Retinitis Pigmentosa/Leber Congenital Amaurosis Panel

Retinitis Pigmentosa/Leber Congenital Amaurosis Panel, Sequencing and Deletion/Duplication 2007085
Method: Massively Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray

Recommended test for confirming a diagnosis of inherited retinal disease, including RP, LCA, Stargardt disease, and cone-rod dystrophy

Familial Mutation, Targeted Sequencing 2001961
Method: Polymerase Chain Reaction/Sequencing
  • Recommended test if there is a known familial sequence variant previously identified in a family member.
  • A copy of the family member’s lab report documenting the known familial variant is required.

Retinitis pigmentosa (RP) is a heterogeneous group of disorders affecting the photoreceptors (rods and cones) and retinal pigment epithelium, leading to visual deterioration. Leber congenital amaurosis (LCA) is a severe retinal dystrophy, with onset in the first year of life. Genetic sequencing and deletion/duplication testing is preferred to confirm a diagnosis of inherited retinal diseases, including RP, LCA, Stargardt disease, and cone-rod dystrophy.

Disease Overview

Symptoms

Retinitis Pigmentosa

  • Most common clinical features:
    • Decreased visual acuity, high myopia, astigmatism
    • Night blindness; onset in childhood
    • Tunnel vision
    • Progressive loss of central vision; usually occurs in third decade of life
    • Various abnormalities on ophthalmic examination
    • Mild hearing loss
  • Individuals with autosomal dominant RP generally have milder disease than those with autosomal recessive or X-linked RP

Leber Congenital Amaurosis

  • Most common clinical features:
    • Initial symptom, poor visual acuity in first year of life
    • Severe retinal dystrophy
    • Congenital nystagmus
    • Poor to near-absent pupillary response
    • Photophobia

Incidence

  • RP – 1/3,500-4,000
  • LCA – ~1/33,000-50,000

Prevalence

Accounts for >5% of all inherited retinopathies

Inheritance

  •   RP – autosomal dominant, autosomal recessive, or X-linked recessive; digenic rarely reported
  •   LCA – autosomal recessive; autosomal dominant rare

Test Description

See Genes Tested table for genes included in the panel.

Clinical Sensitivity

Variable, dependent on phenotype/condition

Limitations

  • A negative result does not exclude a heritable form of RP or LCA.
  • Diagnostic errors can occur due to rare sequence variations.
  • Interpretation of this test result may be impacted if the individual has had an allogeneic stem cell transplantation.
  • The following will not be evaluated:
    • Variants outside the coding regions and intron-exon boundaries of the targeted genes
    • Regulatory region variants and deep intronic variants
    • Breakpoints of large deletions/duplications
    • Deletions/duplications in C8orf37, CHM, CLRN1, FAM161A, IMPG2, IQCB1, KIZ, MAK, NMNAT1, USH1C
    • Noncoding transcripts
    • The following regions are not sequenced due to technical limitations of the assay:
      • CNGA1 (NM_001142564) exon 2
      • CHM (NM_001145414) exon 5
      • RPGR (NM_001034853) exon 15b, also known as amino acids 737-998 or ORF15
  • The following may not be detected:
    • Deletions/duplications/insertions of any size by massively parallel sequencing
    • Deletions/duplications less than 1kb in the targeted genes by array
    • Some variants due to technical limitations in the presence of pseudogenes, repetitive, or homologous regions
    • Low-level somatic variants
    • Single exon deletions/duplications in the following exons:
    • Gene Exon(s)
      CDHR1 (NM_033100) 1
      CEP290 (NM_025114) 52
      CNGA1 (NM_001142564) 2
      CNGB1 (NM_001135639) 13
      CNGB1 (NM_001297) 10, 14, 24, 30
      FSCN2 (NM_001077182) 2, 4, 5
      FSCN2 (NM_012418) 4
      GUCY2D (NM_000180) 11, 16
      IMPDH1 (NM_000883) 1, 4, 7, 10
      IMPDH1 (NM_001142574) 4
      KLHL7 (NM_001031710) 1
      MERTK (NM_006343) 1
      PROM1 (NM_006017) 26
      PRPF3 (NM_004698) 9
      PRPF31 (NM_015629) 11
      RPGR (NM_000328) 1, 2
      RPGRIP1 (NM_020366) 10
      SAG (NM_000541) 13
      SNRNP200 (NM_014014) 1, 43
      SPATA7 (NM_018418) 4
      TTC8 (NM_001288781) 8
      TTC8 (NM_001288782) 6
      TTC8 (NM_198309) 2
      TULP1 (NM_003322) 3, 4, 5

Analytical ​Sensitivity

For massively parallel sequencing:

Variant Class Analytical Sensitivity (PPA) Estimatea (%) Analytical Sensitivity (PPA) 95% Credibility Regiona (%)

SNVs

99.2

96.9-99.4

Deletions 1-10 bp

93.8

84.3-98.2

Deletions 11-44 bp

100

87.8-100

Insertions 1-10 bp

94.8

86.8-98.5

Insertions 11-23 bp

100

62.1-100

aGenes included on this test are a subset of a larger methods-based validation from which the PPA values are derived.

bp, base pairs; PPA, positive percent agreement; SNVs, single nucleotide variants 

Genes Tested

Gene MIM Number Disorder Inheritance

ABCA4

601691

Age-related macular degeneration 2

AD

Stargardt disease 1

Retinitis pigmentosa 19

Cone rode dystrophy 3

AR

AIPL1

604392

Retinitis Pigmentosa

Leber congenital amaurosis 4

AR

BEST1

607854

Macular dystrophy vitelliform 2

Vitreoretinochoroidopathy

Retinitis pigmentosa 50

AD

Bestrophinopathy, autosomal recessive

AR

C8orf37

614477

Cone-rod dystrophy 16

AR

CA4

114760

Retinitis pigmentosa 17

AD

CDHR1

609502

Cone-rod dystrophy 15

Retinitis Pigmentosa 65

AR

CEP290

610142

Senior-Loken Syndrome 6

Leber congenital amaurosis 10

AR

CERKL

608381

Retinitis pigmentosa 26

AR

CHM

300390

Choroideremia

XLD

CLRN1

606397

Usher syndrome, type IIIA

Retinitis pigmentosa 61

AR

CNGA1

123825

Retinitis pigmentosa 49

AR

CNGB1

600724

Retinitis pigmentosa 45

AR

CRB1

604210

Pigmented paravenous chorioretinal atrophy

AD

Retinitis pigmentosa 12

Leber congenital amaurosis 8

AR

CRX

602225

Cone-rod dystrophy 2

AD

Leber congenital amaurosis 7

AD, AR

DHDDS

608172

Retinitis pigmentosa 59

AR

Developmental delay and seizures with or without movement abnormalities

AD

EYS

612424

Retinitis pigmentosa 25

AR

FAM161A

613596

Retinitis pigmentosa 28

AR

FSCN2

607643

Retinitis pigmentosa 30

AD

GUCY2D

600179

Leber congenital amaurosis 1

AR

Cone-rod dystrophy 6

AD, AR

IDH3B

604526

Retinitis pigmentosa 46

AR

IMPDH1

146690

Retinitis pigmentosa 10

Leber congenital amaurosis 11

AD

IMPG2

607056

Retinitis pigmentosa 56

AR

Macular dystrophy vitelliform, 5

AD

IQCB1

609237

Senior-Loken syndrome 5

AR

KIZ

615757

Retinitis pigmentosa 69

AR

KLHL7

611119

Retinitis pigmentosa 42

AD

Crisponi/cold-induced sweating syndrome 3

AR

LCA5

611408

Leber congenital amaurosis 5

AR

LRAT

604863

Leber congenital amaurosis 14

Juvenile retinitis pigmentosa

AR

MAK

154235

Retinitis pigmentosa 62

AR

MERTK

604705

Retinitis pigmentosa 38

AR

NMNAT1

608700

Leber congenital amaurosis 9

AR

NR2E3

604485

Enhanced S-cone syndrome

AR

Retinitis pigmentosa 37

AD, AR

NRL

162080

Retinitis pigmentosa 27

AD

PCARE

613425

Retinitis pigmentosa 54

AR

PDE6A

180071

Retinitis pigmentosa 43

AR

PDE6B

180072

Night blindness, congenital stationary, autosomal dominant 2

AD

Retinitis pigmentosa 40

AR

PRCD

610598

Retinitis pigmentosa 36

AR

PROM1

604365

Stargardt disease 4

Macular dystrophy, retinal, 2

AD

Retinitis pigmentosa 41

AR

Cone-rod dystrophy 12

AD, AR

PRPF3

607301

Retinitis pigmentosa 18

AD

PRPF31

606419

Retinitis pigmentosa 11

AD

PRPF8

607300

Retinitis pigmentosa 13

AD

PRPH2

179605

Retinitis fundus albipunctatus

AD, AR

Macular dystrophy, patterned, 1

Macular dystrophy, vitelliform, 3

Choroidal dystrophy, central areolar 2

AD

Retinitis pigmentosa 7

AD, AR, digenic

RDH12

608830

Leber congenital amaurosis13

AD, AR

RGR

600342

Retinitis pigmentosa 44

AD, AR

RHO

180380

Fundus albipunctatus

AD, AR

Night blindness, congenital stationary, autosomal dominant 1

AD

Retinitis pigmentosa 4

AD, AR rarely

RLBP1

180090

Fundus albipunctatus

AD, AR

Bothnia retinal dystrophy

Newfoundland rod-cone dystrophy

AR

ROM1

180721

Retinitis pigmentosa 7

AD

RP1

603937

Retinitis pigmentosa 1

AD, AR

RP2

300757

Retinitis pigmentosa 2

XL

RPE65

180069

Leber congenital amaurosis 2

Retinitis pigmentosa 20

AR

RPGR

312610

Retinitis pigmentosa 3

Retinitis pigmentosa, X-linked, and sinorespiratory infections, with or without deafness

Macular degeneration, X-linked atrophic

Cone-rod dystrophy, X-linked, 1

XL

RPGRIP1

605446

Cone-rod dystrophy 13

Leber congenital amaurosis 6

AR

SAG

181031

Oguchi disease 1

Retinitis pigmentosa 47

AR

SEMA4A

607292

Retinitis pigmentosa 35

AD, AR

Cone-rod dystrophy 10

AR

SNRNP200

601664

Retinitis pigmentosa 33

AD

SPATA7

609868

Leber congenital amaurosis 3

Juvenile retinitis pigmentosa

AR

TOPORS

609507

Retinitis pigmentosa 31

AD

TTC8

608132

Retinitis pigmentosa 51

AR

TULP1

602280

Retinitis pigmentosa 14

Leber congenital amaurosis 15

AR

USH1C

605242

Usher syndrome, type IC

Deafness, autosomal recessive 18A

AR

USH2A

608400

Usher syndrome, type IIA

Retinitis pigmentosa 39

AR

AD, autosomal dominant; AR, autosomal recessive; XL, X-linked recessive; XLD, X-linked dominant

References 

Chiang JP, Lamey T, McLaren T, Thompson JA, Montgomery H, De Roach J. Progress and prospects of next-generation sequencing testing for inherited retinal dystrophy. Expert Rev Mol Diagn. 2015; 15(10): 1269-75. PubMed

Fahim A, Daiger S, Weleber R. Nonsyndromic Retinitis Pigmentosa Overview. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews, University of Washington, 1993-2018. Seattle, WA [Last Update: Jan 2017; Accessed: Nov 2018]

Huang H, Chen Y, Chen H, Ma Y, Chiang P, Zhong J, Liu X, Wu J, Su Y, Li X, Deng J, Huang Y, Zhang X, Li Y, Fan N, Wang Y, Tang L, Shen J, Chen M, Zhang X, Te D, Banerjee S, Liu H, Qi M, Yi X. Systematic evaluation of a targeted gene capture sequencing panel for molecular diagnosis of retinitis pigmentosa. PLoS One. 2018; 13(4): e0185237. PubMed

Kumaran N, Pennesi M, Yang P, Trzupek K, Schlechter C, Moore A, Weleber R, Michaelides M. Leber Congenital Amaurosis / Early-Onset Severe Retinal Dystrophy Overview. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews, University of Washington, 1993-2018. Seattle, WA [Revised: Oct 2018; Accessed: Nov 2018]

Martin-Merida I, Aguilera-Garcia D, Fernandez-San JP, Blanco-Kelly F, Zurita O, Almoguera B, Garcia-Sandoval B, Avila-Fernandez A, Arteche A, Minguez P, Carballo M, Corton M, Ayuso C. Toward the Mutational Landscape of Autosomal Dominant Retinitis Pigmentosa: A Comprehensive Analysis of 258 Spanish Families. Invest Ophthalmol Vis Sci. 2018; 59(6): 2345-2354. PubMed

Patel N, Aldahmesh MA, Alkuraya H, Anazi S, Alsharif H, Khan AO, Sunker A, Al-Mohsen S, Abboud EB, Nowilaty SR, Alowain M, Al-Zaidan H, Al-Saud B, Alasmari A, Abdel-Salam GM, Abouelhoda M, Abdulwahab FM, Ibrahim N, Naim E, Al-Younes B, AlMostafa AE, AlIssa A, Hashem M, Buzovetsky O, Xiong Y, Monies D, Altassan N, Shaheen R, Al-Hazzaa SA, Alkuraya FS. Expanding the clinical, allelic, and locus heterogeneity of retinal dystrophies. Genet Med. 2016; 18(6): 554-62. PubMed

Last Update: February 2019