Invitae Inherited Retinal Disorders Panel

Test description

The Invitae Inherited Retinal Disorders Panel analyzes 248 genes that are associated with inherited retinal disorders including but not limited to retinitis pigmentosa, cone-rod dystrophy and Leber congenital amaurosis. These genes were selected based on the available evidence to date to provide a broad panel for retinal disorders. Retinal disease is genetically heterogeneous, and broad panel testing allows for an efficient evaluation of many potentially relevant genes based on a single clinical indication.

Genetic testing of these genes may confirm a diagnosis and help guide treatment and management decisions. Identification of a disease-causing variant would also guide testing and diagnosis of at-risk relatives.

This assay does not currently include the RPGR and PRPF31 genes. Pathogenic variants in the RPGR gene account for the majority (70-90%) of X-linked retinitis pigmentosa (XLRP), while variants in PRPF31 account for 2-8% of autosomal dominant RP (adRP). Additional testing for the RPGR and PRPF31 genes should be considered, if not yet performed and clinically appropriate.

*This test is specifically designed for heritable germline mutations and has assay limitations that are different from most of our other diagnostic panels. Please see the Assay section below for more details.

Genes tested (248 genes)

ABCA4 ABHD12 ACBD5 ACO2 ADAM9 ADAMTS18 ADGRA3 ADGRV1
ADIPOR1 AGBL5 AHI1 AHR AIPL1 ARHGEF18 ARL2BP ARL13B
ARL3 ARL6 ARMC9 ARSG ASRGL1 ATF6 ATOH7 BBIP1
BBS1 BBS2 BBS4 BBS5 BBS7 BBS9 BBS10 BBS12
BEST1 C1QTNF5 C2orf71 C8orf37 C21orf2 CA4 CABP4 CACNA1F
CACNA2D4 CAPN5 CC2D2A CCT2 CDH3 CDH23 CDHR1 CEP19
CEP41 CEP78 CEP83 CEP164 CEP250 CEP290 CERKL CHM
CIB2 CLCC1 CLN3 CLRN1 CLUAP1 CNGA1 CNGA3 CNGB1
CNGB3 CNNM4 COL2A1 COL9A1 CRB1 CRX CSPP1 CTNNA1
CWC27 CYP4V2 DHDDS DHX38 DRAM2 DTHD1 EFEMP1 ELOVL4
EMC1 EXOSC2 EYS FAM161A FLVCR1 FRMD7 FSCN2 FZD4
GDF6 GNAT1 GNAT2 GNB3 GNPTG GRM6 GUCA1A GUCA1B
GUCY2D HARS HGSNAT HK1 HMX1 IDH3A IDH3B IFT27
IFT43 IFT80 IFT81 IFT140 IFT172 IMPDH1 IMPG1 IMPG2
INPP5E INVS IQCB1 JAG1 KCNJ13 KCNV2 KIAA1549 KIF11
KIZ KLHL7 LCA5 LRAT LRIT3 LRP5 LZTFL1 MAK
MAPKAPK3 MERTK MFRP MKKS MKS1 MTTP MYO7A NDP
NEUROD1 NMNAT1 NPHP1 NPHP3 NPHP4 NR2E3 NRL NYX
OAT OPN1SW OTX2 P3H2 PCDH15 PCYT1A PDE6A PDE6B
PDE6C PDE6G PDE6H PDZD7 PEX1 PEX2 PEX3 PEX5
PEX6 PEX7 PEX10 PEX11B PEX12 PEX13 PEX14 PEX16
PEX19 PEX26 PHYH PITPNM3 PLA2G5 PLK4 PNPLA6 POC1B
POMGNT1 PRCD PRDM13 PROM1 PRPF3 PRPF4 PRPF6 PRPF8
PRPH2 RAB28 RAX2 RBP3 RBP4 RCBTB1 RD3 RDH5
RDH11 RDH12 REEP6 RGR RGS9 RGS9BP RHO RIMS1
RLBP1 ROM1 RP1 RP2 RPE65 RPGRIP1 RPGRIP1L RS1
RTN4IP1 SAG SAMD11 SDCCAG8 SEMA4A SLC24A1 SLC7A14 SNRNP200
SPATA7 SPP2 TEAD1 TIMP3 TMEM126A TMEM216 TMEM237 TOPORS
TPP1(CLN2) TRAF3IP1 TRIM32 TRNT1 TRPM1 TSPAN12 TTC8 TTLL5
TUB TUBGCP4 TUBGCP6 TULP1 UNC119 USH1C USH1G USH2A
VCAN VPS13B WDPCP WDR19 WHRN ZNF408 ZNF423 ZNF513

DISORDERS TESTED

Inherited Retinal Dystrophy

  • Retinitis pigmentosa (RP)
  • Cone-Rod Dystrophy (CRD)
  • Leber congenital amaurosis (LCA)
  • Congenital non-progressive cone-rod synaptic disorder (CRSD)

Achromatopsia

Bietti crystalline corneoretinal dystrophy (BCD)

Choroideremia

Congenital nystagmus type 1

Congenital stationary night blindness (CSNB)

Early and Late onset Retinal degeneration

Enhanced S-cone syndrome

Familial exudative vitreoretinopathy (FEVR)

Fundus albipunctatus (FA)

Gyrate atrophy of choroid and retina

Isolated microphthalmia

Juvenile retinoschisis

Microcornea, myopic chorioretinal atrophy, and telecanthus (MMCAT)

Microcephaly with chorioretinopathy

Microphthalmia, anophthalmia, coloboma (MAC) spectrum

Myopia with cataract and vitreoretinal degeneration

Neovascular inflammatory vitreoretinopathy (ADNIV)

Optic atrophy

Persistent hyperplastic primary vitreous (PHPVAR)

Snowflake vitreoretinal degeneration

Stargardt disease

Sveinsson chorioretinal atrophy (SCRA)

Vitelliform macular dystrophy (VMD1)

 

Inherited retinal dystrophy (IRD) can also present as part of a syndromic condition including: 

Abetalipoproteinemia

Alagille syndrome

Asphyxiating thoracic dystrophy

Axial spondylometaphyseal dysplasia (SMDAX)

Bardet-Biedl syndrome (BBS)

Bradyopsia

Charcot-Marie-Tooth disease, type 2W

CIB2-related non-syndromic deafness

Cohen syndrome

Hypotrichosis with juvenile macular dystrophy (HJMD)

Infantile cerebellar-retinal degeneration (ICRD)

Joubert syndrome and related disorders (JSRD)

Jalili syndrome

Microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability (MCLID) Mucolipidosis type III gamma

Mucopolysaccharidosis type IIIC (MPS IIIC or Sanfilippo C)

Muscular dystrophy-dystroglycanopathy

Nephronophthisis (NPHP)

Neuronal ceroid lipofuscinosis

  • neuronal ceroid lipofuscinosis, type 2
  • neuronal ceroid lipofuscinosis, type 3

NEUROD1-related early onset diabetes

Oculoauricular syndrome

Oguchi disease type 1

Osteoporosis-pseudoglioma syndrome (OPPG)

PDZD7-related nonsyndromic deafness

PNPLA6-related neurological syndromes

Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract (PHARC)

Refsum disease

Rhizomelic chondrodysplasia punctata (RCDP)

Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD)

Spondylometaphyseal dysplasia with cone-rod dystrophy

Stickler syndrome

  • Stickler syndrome, type I
  • Stickler syndrome, type IV

Usher syndrome

  • Usher syndrome, type 1
  • Usher syndrome, type 1C
  • Usher syndrome, type 1D
  • Usher syndrome, type 1G
  • Usher syndrome, type 2A
  • Usher syndrome, type 2C
  • Usher syndrome, type 2D
  • Usher syndrome, type 3A

Wagner syndrome

Zellweger spectrum disorder (ZSD)

Clinical description

Inherited retinal dystrophy (IRD) is a heterogenous group of disorders characterized by loss of photoreceptor function and is a major cause of blindness. IRD can present in various forms with retinitis pigmentosa (RP) being the most common. RP typically presents with night blindness followed by constriction of peripheral visual fields, which leads to tunnel vision and eventually loss of central vision (PMID: 17296890). In cone-rod dystrophies (CRD), patients experience decreased visual acuity, photophobia, nystagmus and progressive loss of color perception (PMID: 1583653). Onset for CRD is typically in early childhood or adolescence (PMID: 17270046). Leber congenital amaurosis (LCA) is a severe retinal dystrophy with early onset and is characterized by early vision loss in infancy, absent or sluggish pupillary response, and severely abnormal or absent ERG response (PMID: 25685757, 12615170).

Retinal dystrophy can also present in individuals with an underlying genetic syndrome and include extraocular features including but not limited to developmental delay or intellectual disability, hearing loss, ataxia, laterality defects and abnormalities of the skeletal, cardiac and genitourinary systems.

Inheritance

Inherited retinal disorders can occur in several inheritance patterns including autosomal dominant, autosomal recessive and X-linked.

Prevalence

Inherited retinal dystrophy (IRD) is a large group of clinically and genetically heterogeneous disorders that affect more than 2 million people worldwide (1 in 3000).

Clinical sensitivity

The clinical sensitivity of this test is dependent on the individual’s underlying genetic condition. For many rare conditions not listed in the table, the clinical sensitivity is unknown or not well-established.

 

Percent of disorder attributed to pathogenic variants in specific genes:

 

Gene

% pathogenic variants in gene (clinical condition)

ABCA4

2 - 5% (arRP)

ADGRA3

Rare (arRP)

ADGRV1

6 - 19% (Usher syndrome, type 2)

AGBL5

Rare (arRP)

AHI1

7 - 10% (JSRD)

AIPL1

<5% (LCA)

ARL13B

Rare (JSRD)

ARL2BP

Rare (arRP)

ARL3

Rare (adRP)

ARL6

Rare (adRP, BBS)

ATF6

~1.5% Achromatopsia

BBIP1

Rare (BBS)

BBS1

~23% (BBS), ≤1% (arRP)

BBS10

20% (BBS)

BBS12

5% (BBS)

BBS2

~8% (BBS), ≤1% (arRP)

BBS4

~2% (BBS)

BBS5

Rare (BBS)

BBS7

1.5% (BBS)

BBS9

6% (BBS)

BEST1

Rare (adRP), ≤1% (arRP)

C8orf37

≤1% (arRP)

CA4

Rare (adRP)

CACNA1F

55% XL CSNB

CC2D2A

8-11% (JSRD)

CDH23

7-20% (Usher syndrome, type 1)

CEP290**

15-20% (LCA), 7-10% (JSRD), Rare (BBS), 2-3% (NPHP)

CEP41

Rare (JSRD)

CERKL

3-4% (arRP in Spain)

CHM

95% (Choroideremia in males)

CLN3

>98% (NCL3)

CLRN1

≤1% (arRP)

CNGA1

1-2% (arRP)

CNGA3

5-33% to 80% (Achromatopsia, depending on population)

CNGB1

≤1% (arRP)

CNGB3

16-60% (Achromatopsia, depending on population)

COL2A1

80-90% (Stickler syndrome)

CRB1

10% (LCA), 6-7% (arRP in Spain)

CRX

1% (LCA), 1% (adRP)

CSPP1

2-4% (JSRD)

CYP4V2

≤1% (arRP)

DHDDS

≤1% (arRP)

DHX38

≤1% (arRP)

EMC1

≤1% (arRP)

EYS

10-30% (arRP in Spain, common in China)

FAM161A

≤1% (arRP)

FZD4

20-40% (FEVR)

GNAT2

~2% (Achromatopsia)

GNPTG

>95% (Mucolipidosis III C)

GUCA1B

5% (adRP in Japan)

GUCY2D

10-20% (LCA)

HGSNAT

≤1% (arRP)

HK1

Rare (adRP)

IDH3B

≤1% (arRP)

IFT140

≤1% (arRP)

IFT172

≤1% (arRP), Rare (JSRD)

IFT27

Rare (BBS)

IMPDH1

5% (LCA), 2-3% (adRP)

IMPG2

≤1% (arRP)

INPP5E

2-4% (JSRD)

INVS

1-2% (NPHP)

IQCB1

2-3% (NPHP)

JAG1

94-96% (Alagille syndrome)

KIZ

Rare (arRP)

KLHL7

1-2% (adRP)

LCA5

1-2% (LCA)

LRAT

<1% (LCA), ≤1% (arRP)

LRP5

12-25% (AD FEVR)

MAK

≤1% (arRP)

MERTK

≤1% (arRP)

MKKS

~6% (BBS)

MKS1

~5% (BBS), 2-6% (JSRD)

MYO7A

53-63% (Usher syndrome, type 1)

NDP

95% (Norrie disease)

NEUROD1

Rare (arRP)

NPHP1

1-2% (JSRD), 20-25% (NPHP)

NPHP3

1-2% (NPHP)

NPHP4

3-4% (NPHP)

NYX

45% (XL CSNB)

PCARE (formerly C2orf71)

≤1% (arRP)

PCDH15

7-12% (Usher syndrome, type 1)

PDE6A

2-5% (arRP)

PDE6B

2-5% (arRP)

PDE6C

2.5% (Achromatopsia)

PDE6G

≤1% (arRP)

PDE6H

0.1% (Achromatopsia)

PEX1

60.5% (ZSD)

PEX10

3.4% (ZSD)

PEX11B

0.1% (ZSD)

PEX12

7.6% (ZSD)

PEX13

1.5% (ZSD)

PEX14

0.5% (ZSD)

PEX16

1.1% (ZSD)

PEX19

0.6% (ZSD)

PEX2

3.1% (ZSD)

PEX26

4.2% (ZSD)

PEX3

0.7% (ZSD)

PEX5

2% (ZSD)

PEX6

14.5% (ZSD)

PEX7

10% (Refsum)

PHYH

90% (Refsum)

POC1B

Rare (JSRD)

POMGNT1

Rare (arRP)

PRCD

≤1% (arRP)

PROM1

≤1% (arRP)

PRPF3

1% (adRP)

PRPF6

Rare (adRP)

PRPF8

2-3% (adRP)

PRPH2

5-10% (adRP)

RBP3

≤1% (arRP)

RD3

<1% (LCA)

RDH12

10% (LCA)

RGR

≤1% (arRP)

RHO

≤1% (arRP), 20-30% (adRP)

RLBP1

≤1% (arRP)

ROM1

Rare (adRP)

RP1

≤1% (arRP), 3-4% (adRP)

RP2

10-20% (XLRP)

RPE65

5-10% (LCA), Rare (adRP), 2-5% (arRP)

RPGRIP1

5% (LCA)

RPGRIP1L

1-4% (JSRD)

RS1

100% (XL juvenile retinoschisis)

SAG

2-3% (arRP in Japan)

SDCCAG8

Rare (BBS)

SEMA4A

3-4% (adRP in Pakistan)

SLC7A14

Rare (arRP)

SNRNP200

1-2% (adRP)

SPATA7

3% (LCA), ≤1% (arRP)

SPP2

Rare (adRP)

TMEM216

2-3% (JSRD)

TMEM237

Rare (JSRD)

TPP1

~97% (NCL2)

TRIM32

Rare (BBS)

TRNT1

Rare (arRP)

TSPAN12

3-10% (AD FEVR)

TTC8

≤1% (arRP), ~1% (BBS)

TULP1

<1% (LCA), ≤1% (arRP)

USH1C

1-15% (Usher syndrome, type 1)

USH1G

~4% (Usher syndrome, type 1)

USH2A

10-15% (arRP), 57-79% (Usher syndrome, type 2)

WDPCP

Rare (BBS)

WHRN

<10% (Usher syndrome, type 2)

ZNF408

≤1% (arRP)

ZNF423

Rare (JSRD)

ZNF513

≤1% (arRP)

Clinical Sensitivity Table: arRP (autosomal recessive retinitis pigmentosa), adRP (autosomal dominant retinitis pigmentosa), XLRP (X-linked retinitis pigmentosa, JSRD (Joubert syndrome and related disorders), LCA (Leber congenital amaurosis), Bardet-Biedl syndrome (BBS), XL CSNB (X-linked congenital stationary night blindness), NPHP (nephronophthisis), FEVR (familial exudative vitreoretinopathy), ZSD (Zellweger spectrum disorder), NCL (neuronal ceroid lipofuscinosis)

**CEP290: Analysis includes the intronic variant NM_025114.3:c.2991+1655A>G.

Considerations for testing

This test may be appropriate for individuals with:

A clinical diagnosis of retinitis pigmentosa (RP), Leber congenital amaurosis (LCA), or cone-rod dystrophy (CRD)

A combination of the following features:

  • Night blindness
  • Peripheral or central vision loss, with or without loss of visual acuity
  • Photophobia
  • Deterioration of color vision
  • Retinal vascular attenuation
  • Optic disc pallor
  • Optic nerve atrophy
  • Appearance of bone spicules
  • Abnormal fundus appearance (arteriolar narrowing, dust-like intraretinal pigmentation, and loss of pigment from pigment epithelium)
  • Abnormal ERG

Note: This test is not appropriate for patients with age-related macular degeneration or ocular/oculocutaneous albinism.

Management guidelines

The American Academy of Ophthalmology (AAO) provides recommendations for evaluation and clinical assessment of patients with inherited retinal degenerations (IRDs): https://www.aao.org/clinical-statement/recommendations-on-clinical-assessment-of-patients

References

  • Bessant D et al. Molecular genetics and prospects for therapy of the inherited retinal dystrophies. Curr Opin Genet Dev. 2001;11(3):307-16.

  • Bravo-Gil N et al. Unravelling the genetic basis of simplex Retinitis Pigmentosa cases. Scientific Reports. 2017;7(1).

  • Chacon-Camacho O et al. Review and update on the molecular basis of Leber congenital amaurosis. World J Clin Cases. 2015:3(2):112.

  • Daiger S et al. Perspective on genes and mutations causing retinitis pigmentosa. Arch Ophthalmol. 2007;125(2):151.

  • Fazzi E et al. Leber's congenital amaurosis: an update. Eur J Paediatr Neurol. 2003:7(1):13-22.

  • Francis P et al. Genetics of inherited retinal disease. J Royal Soc Med. 2006;99(4):189-191.

  • Gregori N et al. Current concepts and emerging gene therapies for inherited retinal diseases. Int Ophthalmol Clin. 2019;59(1):83-110.

  • Hafler B et al. Clinical progress in inherited retinal degenerations. Retina. 2017;37(3):417-423.

  • Hamel C et al. Cone rod dystrophies. Orph J Rare Dis. 2007;2(1).

  • Moore A et al. Cone and cone-rod dystrophies. J Med Genet. 1992;29(5):89-290.