita Salute San Raffaele, Milan, Italy; 2Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands; 3Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, The Netherlands; 4Department of Ophthalmology, Radboud University Medical Centre, Nijmegen, The Netherlands; 5Oxford Eye Hospital, University of Oxford, Oxford, UK; 6Department of Ophthalmology, University Paris Est Creteil, Centre Hospitalier Intercommunal de Creteil, Creteil, France *Correspondence: Dr MP Manitto, Department of Ophthalmology, University Vita Salute San Raffaele, Via Olgettina 60, Milan 20132, Italy. Tel: +390226432648; Fax: +390226433643; E-mail: 7Current address: Howard Hughes Medical Institute, Laboratory for Pediatric Brain Diseases, The Rockefeller University, New York, NY 10021-6399, USA. Received 29 June 2013; revised 5 March 2015; accepted 20 March 2015; published online 15 April 2015 Clinical Utility Gene Card e2 of inheritance. The variant should be tested in ethnically matched unaffected control individuals. Variant with known causality may have been entered in the human gene mutation database (HGMD, http:// www.hgmd.org/) or gene specific databases Leiden Open Variation Database (LOVD; http://www.lovd.nl/2.0/index.php). The importance of these databases lies in the fact of sharing significant results as well as findings that are debatable due to their low presence or inheritance pattern. These findings might lack support due to their low frequency; however, their contribution in databases may yield to significance by combining data worldwide. Variants should be compared with the presence in the Exome Variant Server (http://evs.gs.washington.edu/ EVS/) and in dbSNP (http://www.ncbi.nlm.nih.gov/SNP/) to assess the frequency in general and in the unaffected population, respectively. Importantly, the presence of variants in dbSNP does not exclude pathogenicity as mutations may have been typed as rare variant or polymorphism in the past. The Exome Variant Server and dbSNP should serve as a library to consult the variant of interest on the frequency in the healthy population that should be consistent with the frequency of the disease; however, these databases should not be used to systematically discard variants from investigations. The pathogenicity of the variant can be assessed using several in silico predicting online available programs like SIFT (http://www.blocks.fhcrc. org/sift/SIFT.html), polyphen-2 (http://www.bork.embl-heidelberg.de/ PolyPhen) and MutPred (http://mutpred.mutdb.org) for missense variants, together with the nucleotide conservation (PhyloP), and score for amino-acid change (Grantham score). These assessments together provide information on the pathogenicity of the variant. Variant (...truncated)