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Pan Retinal Disorders Panel

The Pan Retinal Disorders Panel is a comprehensive next-generation sequencing (NGS) panel that can be used to confirm a clinical diagnosis of an inherited retinal disorder or identify at-risk individuals.

Inherited retinal disorders are hereditary conditions that involve deterioration of the light sensing region at the back of the eye, the retina, which result in loss of visual acuity or vision loss. Retinal disorders are either congenital and stable, or occur in childhood or adulthood, and are progressive in nature. In some cases vision loss is the only symptom, or occurs as part of a syndromic condition. Some of the most common forms of nonsyndromic retinal disorders include achromatopsia, cone-rod dystrophy, congenital stationary night blindness, macular dystrophy, Leber congenital amaurosis, and retinitis pigmentosa. Syndromic retinal disorders include Bardet-Biedl syndrome and Usher syndrome.

Included disorders

This panel includes genes associated with:

  • Achromatopsia
  • Bardet-Biedl syndrome
  • Cone-rod dystrophy
  • Congenital stationary night blindness
  • Macular dystrophy
  • Leber congenital amaurosis
  • Retinitis pigmentosa
  • Usher syndrome
  • Other retinal disorders

Prevalence

The prevalences of various forms of inherited retinal disorders are:

  • Achromatopsia: 1/30,000 (Kohl et al, 2004)
  • Leber congenital amaurosis: 1/30,000-1/50,000 (Weleber et al, 2004)
  • Bardet-Biedl syndrome: 1/100,000 (Forsyth and Beales, 2003)
  • Macular dystrophy: ~1/8,000 for Stargardt disease (Molday and Zhang, 2010)
  • Cone-rod dystrophy: 1/40,000 (Hamel, 2007)
  • Retinitis Pigmentosa: 1/3,500 -1/4000 (Haim, 2002)
  • Congenital stationary night blindness: Unknown
  • Usher syndrome: 1/6,000 (Kimberling et al, 2010)

Inheritance and Penetrance

Inherited retinal disorders are inherited in autosomal dominant, autosomal recessive, and X-linked fashions.

Clinical Sensitivity

The clinical sensitivity of this test is dependent on the patient’s phenotype. In general, the clinical sensitivity for each condition is listed below:

  • Achromatopsia: 75-90% (Kohl and Hamel, 2013)
  • Leber congenital amaurosis: 50-70% (Chacon-camacho and Zenteno, 2015)
  • Bardet-Biedl syndrome: ~77% (Forsyth and Beales, 2003)
  • Macular dystrophy: ~80% for Stargardt disease (Shroyer et al, 2001)
  • Cone-rod dystrophy: ~50% (Hamel, 2007)
  • Usher syndrome: 90% (Bolz and Roux, 2011)
  • Congenital stationary night blindness: 93% (Bijveld et al, 2013)
  • Retinitis pigmentosa: ~70% for dominant, ~30% for recessive, ~90% for X-linked forms (Daiger et al, 2013)

Methodology and Analytical Sensitivity

Next-generation sequencing technology is used to test clinically relevant portions of each gene, including coding exons, adjacent flanking bases, and selected introns/noncoding variants. Pathogenic and likely pathogenic variants are confirmed by orthogonal methods. Copy number variants, including intragenic deletions and duplications are detected to a resolution of a single exon. To request analysis of a specific single exon copy number variant, please contact our Client Services team prior to ordering. Analytical sensitivity and specificity of the assay is >99%.

Indications for Testing

  • Confirmation of a clinical diagnosis
  • Individuals with isolated or syndromic retinal disorders
  • Risk assessment for asymptomatic family members of proband with molecular diagnosis of inherited retinal disorder

Included Genes (146)

ABCA4 CACNA2D4 EFEMP1 IFT172 NMNAT1 PRPF8 SLC24A1
ABHD12 CAPN5 ELOVL4 IMPDH1 NPHP1 PRPH2 SNRNP200
ADAM9 CDH23 EMC1 IMPG1 NPHP4 RAX2 SPATA7
ADGRV1 CDH3 EYS IMPG2 NR2E3 RBP3 TIMP3
AIPL1 CDHR1 FAM161A IQCB1 NRL RBP4 TMEM126A
ARL6 CEP290 FBLN5 KCNJ13 NYX RD3 TOPORS
ATF6 CERKL FLVCR1 KCNV2 OAT RDH12 TRIM32
BBS1 CIB2 FZD4 KIZ OPA3 RDH5 TRNT1
BBS10 CLRN1 GDF6 KLHL7 OTX2 RGR TRPM1
BBS12 CNGA1 GNAT1 LCA5 PCDH15 RHO TSPAN12
BBS2 CNGA3 GNAT2 LRAT PDE6A RLBP1 TTC8
BBS4 CNGB1 GPR179 LRIT3 PDE6B RP1 TULP1
BBS5 CNGB3 GRK1 LZTFL1 PDE6C RP1L1 USH1C
BBS7 CNNM4 GRM6 MAK PDE6G RP2 USH1G
BBS9 COL11A1 GUCA1A MERTK PDE6H RPE65 USH2A
BEST1 COL2A1 GUCY2D MKKS PDZD7 RPGR VCAN
C2ORF71 COL9A1 HARS MKS1 PRCD RPGRIP1 WDPCP
C8ORF37 CRB1 HGSNAT MVK PROM1 RS1 WDR19
CA4 CRX HK1 MYO7A PRPF3 SAG WHRN
CABP4 CYP4V2 IDH3B NDP PRPF31 SDCCAG8 ZNF513
CACNA1F DHDDS IFT140 NEK2 PRPF6 SEMA4A

 

Additions to the Pan Retinal Disorders Panel

Emerging evidence genes can also be added to the Pan Retinal Disorders Panel. These genes do not have a clear association with inherited retinal disorders, but emerging evidence suggests that they may play a role in disease pathogenesis:

Emerging Evidence Genes (17)

DHX38 GUCA1B NEK2 RIMS1 SLC24A1 UNC119
DTHD1 INPP5E PITPNM3 ROM1 SLC7A14 ZNF408
FSCN2 KIAA1549 PRDM13 RP9 SPP2

 

References

  1. Bijveld MM, Florijn RJ, Bergen AA, et al. Genotype and phenotype of 101 dutch patients with congenital stationary night blindness. Ophthalmology. 2013;120(10):2072-81.
  2. Bolz HJ, Roux AF. Clinical utility gene card for: Usher syndrome. Eur J Hum Genet. 2011;19(8)
  3. Chacon-camacho OF, Zenteno JC. Review and update on the molecular basis of Leber congenital amaurosis. World J Clin Cases. 2015;3(2):112-24.
  4. Daiger SP, Sullivan LS, Bowne SJ. Genes and mutations causing retinitis pigmentosa. Clin Genet. 2013;84(2):132-41.
  5. Forsythe E, Beales PL. Bardet-Biedl Syndrome. 2003 Jul 14 [Updated 2015 Apr 23]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017.
  6. Hamel CP. Cone rod dystrophies. Orphanet J Rare Dis. 2007;2:7.
  7. Haim M. Epidemiology of retinitis pigmentosa in Denmark. Acta Ophthalmol Scand Suppl. 2002;(233):1-34.
  8. Kimberling WJ, Hildebrand MS, Shearer AE, et al. Frequency of Usher syndrome in two pediatric populations: Implications for genetic screening of deaf and hard of hearing children. Genet Med. 2010;12(8):512-6.
  9. Kohl S, Hamel C. Clinical utility gene card for: Achromatopsia – update 2013. Eur J Hum Genet. 2013;21(11)
  10. Kohl S, Jägle H, Wissinger B. Achromatopsia. 2004 Jun 24 [Updated 2016 Feb 25]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017.
  11. Molday RS, Zhang K. Defective lipid transport and biosynthesis in recessive and dominant Stargardt macular degeneration. Prog Lipid Res. 2010;49(4):476-92.
  12. Shroyer NF, Lewis RA, Yatsenko AN, Wensel TG, Lupski JR. Cosegregation and functional analysis of mutant ABCR (ABCA4) alleles in families that manifest both Stargardt disease and age-related macular degeneration. Hum Mol Genet. 2001;10(23):2671-8.
  13. Weleber RG, Francis PJ, Trzupek KM, et al. Leber Congenital Amaurosis. 2004 Jul 7 [Updated 2013 May 2]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017.