Retinal Dystrophy Panel

Last modified: Oct 04, 2018

Summary

  • Is a 266 gene panel that includes assessment of non-coding variants
  • Is ideal for patients with a clinical suspicion / diagnosis of an isolated or syndromic retinal dystrophy.

    Is not ideal for patients suspected to have blue cone monochromacy, caused by variants in the OPN1LW and OPN1MW genes.

Analysis methods

  • PLUS
  • SEQ
  • DEL/DUP

Availability

4 weeks

Number of genes

266

Test code

OP0801

Panel size

Large

CPT codes

SEQ 81434
DEL/DUP 81479

Summary

The Blueprint Genetics Retinal Dystrophy Panel (test code OP0801):

  • Is a 266 gene panel that includes assessment of selected non-coding disease-causing variants
  • The majority of the X-linked RP is caused by mutations in the RPGR gene, which contains a mutational hotspot at a unique 567-aa exon called ORF15 accounting for two-thirds of all disease-causing mutations. The exon ORF15, however, includes a highly repetitive, purine-rich sequence, which generally performs poorly in NGS-based assays. Blueprint Genetics custom assay has good coverage (>20x) with high mapping rates (mapping quality >20) for 100.0% of the target regions inRPGR gene. Our validation showed high mean coverage of 139X for the RPGR gene. Thus, our NGS Panel is not expected to have major limitations in detecting variants in RPGR gene including ORF15 exon.

  • Is available as PLUS analysis (sequencing analysis and deletion/duplication analysis), sequencing analysis only or deletion/duplication analysis only

Test Specific Strength

The majority of the X-linked RP is caused by mutations in the RPGR gene, which contains a mutational hotspot at a unique 567-aa exon called ORF15 accounting for two-thirds of all disease-causing mutations. The exon ORF15, however, includes a highly repetitive, purine-rich sequence, which generally performs poorly in NGS-based assays. Blueprint Genetics custom assay has good coverage (>20x) with high mapping rates (mapping quality >20) for 100.0% of the target regions inRPGR gene. Our validation showed high mean coverage of 139X for the RPGR gene. Thus, our NGS Panel is not expected to have major limitations in detecting variants in RPGR gene including ORF15 exon.

ICD codes

Commonly used ICD-10 code(s) when ordering the Retinal Dystrophy Panel

ICD-10 Disease
H35.50 Retinal dystrophy

Sample Requirements

  • EDTA blood, min. 1 ml
  • Purified DNA, min. 3μg
  • Saliva (Oragene DNA OG-500 kit)

Label the sample tube with your patient’s name, date of birth and the date of sample collection.

Note that we do not accept DNA samples isolated from formalin-fixed paraffin-embedded (FFPE) tissue.

Please include fundus photographs, electroretinogram (ERG) findings, visual field findings and visual acuity, if available, for expert review and clinical correlation with test results

Subpanel description

This comprehensive panel includes genes from the following panels: Achromatopsia, Macular Dystrophy, Leber Congenital Amaurosis, Congenital Stationary Night Blindness, Flecked Retina Disorders, Vitreoretinopathy, Cone Rod Dystrophy, Retinitis Pigmentosa, Usher Syndrome, Stickler Syndrome, Bardet-Biedl Syndrome, Senior-Loken Syndrome and Joubert Syndrome.

Retinal dystrophies are a broad group of clinically and genetically heterogenous disorders affecting the retina (Reviewed in PMID: 26835369). Common presentations among these disorders include night or colour blindness, tunnel vision and subsequent progression to complete blindness. Vision loss can occur anywhere from early infancy to late adulthood and both stationary and progressive diseases have been described. The inheritance pattern may be autosomal recessive, autosomal dominant or X-linked. Sporadic cases are also observed. Mutations within the same gene have been shown to cause different disease phenotypes, even among affected individuals within the same family highlighting further levels of complexity. Retinal dystrophy can be nonsyndromic or part of a syndrome in which clinical presentations extend to more than the affected retina. Examples of retinal dystrophies associated with syndromic features are Usher syndrome, Bardet-Biedl syndrome, Joubert syndrome, Senior-Loken syndrome, Cohen syndrome and Alström syndrome. For detailed description of different retinal dystrophies, please see the ophthalmology subpanel descriptions.

Genes in the Retinal Dystrophy Panel and their clinical significance

Gene Associated phenotypes Inheritance ClinVar HGMD
ABCA4 Stargardt disease, Retinitis pigmentosa, Cone rod dystrophy, Retinal dystrophy, early-onset severe, Fundus flavimaculatus AR 306 1116
ABHD12 Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract AR 14 18
ACO2 Optic atrophy, Infantile cerebellar-retinal degeneration AR 16 13
ADAM9 Cone rod dystrophy AR 6 8
ADAMTS18 Knobloch syndrome 2, Microcornea, myopic chorioretinal atrophy, and telecanthus, Retinal dystrophy, early onset, autosomal recessive AR 4 11
ADGRV1 Usher syndrome, Febrile seizures, familial, 4 AR/Digenic 69 207
ADIPOR1* Complement system AD/AR 4
AGBL5 Retinitis pigmentosa 75 AR 2 9
AHI1 Joubert syndrome AR 58 90
AIPL1 Retinitis pigmentosa, Cone rod dystrophy, Leber congenital amaurosis AD/AR 8 74
ALMS1* Alström syndrome AR 64 295
ARHGEF18 Retinitis pigmentosa 78 AR 5 6
ARL2BP Retinitis pigmentosa with or without situs inversus AR 3 4
ARL6 Bardet-Biedl syndrome, Retinitis pigmentosa AR 13 21
ARL13B Joubert syndrome AR 10 10
ARMC9 Joubert syndrome 30 AR 12 11
ATF6 Achromatopsia AR 13 13
ATOH7 Persistent hyperplastic primary vitreous, autosomal recessive AR 4 9
B9D1 Meckel syndrome AR 7 9
B9D2 Meckel syndrome AR 8 4
BBIP1# Bardet-Biedl syndrome 18 AR 1 1
BBS1 Bardet-Biedl syndrome AR 49 103
BBS2 Bardet-Biedl syndrome, Retinitis pigmentosa AR 35 90
BBS4 Bardet-Biedl syndrome AR 21 52
BBS5 Bardet-Biedl syndrome AR 14 30
BBS7 Bardet-Biedl syndrome AR 16 39
BBS9 Bardet-Biedl syndrome AR 24 51
BBS10 Bardet-Biedl syndrome AR 59 100
BBS12 Bardet-Biedl syndrome AR 12 57
BEST1 Vitreoretinochoroidopathy, Microcornea, Rod-cone dystrophy, Posterior staphyloma, Bestrophinopathy, Vitelliform macular dystrophy, Cataract, Retinitis pigmentosa, Macular dystrophy, vitelliform, adult-onset, Retinitis pigmentosa 50, Macular dystrophy, vitelliform 2, Best macular dystrophy, Bestrophinopathy, autosomal recessive AD/AR 56 305
C1QTNF5 Late-onset retinal degeneration AD 25 7
C2ORF71 Retinitis pigmentosa AR 16 49
C5ORF42 Orofaciodigital syndrome, Joubert syndrome AR 84 100
C8ORF37 Retinitis pigmentosa, Cone rod dystrophy AR 8 15
C21ORF2 Retinal dystrophy with or without macular staphyloma (RDMS), Spondylometaphyseal dysplasia, axial (SMDAX) AR 13 19
CA4 Retinitis pigmentosa 17 AD 3 8
CABP4 Night blindness, congenital stationary AR 6 11
CACNA1F Aland Island eye disease, Cone rod dystrophy, Night blindness, congenital stationary XL 39 179
CACNA2D4 Retinal cone dystrophy AR 3 9
CAPN5 Vitreoretinopathy, neovascular inflammatory AD 3 8
CC2D2A COACH syndrome, Joubert syndrome, Meckel syndrome AR 75 90
CDH3 Hypotrichosis, congenital, with juvenile macular dystrophy, Ectodermal dysplasia, ectrodactyly, and macular dystrophy syndrome AR 7 30
CDH23 Deafness, Usher syndrome AR/Digenic 90 351
CDHR1 Retinitis pigmentosa, Cone rod dystrophy AR 12 41
CEP41 Joubert syndrome AR/Digenic 7 10
CEP78 Cone rod dystrophy and hearing loss AR 7 9
CEP104 Joubert syndrome AR 5 4
CEP120 Short-rib thoracic dysplasia 13 with or without polydactyly AR 9 9
CEP164 Nephronophthisis AR 8 9
CEP290* Bardet-Biedl syndrome, Leber congenital amaurosis, Joubert syndrome, Senior-Loken syndrome, Meckel syndrome AR 117 280
CERKL Retinitis pigmentosa AR 20 33
CHM Choroideremia XL 45 278
CIB2 Deafness, Usher syndrome AR 5 15
CISD2* Wolfram syndrome 2 AR 2 4
CLN3 Neuronal ceroid lipofuscinosis, type 3 AR 87 71
CLRN1 Retinitis pigmentosa, Usher syndrome AR 17 39
CNGA1 Retinitis pigmentosa AR 13 31
CNGA3 Leber congenital amaurosis, Achromatopsia AR 31 149
CNGB1 Retinitis pigmentosa AR 25 53
CNGB3 Macular degeneration, juvenile, Achromatopsia AR 111 123
CNNM4 Jalili syndrome AR 10 23
COL2A1 Avascular necrosis of femoral head, Rhegmatogenous retinal detachment, 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 AD 166 544
COL9A1 Stickler syndrome recessive type, Multiple epiphyseal dysplasia type 6 (EDM6) AR 9 5
COL9A2 Stickler syndrome, Multiple epiphyseal dysplasia type 2 (EDM2) AD/AR 7 12
COL9A3 Multiple epihyseal dysplasia type 3 (EDM3) AD/AR 10 15
COL11A1 Marshall syndrome, Fibrochondrogenesis, Stickler syndrome type 2 AD/AR 30 86
COL11A2 Weissenbacher-Zweymuller syndrome, Deafness, Otospondylomegaepiphyseal dysplasia, Fibrochondrogenesis, Stickler syndrome type 3 (non-ocular) AD/AR 28 55
COL18A1 Knobloch syndrome AR 24 29
CRB1 Retinitis pigmentosa, Pigmented paravenous chorioretinal atrophy, Leber congenital amaurosis AD/AR 51 319
CRX Cone rod dystrophy, Leber congenital amaurosis AD/AR 29 94
CSPP1 Jeune asphyxiating thoracic dystrophy, Joubert syndrome AR 27 27
CTC1 Cerebroretinal microangiopathy with calcifications and cysts AR 16 30
CTNNA1 Macular dystrophy, patterned 2 AD 6 9
CTNNB1 Exudative vitreoretinopathy 7, Mental retardation, autosomal dominant 19 AD 83 48
CWC27 Retinitis pigmentosa with or without skeletal anomalies (RPSKA) AR 5 7
CYP4V2 Retinitis pigmentosa, Bietti crystalline corneoretinal dystrophy AR 31 88
DFNB31 Deafness, Usher syndrome AR 11 31
DHDDS Retinitis pigmentosa AR 4 7
DHX38 Retinitis pigmentosa AR 1
DRAM2 Cone-rod dystrophy 21 AR 8 8
DTHD1 Leber congenital amaurosis with muscle dystrophy AR 1
EFEMP1 Doyne honeycomb degeneration of retina, Malattia leventinese AD/AR 2 7
ELOVL4 Stargardt disease, Icthyosis, spastic quadriplegia, and mental retardation, Spinocerebellar ataxia AD/AR 11 12
EMC1 Cerebellar atrophy, visual impairment, and psychomotor retardation AR 3 6
EYS* Retitinis pigmentosa AR 77 277
FAM161A Retitinis pigmentosa AR 11 18
FLVCR1 Ataxia, posterior column, with retinitis pigmentosa AR 9 15
FRMD7 Nystagmus, infantile periodic alternating XL 15 90
FZD4 Retinopathy of prematurity, Exudative vitreoretinopathy AD/Digenic 12 89
GNAT1 Night blindness, congenital stationary AD/AR 4 7
GNAT2 Achromatopsia AR 7 14
GNB3 Night blindness, congenital stationary, type 1H AR 3 6
GNPTG Mucolipidosis AR 28 45
GPR179 Night blindness, congenital stationary AR 13 15
GRM6 Night blindness, congenital stationary AR 11 37
GUCA1A Cone dystrophy 3/Cone rod dystrophy AD 6 21
GUCY2D Cone rod dystrophy, Leber congenital amaurosis AD/AR 31 222
HARS* Usher syndrome, Charcot-Marie-Tooth disease, axonal, type 2W AR 4 9
HGSNAT Mucopolysaccharidosis (Sanfilippo syndrome), Retinitis pigmentosa AR 24 70
HK1 Hemolytic anemia, nonspherocytic, due to hexokinase deficiency, Retinitis pigmentosa 79, Neuropathy, motor and sensory, Russe type (Charcot-Marie-Tooth disease type 4G) AD/AR 9 7
HMX1 Oculoauricular syndrome AR 3 2
IDH3B Retinitis pigmentosa AR 2 3
IFT81 Short rib thoracic dysplasia with polydactyly, Cone-Rod dystrophy, autosomal recessive AR 4 8
IFT140 Short -rib thoracic dysplasia with or without polydactyly, Asphyxiating thoracic dysplasia (ATD; Jeune) AR 37 54
IFT172 Retinitis pigmentosa, Short -rib thoracic dysplasia with or without polydactyly, Asphyxiating thoracic dysplasia (ATD; Jeune) AR 21 23
IMPDH1 Retinitis pigmentosa, Leber congenital amaurosis AD 7 19
IMPG1 Macular dystrophy, vitelliform AD/AR 8 11
IMPG2 Retinitis pigmentosa, Vitelliform macular dystrophy AD/AR 25 38
INPP5E Joubert syndrome, Mental retardation, truncal obesity, retinal dystrophy, and micropenis (MORM syndrome) AR 24 48
INVS Nephronophthisis AR 12 33
IQCB1 Senior-Loken syndrome AR 21 41
JAG1 Alagille syndrome AD 121 569
KCNJ13 Snowflake vitreoretinal degeneration, Leber congenital amaurosis AD/AR 6 10
KCNV2 Retinal cone dystrophy AR 16 94
KIAA0556 Joubert syndrome 26 AR 2 2
KIAA0586 Short rib thoracic dysplasia with polydactyly, Joubert syndrome AR 21 29
KIAA0753 Orofaciodigital syndrome XV AR 6 7
KIF7 Acrocallosal syndrome, Hydrolethalus syndrome, Al-Gazali-Bakalinova syndrome, Joubert syndrome AR/Digenic 23 40
KIF11 Microcephaly AD 37 64
KIZ Retinitis pigmentosa 69 AR 3 4
KLHL7 Retinitis pigmentosa, Retinitis pigmentosa 42 AD 12 11
LCA5 Leber congenital amaurosis AR 10 47
LRAT Retinitis pigmentosa, juvenile, Leber congenital amaurosis, Retinitis punctata albescens, Retinal-dystrophy, early-onset severe AR 8 21
LRIT3 Night blindness, congenital stationary AR 4 9
LRP2 Donnai-Barrow syndrome, Faciooculoacousticorenal syndrome AR 23 30
LRP5* Van Buchem disease, Osteoporosis-pseudoglioma syndrome, Hyperostosis, endosteal, Osteosclerosis, Exudative vitreoretinopathy, Osteopetrosis late-onset form type 1, LRP5 primary osteoporosis AD/AR/Digenic 55 188
LZTFL1 Bardet-Biedl syndrome 17 AR 6 3
MAK Retinitis pigmentosa AR 11 17
MERTK Retinitis pigmentosa AR 25 68
MFN2 Hereditary motor and sensory neuropathy, Charcot-Marie-Tooth disease AD/AR 59 220
MFRP Microphthalmia, isolated 5, Nanophthalmos 2, Retinitis pigmentosa, autosomal recessive AR 25 29
MFSD8 Ceroid lipofuscinosis, neuronal AR 25 46
MKKS Bardet-Biedl syndrome, McKusick-Kaufman syndrome AR 18 59
MKS1 Bardet-Biedl syndrome, Meckel syndrome AR 43 52
MMACHC Methylmalonic aciduria and homocystinuria AR 30 93
MTTP Abetalipoproteinemia AR 11 68
MVK Mevalonic aciduria, Hyper-IgD syndrome, Porokeratosis 3, multiple types AR 30 180
MYO7A Deafness, Usher syndrome, Deafness, autosomal dominant 11 AD/AR 165 491
NDP Exudative vitreoretinopathy, Norrie disease XL 31 165
NEK2 Retinitis pigmentosa 67 AR 1 1
NMNAT1 Leber congenital amaurosis AR 18 69
NPHP1 Nephronophthisis, Joubert syndrome, Senior-Loken syndrome AR 16 73
NPHP3 Nephronophthisis, Renal-hepatic-pancreatic dysplasia, Meckel syndrome AR 31 74
NPHP4 Nephronophthisis, Senior-Loken syndrome AR 15 109
NR2E3 Retinitis pigmentosa, Enhanced S-cone syndrome AD/AR 17 75
NR2F1 Bosch-Boonstra optic atrophy syndrome AD 20 31
NRL Retinitis pigmentosa, Clumped pigmentary retinal degeneration AD/AR 7 25
NYX Night blindness, congenital stationary XL 12 88
OAT Gyrate atrophy of choroid and retina AR 66 70
OFD1 Simpson-Golabi-Behmel syndrome, Retinitis pigmentosa, Orofaciodigital syndrome, Joubert syndrome XL 142 157
OPA1 Optic atrophy, Optic atrophy 1, Optic atrophy with or without deafness, Ophthalmoplegia, myopathy, ataxia, and neuropathy, Behr synrome, Mitochondrial DNA depletion syndrome 14 AD/AR 97 387
OPA3 Optic atrophy, 3-methylglutaconic aciduria AD/AR 9 15
OTX2 Microphthalmia, syndromic, Pituitary hormone deficiency, combined, Retinal dystrophy, early-onset, and pituitary dysfunction AD 21 68
P3H2 Myopia, high, with cataract and vitreoretinal degeneration AR 7 7
PANK2 Hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration, Neurodegeneration with brain iron accumulation AR 30 176
PAX2 Isolated renal hypoplasia, Papillorenal syndrome, Focal segmental glomerulosclerosis 7 AD 24 89
PCDH15 Deafness, Usher syndrome AR/Digenic 73 116
PCYT1A Spondylometaphyseal dysplasia with cone-rod dystrophy AR 12 20
PDE6A Retinitis pigmentosa AR 16 43
PDE6B Retinitis pigmentosa, Night blindness, congenital stationary AD/AR 30 120
PDE6C Cone dystrophy AR 23 41
PDE6D Joubert syndrome 22 AR 3 1
PDE6G Retinitis pigmentosa AR 1 2
PDE6H Retinal cone dystrophy, Achromatopsia AR 2 2
PDZD7 Usher syndrome Digenic 1 18
PEX1 Heimler syndrome, Peroxisome biogenesis factor disorder 1A, Peroxisome biogenesis factor disorder 1B AR 80 132
PEX2 Zellweger syndrome, Peroxisome biogenesis disorder AR 11 18
PEX3 Zellweger syndrome, Peroxisome biogenesis disorder AR 4 10
PEX5 Adrenoleukodystrophy, neonatal, Rhizomelic chondrodysplasia punctata, Zellweger syndrome, Peroxisome biogenesis disorder AR 8 14
PEX6 Heimler syndrome, Peroxisome biogenesis disorder 4A, Peroxisome biogenesis disorder 4B AR 32 106
PEX7 Refsum disease, Rhizomelic CDP type 1 AR 37 52
PEX10 Adrenoleukodystrophy, neonatal, Zellweger syndrome, Peroxisome biogenesis disorder, Ataxia AR 19 29
PEX11B Zellweger syndrome, Peroxisome biogenesis disorder AR 5 7
PEX12 Zellweger syndrome, Peroxisome biogenesis disorder AR 22 37
PEX13 Adrenoleukodystrophy, neonatal, Zellweger syndrome, Peroxisome biogenesis disorder AR 5 10
PEX14 Peroxisome biogenesis factor disorder 14, Zellweger syndrome AR 5 4
PEX16 Zellweger syndrome, Peroxisome biogenesis disorder AR 8 12
PEX19 Peroxisome biogenesis disorder, 19, Zellweger syndrome AR 3 3
PEX26 Adrenoleukodystrophy, neonatal, Zellweger syndrome, Peroxisome biogenesis disorder AR 13 27
PHYH Refsum disease AR 11 36
PITPNM3 Cone-rod dystrophy 5 AD 4
PLA2G5 Fleck retina, familial benign AR 1 7
PNPLA6 Laurence-Moon syndrome, Boucher-Neuhauser syndrome, Spastic paraplegia 39 AR 25 50
POC1B Cone-rod dystrophy 20 AR 4 3
PRCD Retinitis pigmentosa AR 3 7
PRDM13 Macular dystrophy, retinal 1, North Carolina type AD 6
PRKCG Spinocerebellar ataxia AD/AR 28 43
PROM1# Stargardt disease, Retinitis pigmentosa, Cone rod dystrophy, Macular dystrophy, retinal, AD/AR 20 70
PRPF3 Retinitis pigmentosa AD 3 7
PRPF4 Retinitis pigmentosa 70 AD 2 4
PRPF6 Retinitis pigmentosa 60 AD 4 7
PRPF8 Retinitis pigmentosa AD 12 38
PRPF31 Retinitis pigmentosa AD 34 148
PRPH2 Choriodal dystrophy, central areolar, Macular dystrophy, vitelliform, Retinitis pigmentosa, Retinitis punctata albescens, Macula dystrophy, patterned AD/Digenic 46 160
PRPS1* Deafness, Phosphoribosylpyrophosphate synthetase I superactivity, Arts syndrome, Charcot-Marie-Tooth disease, X-linked recessive, 5, Nonsyndromic sensorineural deafness, 2, X-linked XL 27 31
RAB28 Cone-rod dystrophy 18 AR 4 5
RAX2 Cone rod dystrophy AD 5 4
RBP3 Retinitis pigmentosa AR 5 17
RBP4 Retinol dystrophy, iris coloboma, and comedogenic acne syndrome AR 8 7
RD3 Leber congenital amaurosis AR 5 13
RDH5 Fundus albipunctatus AR 11 50
RDH11 Microphthalmia, isolated, with coloboma 10, Retinal dystrophy, juvenile cataracts, and short stature syndrome AD/AR 2 2
RDH12 Retinitis pigmentosa, Leber congenital amaurosis AD/AR 22 99
REEP6 Retinitis pigmentosa 77 AR 4 6
RGR Retinitis pigmentosa AD/AR 2 11
RGS9 Bradyopsia AR 2 2
RGS9BP Bradyopsia AR 2 7
RHO Retinitis pigmentosa, Night blindness, congenital stationary, Retinitis punctata albescens AD/AR 58 205
RIMS1 Cone-rod dystrophy 7 AD 3 8
RLBP1 Newfoundland rod-cone dystrophy, Fundus albipunctatus, Bothnia retinal dystrophy, Retinitis punctata albescens AR 9 35
ROM1 Retinitis pigmentosa 7, digenic Digenic 4 16
RP1 Retinitis pigmentosa AD/AR 41 171
RP1L1 Occult macular dystrophy, Retinitis pigmentosa AD/AR 7 40
RP2 Retinitis pigmentosa XL 24 112
RPE65 Retinitis pigmentosa, Leber congenital amaurosis AR 27 186
RPGR Retinitis pigmentosa, Cone-rod dystrophy, X-linked, 1, Macular degeneration, X-linked atrophic, Retinitis pigmentosa 3 XL 69 203
RPGRIP1 Cone rod dystrophy, Leber congenital amaurosis AR 39 137
RPGRIP1L COACH syndrome, Joubert syndrome, Meckel syndrome, Retinal degeneration in ciliopathy, modifier AD/AR 36 45
RS1 Retinoschisis XL 42 252
RTN4IP1 Optic atrophy 10 with or without ataxia, mental retardation, and seizures AR 2 12
SAG Retinitis pigmentosa, Oguchi disease AD/AR 6 15
SAMD11 Retinitis pigmentosa AR 2 5
SDCCAG8 Bardet-Biedl syndrome, Senior-Loken syndrome AR 14 18
SEMA4A Retinitis pigmentosa, Cone rod dystrophy AR 4 12
SLC7A14 Retinitis pigmentosa 68 AR 4 8
SLC24A1 Night blindness, congenital stationary, type 1D AR 5 26
SLC25A46 Neuropathy, hereditary motor and sensory, type VIB AR 12 13
SNRNP200 Retinitis pigmentosa AD 6 28
SPATA7 Leber congenital amaurosis, Retitinitis pigmentosa AR 15 35
SPP2 Retinitis pigmentosa AD 1 2
TCTN1 Joubert syndrome AR 6 6
TCTN2 Joubert syndrome, Meckel syndrome AR 19 13
TCTN3 Orofaciodigital syndrome (Mohr-Majewski syndrome), Joubert syndrome AR 9 10
TEAD1 Sveinsson choreoretinal atrophy AD 1 2
TIMM8A* Mohr-Tranebjaerg syndrome, Jensen syndrome, Opticoacoustic nerve atrophy with dementia XL 10 21
TIMP3 Sorsby fundus dystrophy AD 5 17
TMEM67 Nephronophthisis, COACH syndrome, Joubert syndrome, Meckel syndrome AR 87 157
TMEM107 Joubert syndrome AD/AR 10 3
TMEM126A Optic atrophy AR 2 1
TMEM138 Joubert syndrome AR 6 8
TMEM216 Joubert syndrome, Meckel syndrome AR 13 8
TMEM231 Joubert syndrome, Meckel syndrome AR 11 19
TMEM237 Joubert syndrome AR 7 11
TOPORS Retitinis pigmentosa AD 6 19
TRAF3IP1 Senior-Loken syndrome 9 AR 11 11
TREX1 Vasculopathy, retinal, with cerebral leukodystrophy, Chilblain lupus, Aicardi-Goutières syndrome AD/AR 30 68
TRIM32 Bardet-Biedl syndrome, Muscular dystrophy, limb-girdle AR 13 16
TRPM1 Night blindness, congenital stationary AR 21 75
TSPAN12 Exudative vitreoretinopathy, Retinal dysplasia and severe familial exudative vitreoretinopathy AD/AR 16 49
TTC8 Bardet-Biedl syndrome, Retinitis pigmentosa AR 5 16
TTC21B Short-rib thoracic dysplasia, Nephronophthisis, Asphyxiating thoracic dysplasia (ATD; Jeune) AR 17 53
TTLL5 Cone-rod dystrophy 19 AR 12 10
TTPA Ataxia with isolated vitamin E deficiency AR 27 28
TUB Retinal dystrophy and obesity AR 1 1
TULP1 Retinitis pigmentosa, Leber congenital amaurosis AR 24 71
USH1C Deafness, Usher syndrome AR 21 51
USH1G Usher syndrome AR 10 31
USH2A Usher syndrome, Retinitis pigmentosa, Retinitis pigmentosa 39 AR 257 1127
VCAN Wagner disease AD 11 19
VPS13B Cohen syndrome AR 248 199
WDPCP Meckel-Gruber syndrome, modifier, Bardet-Biedl syndrome, Congenital heart defects, hamartomas of tongue, and polysyndactyly AR 5 7
WDR19 Retinitis pigmentosa, Nephronophthisis, Short -rib thoracic dysplasia with or without polydactyly, Senior-Loken syndrome, Cranioectodermal dysplasia (Levin-Sensenbrenner) type 1, Cranioectodermal dysplasia (Levin-Sensenbrenner) type 2, Asphyxiating thoracic dysplasia (ATD; Jeune) AD/AR 30 28
WFS1 Wolfram syndrome, Deafness, Wolfram-like syndrome, autosomal dominant, Deafness, autosomal dominant 6/14/38, Cataract 41 AD/AR 68 351
ZNF408 Exudative vitreoretinopathy 6, Retinitis pigmentosa 72 AD/AR 3 9
ZNF423 Nephronophthisis, Joubert syndrome AD/AR 10 7
ZNF513 Retinitis pigmentosa AR 1 3

* Some, or all, of the gene is 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).

The sensitivity to detect variants may be limited in genes marked with an asterisk (*) or number sign (#)

Gene refers to the HGNC approved gene symbol; Inheritance refers to inheritance patterns such as autosomal dominant (AD), autosomal recessive (AR), 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 Orphanet databases.

Non-coding variants covered by the panel

Gene Genomic location HG19 HGVS RefSeq RS-number
ABCA4 Chr1:94526934 c.1938-619A>G NM_000350.2
ABCA4 Chr1:94525509 c.2160+584A>G NM_000350.2
ABCA4 Chr1:94576926 c.302+68C>T NM_000350.2 rs761188244
ABCA4 Chr1:94509799 c.3050+370C>T NM_000350.2
ABCA4 Chr1:94493272 c.4539+1729G>T NM_000350.2
ABCA4 Chr1:94493073 c.4539+1928C>T NM_000350.2
ABCA4 Chr1:94493000 c.4539+2001G>A NM_000350.2
ABCA4 Chr1:94492973 c.4539+2028C>T NM_000350.2 rs869320785
ABCA4 Chr1:94492937 c.4539+2064C>T NM_000350.2
ABCA4 Chr1:94484082 c.5196+1056A>G NM_000350.2
ABCA4 Chr1:94484001 c.5196+1137G>A NM_000350.2 rs778234759
ABCA4 Chr1:94484001 c.5196+1137G>T NM_000350.2
ABCA4 Chr1:94566773 c.570+1798A>G NM_000350.2
ABCA4 Chr1:94468019 c.6148-471C>T NM_000350.2
ABCA4 Chr1:94578638 c.67-16T>A NM_000350.2
BBS1 Chr11:66291682 c.1110+329C>T NM_024649.4 rs571170303
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
BEST1 Chr11:61717900 c.-29+1G>T NM_001139443.1
BEST1 Chr11:61717904 c.-29+5G>A NM_001139443.1
C21ORF2 Chr21:45750232 c.1000-23A>T NM_001271441.1
CA4 Chr17:58236874 c.*89G>A NM_000717.3
CDH23 Chr10:73403617 c.1135-1G>T NM_022124.5
CEP290 Chr12:88494960 c.2991+1655A>G NM_025114.3 rs281865192
CEP290 Chr12:88462434 c.6012-12T>A NM_025114.3 rs752197734
CHM ChrX:85220593 c.315-1536A>G NM_000390.2
CHM ChrX:85223644 c.315-4587T>A NM_000390.2
CLN3 Chr16:28497984 c.461-13G>C NM_000086.2 rs386833721
COL11A1 Chr1:103488576 c.1027-24A>G NM_080629.2
COL11A1 Chr1:103386637 c.3744+437T>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
DHDDS Chr1:26774026 c.441-24A>G NM_024887.3 rs764831063
EYS Chr6:66417023 c.-448+5G>A NM_001142800.1
FRMD7 ChrX:131228285 c.285-118C>T NM_194277.2
GNAT2 Chr1:110151229 c.461+24G>A NM_005272.3 rs397515384
GNPTG Chr16:1412562 c.610-16_609+28del NM_032520.4 rs193302853
GUCY2D Chr17:7906220 c.-9-137T>C NM_000180.3
HK1 Chr10:71038467 c.-390-3818G>C NM_033500.2 rs397514654
HK1 Chr10:71038447 c.-390-3838G>C NM_033500.2 rs797044964
HK1 Chr10:71075518 c.27+14901A>G NM_033500.2 rs187500777
IMPDH1 Chr7:128043703 c.402+57G>A NM_000883.3 rs72624951
JAG1 Chr20:10629767 c.1349-12T>G NM_000214.2
MTTP Chr4:100522736 c.1237-28A>G NM_000253.2
MTTP Chr4:100512792 c.619-5_619-2delTTTA NM_000253.2 rs755155385
MYO7A Chr11:76839534 c.-48A>G NM_000260.3
MYO7A Chr11:76893448 c.3109-21G>A NM_000260.3
NDP ChrX:43818099 c.-207-1G>A NM_000266.3
NDP ChrX:43832549 c.-208+1G>A NM_000266.3
NDP ChrX:43832548 c.-208+2T>G NM_000266.3
NDP ChrX:43832545 c.-208+5G>A NM_000266.3
NMNAT1 Chr1:10003561 c.-69C>T NM_022787.3
NMNAT1 Chr1:10003560 c.-70A>T NM_022787.3
OFD1 ChrX:13773245 c.1130-22_1130-19delAATT NM_003611.2 rs312262865
OFD1 ChrX:13768358 c.935+706A>G NM_003611.2 rs730880283
OPA1 Chr3:193374829 c.2179-40G>C NM_130837.2
OPA1 Chr3:193335986 c.610+360G>A NM_130837.2
OPA1 Chr3:193335990 c.610+364G>A NM_130837.2
PCDH15 Chr10:56560684 c.-29+1G>C NM_001142763.1
PDE6C Chr10:95380377 c.481-12T>A NM_006204.3 rs786200909
PEX6 Chr6:42933952 c.2300+28G>A NM_000287.3 rs267608237
PEX6 Chr6:42933858 c.2301-15C>G NM_000287.3 rs267608236
PEX7 Chr6:137143759 c.-45C>T NM_000288.3 rs267608252
PRDM13 Chr6:100041040 c.-13871C>T .
PRDM13 Chr6:100040987 c.-13924G>C .
PRDM13 Chr6:100040906 c.-14005G>T .
PROM1 Chr4:15989860 c.2077-521A>G NM_006017.2 rs796051882
PRPF31 Chr19:54633399 c.1374+654C>G NM_015629.3
PRPH2 Chr6:42666249 c.829-4C>G NM_000322.4
RPE65 Chr1:68910577 c.246-11A>G NM_000329.2
RPGR ChrX:38160137 c.1059+363G>A NM_001034853.1
RPGRIP1 Chr14:21795769 c.2711-13G>T NM_020366.3 rs369991630
TMEM231 Chr16:75575364 c.824-11T>C NM_001077416.2
USH2A Chr1:216596610 c.-259G>T NM_206933.2
USH2A Chr1:215821092 c.14583-20C>G NM_206933.2
USH2A Chr1:216247476 c.5573-834A>G NM_206933.2
USH2A Chr1:216064540 c.7595-2144A>G NM_206933.2 rs786200928
USH2A Chr1:216039721 c.8845+628C>T NM_206933.2
USH2A Chr1:215967783 c.9959-4159A>G NM_206933.2
WFS1 Chr4:6271704 c.-43G>T NM_006005.3

Added and removed genes from the panel

Genes added Genes removed
ACO2
ADAMTS18
ADIPOR1
AGBL5
ARHGEF18
ARL2BP
ARMC9
ATOH7
BBIP1
C1QTNF5
C21ORF2
CA4
CDH3
CEP104
CEP120
CEP78
CISD2
CTC1
CTNNA1
CTNNB1
CWC27
DHX38
DRAM2
EMC1
GNB3
HGSNAT
IFT81
JAG1
KIAA0556
KIAA0753
KIZ
LZTFL1
MFN2
MFRP
MFSD8
MMACHC
MTTP
NEK2
NR2F1
P3H2
PAX2
PCYT1A
PDE6D
PEX10
PEX11B
PEX12
PEX13
PEX14
PEX16
PEX19
PEX26
PEX3
PEX5
PEX6
PITPNM3
PLA2G5
PNPLA6
POC1B
PRDM13
PRKCG
PRPF4
PRPF6
PRPS1
RAB28
RBP4
RDH11
REEP6
RGS9
RGS9BP
RIMS1
ROM1
RTN4IP1
SAMD11
SLC24A1
SLC25A46
SLC7A14
SPP2
TEAD1
TIMM8A
TIMP3
TRAF3IP1
TREX1
TTLL5
TUB
WDPCP
WFS1
ZNF408
FBLN5
GRK1

Test strength

The majority of the X-linked RP is caused by mutations in the RPGR gene, which contains a mutational hotspot at a unique 567-aa exon called ORF15 accounting for two-thirds of all disease-causing mutations. The exon ORF15, however, includes a highly repetitive, purine-rich sequence, which generally performs poorly in NGS-based assays. Blueprint Genetics custom assay has good coverage (>20x) with high mapping rates (mapping quality >20) for 100.0% of the target regions inRPGR gene. Our validation showed high mean coverage of 139X for the RPGR gene. Thus, our NGS Panel is not expected to have major limitations in detecting variants in RPGR gene including ORF15 exon.

The strengths of this test include:
  • CAP and ISO-15189 accreditations covering all operations at Blueprint Genetics including all Whole Exome Sequencing, NGS panels and confirmatory testing
  • 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
  • Our Nucleus online portal providing transparent and easy access to quality and performance data at the patient level
  • Our publically available analytic validation demonstrating complete details of test performance
  • ~1,500 non-coding disease causing variants in Blueprint WES assay (please see below ‘Non-coding disease causing variants covered by this panel’)
  • Our rigorous variant classification based on modified ACMG 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

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 detect the following:
  • Complex inversions
  • Gene conversions
  • Balanced translocations
  • Mitochondrial DNA variants
  • 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 (variant with a minor allele fraction of 14.6% is detected with 90% probability)
  • Stretches of mononucleotide repeats
  • Indels larger than 50bp
  • Single exon deletions or duplications
  • Variants within pseudogene regions/duplicated segments

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.

The Blueprint Genetics retinal dystrophy panel covers classical genes associated with Bardet-Biedl syndrome, Alström syndrome, Joubert syndrome, Usher syndrome, Stickler syndrome, Norrie disease, Stargardt disease, x-linked retinoschisis, Cohen syndrome, Leber congenital amaurosis, retinal dystrophy, cone rod dystrophy, congenital stationary night blindness, achromatopsia, fundus albipunctatus, Senior-Loken syndrome, Refsum disease, retinitis pigmentosa, choroideremia, gyrate atrophy of choroid and retina and familial exudative vitreoretinopathy. The genes on the panel have been carefully selected based on scientific literature, mutation databases and our experience.

Our panels are sliced from our high-quality whole exome sequencing data. Please see our sequencing and detection performance table for different types of alterations at the whole exome level (Table).

Assays have been validated for different starting materials including EDTA-blood, isolated DNA (no FFPE), saliva and dry blood spots (filter card) and all provide high-quality results. The diagnostic yield varies substantially depending on the assay used, referring healthcare professional, hospital and country. Blueprint Genetics’ Plus Analysis (Seq+Del/Dup) maximizes the chance to find a molecular genetic diagnosis for your patient although Sequence Analysis or Del/Dup Analysis may be a cost-effective first line test if your patient’s phenotype is suggestive of a specific mutation type.

Performance of Blueprint Genetics Whole Exome Sequencing (WES) assay. All individual panels are sliced from WES data.

Sensitivity % (TP/(TP+FN) Specificity %
Single nucleotide variants 99.65% (412,456/413,893) >99.99%
Insertions, deletions and indels by sequence analysis
1-10 bps 96.94% (17,070/17,608) >99.99%
11-50 bps 99.07% (957/966) >99.99%
Copy number variants (exon level dels/dups)
Clinical samples (small CNVs, n=52)
1 exon level deletion 92.3% (24/26) NA
2 exons level deletion/duplication 100.0% (11/11) NA
3-7 exons level deletion/duplication 93.3% (14/15) NA
Microdeletion/-duplication sdrs (large CNVs, n=37))
Size range (0.1-47 Mb) 100% (37/37)
Simulated CNV detection
2 exons level deletion/duplication 90.98% (7,357/8,086) 99.96%
5 exons level deletion/duplication 98.63% (7,975/8,086) 99.98%
     
The performance presented above reached by WES with the following coverage metrics
     
Mean sequencing depth at exome level 174x
Nucleotides with >20x sequencing coverage (%) 99.4%

Bioinformatics

The target region for each gene includes coding exons and ±20 base pairs from the exon-intron boundary. In addition, the panel includes non-coding variants if listed above (Non-coding variants covered by the panel). Some regions of the gene(s) may be removed from the panel if specifically mentioned in the ‘Test limitations” section above. The sequencing data generated in our laboratory is analyzed with our proprietary data analysis and annotation pipeline, integrating state-of-the art algorithms and industry-standard software solutions. Incorporation of rigorous quality control steps throughout the workflow of the pipeline ensures the consistency, validity and accuracy of results. Our pipeline is streamlined to maximize sensitivity without sacrificing specificity. We have incorporated a number of reference population databases and mutation databases such as, but not limited, to 1000 Genomes Project, gnomAD, ClinVar and HGMD into our clinical interpretation software to make the process effective and efficient. For missense variants, in silico variant prediction tools such as SIFT, PolyPhen, MutationTaster are used to assist with variant classification. Through our online ordering and statement reporting system, Nucleus, the customer has an access to details of the analysis, including patient specific sequencing metrics, a gene level coverage plot and a list of regions with inadequate coverage if present. This reflects our mission to build fully transparent diagnostics where customers have easy access to crucial details of the analysis process.

Clinical interpretation

We provide customers with the most comprehensive clinical report available on the market. Clinical interpretation requires a fundamental understanding of clinical genetics and genetic principles. At Blueprint Genetics, our PhD molecular geneticists, medical geneticists and clinical consultants prepare the clinical statement together by evaluating the identified variants in the context of the phenotypic information provided in the requisition form. Our goal is to provide clinically meaningful statements that are understandable for all medical professionals regardless of whether they have formal training in genetics.

Variant classification is the corner stone of clinical interpretation and resulting patient management decisions. Our classifications follow the Blueprint Genetics Variant Classification Schemes based on the ACMG guideline 2015. Minor modifications were made to increase reproducibility of the variant classification and improve the clinical validity of the report. Our experience with tens of thousands of clinical cases analyzed at our laboratory allowed us to further develop the industry standard.

The final step in the analysis of sequence variants is confirmation of variants classified as pathogenic or likely pathogenic using bi-directional Sanger sequencing. Variant(s) fulfilling all of the following criteria are not Sanger confirmed: 1) the variant quality score is above the internal threshold for a true positive call, 2) an unambiguous IGV in-line with the variant call and 3) previous Sanger confirmation of the same variant at least three times at Blueprint Genetics. Reported variants of uncertain significance are confirmed with bi-directional Sanger sequencing only if the quality score is below our internally defined quality score for true positive call. Reported copy number variations with a size <10 exons are confirmed by orthogonal methods such as qPCR if the specific CNV has been seen less than three times at Blueprint Genetics.

Our clinical statement includes tables for sequencing and copy number variants that include basic variant information (genomic coordinates, HGVS nomenclature, zygosity, allele frequencies, in silico predictions, OMIM phenotypes and classification of the variant). In addition, the statement includes detailed descriptions of the variant, gene and phenotype(s) including the role of the specific gene in human disease, the mutation profile, information about the gene’s variation in population cohorts and detailed information about related phenotypes. We also provide links to the references used, congress abstracts and mutation databases to help our customers further evaluate the reported findings if desired. The conclusion summarizes all of the existing information and provides our rationale for the classification of the variant.

Identification of pathogenic or likely pathogenic variants in dominant disorders or their combinations in different alleles in recessive disorders are considered molecular confirmation of the clinical diagnosis. In these cases, family member testing can be used for risk stratification within the family. In the case of variants of uncertain significance (VUS), we do not recommend family member risk stratification based on the VUS result. Furthermore, in the case of VUS, we do not recommend the use of genetic information in patient management or genetic counseling.

Our interpretation team analyzes millions of variants from thousands of individuals with rare diseases. Thus, our database, and our understanding of variants and related phenotypes, is growing by leaps and bounds. Our laboratory is therefore well positioned to re-classify previously reported variants as new information becomes available. If a variant previously reported by Blueprint Genetics is re-classified, our laboratory will issue a follow-up statement to the original ordering health care provider at no additional cost.

General resources