Table 2 Overview of CNVs identified in this study

From: Mapping the genomic landscape of inherited retinal disease genes prioritizes genes prone to coding and noncoding copy-number variations

Patient

Gene

CNV type

Zygosity

Clinical diagnosis

Exons

Allele 1

Allele 2

Detection method

Delineation method

Genomic coordinates at nt level

Segregation

Reference

P1

BEST1

Del

Het

arB

E1-2 (fs)

c.-580-5983_152+380del

NA

MLPA

TLA

chr11:g.61711373_61719810del

No

This study

P2

BEST1

Del

Het

adBMD

E1-2 (fs)

c.-580-5983_152+380del

NA

MLPA

TLA

chr11:g.61711373_61719810del

Yes

This study

P3

EYS

Del

Hom

arRP

Upstream (NC)

Upstream deletion + complex insertion

Upstream deletion + complex insertion

SNP chip

TLA

chr6: g.66631318_66647641del + ins of chr6: 66628168_66628444 + ins of chr6: 66642009_66642186 (inv)

Yes

This study

P4

EYS

Del

Hom

arRP

E1 (NC)

c.-538-?_-448+?del

c.-538-?_-448+?del

SNP chip

TLA

?

Yes

Ref. 34

P5

KCNV2

Del

Het

arCRD

E2 (end)

c.1356+4642_*37095del

c.1357-5153_1638+897del

PCR

PCR

chr9: g.2723737_2766822del

Yes

This study

P5

KCNV2

Del

Het

arCRD

E2 (end)

c.1357-5153_*897del

c.1356+4642_1638+37095del

PCR

PCR

chr9: g.2724293_2730624del

Yes

This study

P6

MERTK

Del

Het

arRP

E1- 19 (WG)

c.1-?_*504+?del

c.2323C>T, p.(Arg775*) (ExAC MAF: 0.00082%)

qPCR

NA

?

Yes

This study

P7

OPA1

Dup

Het

adOPA

E6-27 (fs)

c.625-?_2818+?dup

NA

MLPA

TLA

?

No

This study

P8

OPA1

Del

Het

adOPA

E1-29 (WG)

c.1-?_*3211+?del

NA

MLPA

NA

?

No

PMID: 17306754

P9

PCDH15

Del

Hom

arRP

E1 (NC)

c.-395-1216883_-28-54604del

c.-395-1216883_-28-54604del

SNP chip

PCR

chr10: g.56478660_57777934del

No

Ref. 20

P10

PDE6G

Del

Hom

arRP

E3-4 (end)

NM_001290212.1(TSPAN10):c.658_NM_002602.3(PDE6G):c.147-456del

NM_001290212.1(TSPAN10):c.658_NM_002602.3(PDE6G):c.147-456del

arrEYE

PCR

chr17: g.79612525_79619171del

No

This study

P11

PDE6G

Del

Hom

arRP

E3-4 (end)

NM_001290212.1(TSPAN10):c.658_NM_002602.3(PDE6G):c.147-456del

NM_001290212.1(TSPAN10):c.658_NM_002602.3(PDE6G):c.147-456del

arrEYE

PCR

chr17: g.79612525_79619171del

No

This study

P12

PRPH2

Del

Het

adMD

E3 (end)

c.829-?_*1700+?del

NA

MLPA

NA

?

No

This study

P13

PRPH2

Del

Het

adMD

E1-3 (WG)

c.1-26916_*34871delinsTATTTTT

NA

MLPA

TLA

chr6:g.42631162_42716988delinsTATTTTT

Yes

This study

P14

SPATA7

Del

Hom

arLCA

E1-4 (fs)

c.1-7152_239-734del+c.239-729_239-721dup

c.1-7152_239-734del+c.239-729_239-721dup

PCR

TLA

chr14: g.88845011_88882321del + chr14: g.88882326_88882334dup

Yes

This study

P15

USH2A

Del

Het

arUS

E3 (fs)

c.486-1344_651+2629del

c.2299del, p.(Glu767Serfs*21) (ExAC MAF: 0.079%)

MLPA

PCR

chr1: g.216589227_216593365del

No

This study

P16

USH2A

Dup

Het

arUS

E4-13 (fs)

c.652-23900_2809+1417dupinsTTACTTGATTATTACTG

c.2276G>T, p.(Cys759Phe) (ExAC MAF : 0.078%)

MLPA

TLA

chr1: g.216418510_216562327dupinsTTACTTGATTATTACTG

Yes

Ref. 19

P17

USH2A

Dup

Het

arRP

E4-13 (fs)

c.652-23900_2809+1417dupinsTTACTTGATTATTACTG

c.2276G>T, p.(Cys759Phe)

(ExAC MAF : 0.078%)

MLPA

TLA

chr1: g.216418510_216562327dupinsTTACTTGATTATTACTG

No

Ref. 19

P18

USH2A

Dup

Het

arUS

E4-13 (fs)

c.652-23900_2809+1417dupinsTTACTTGATTATTACTG

c.2209C>T, p.(Arg737*)

(ExAC MAF : 0.00083%)

MLPA

TLA

chr1: g.216418510_216562327dupinsTTACTTGATTATTACTG

No

Ref. 19

P19

USH2A

Dup

Het

arUS

E4-13 (fs)

c.652-23900_2809+1417dupinsTTACTTGATTATTACTG

c.6587G>C, p.(Ser2196Thr)

(ExAC MAF: 1.15%, benign)

MLPA

TLA

chr1: g.216418510_216562327dupinsTTACTTGATTATTACTG

No

Ref. 19

P20

USH2A

Dup

Het

arRP

E4-13 (fs)

c.652-23900_2809+1417dupinsTTACTTGATTATTACTG

c.2276G>T, p.(Cys759Phe)

(ExAC MAF : 0.078%)

MLPA

TLA

chr1: g.216418510_216562327dupinsTTACTTGATTATTACTG

No

Ref. 19

P21

USH2A

Del

Hom

arUS

E5-10 (if)

c.785-6636_1840+208del

c.785-6636_1840+208del

MLPA

PCR

chr1: g.216465309_216507632del

No

PMID: 24944099

P22

USH2A

Del

Het

arUS

E12-13 (fs)

c.1972-10840_2809+4440del

c.2299del, p.(Glu767Serfs*21)

(ExAC MAF: 0.079%)

MLPA

PCR

chr1: g.216415487_216435280del

Yes

This study

P23

USH2A

Del

Het

arUS

E22 (fs)

c.4628-?_4758+?del

c.8167C>T, p.(Arg2723*)

(ExAC MAF: 0.00082%)

MLPA

NA

?

No

PMID: 25558175

P24

USH2A

Del

Het

arUS

E22-24 (if)

c.4627+25434_4987+657del

c.14587G>T, p.(Glu4863*)

(not present in ExAC)

MLPA

TLA

chr1: g.216259404_216323160del

No

PMID: 25804404

P25

USH2A

Del

Het

arUS

E44 (fs)

c.8682-1666_8845+139del

c.10689T>A, p.(Tyr3563*)

(not present in ExAC)

MLPA

PCR

chr1: g.216040210_216042178del

No

PMID: 25404053

P26

USH2A

Del

Het

arUS

E44 (fs)

c.8682-1666_8845+139del

c.921_922insCAGC

(ExAC MAF: 0.011%)

MLPA

PCR

chr1: g.216040210_216042178del

No

PMID: 25404053

P27

USH2A

Dup

Het

arUS

E62 (if)

c.12067-?_12294+?dup

c.653T>A, p.(Val218Glu)

(ExAC MAF: 0.0041%)

MLPA

TLA

?

No

This study

P28

USH2A

Dup

Het

arUS

E62 (if)

c.12067-?_12294+?dup

c.1256G>T, p.(Cys419Phe)

(ExAC MAF: 0.0051%)

MLPA

TLA

?

No

This study

P29

USH2A

Dup

Het

arUS

E62 (if)

c.12067-?_12294+?dup

c.11864G>A, p.(Trp3955*)

(ExAC MAF: 0.011%)

MLPA

TLA

?

No

This study

  1. ad, autosomal dominant; ar, autosomal recessive; B, bestrophinopathy; BMD, Best macular dystrophy; CNV, copy-number variation; CRD, cone rod dystrophy; Del, deletion; Dup, duplication; end, CNV extends until 3′ UTR; fs, frameshift; Het, heterozygous; Hom, homozygous; if, in-frame; LCA, Leber congenital amaurosis; MAF, minor allele frequency; MD, macular dystrophy; MLPA, multiplex ligation-dependent probe amplification; NC, noncoding; nt, nucleotide; OPA, optic atrophy; PCR, polymerase chain reaction; qPCR, quantitative PCR; RP, retinitis pigmentosa; SNP, single-nucleotide polymorphism; TLA, targeted locus amplification; US, Usher syndrome; UTR, untranslated region; WG, whole gene.
  2. This table presents an overview of the different CNVs identified in this study, novel CNVs are indicated in bold. The “Exons” column shows which exons of the gene are affected by the CNV and shows whether the change is in-frame, causes a frameshift, affects the end of the gene including the 3′ UTR, is noncoding, or encompasses the whole gene. Most of the CNVs have been picked up by MLPA (P1, P2, P7, P8, P12, P13, P15–29); two are found using arrEYE (P10, P11), an in-house developed customized microarray (Van Cauwenbergh et al. 2016); three have been identified by SNP chip analysis in consanguineous families (P3, P4, P9); one homozygous deletion (P14) and another apparently homozygous deletion (P5, which later turned out to be two different overlapping heterozygous deletions) have been discovered by nonamplification when performing conventional PCR; and the presence of a last heterozygous CNV has been demonstrated by qPCR (P6). Apart from conventional PCR, targeted locus amplification (TLA) has been used to delineate the CNVs at nucleotide level. The last column shows whether the identified CNVs are novel or have been previously published. Novelty has been assessed based on exon level, not on nucleotide level. The variant identified in P19 in addition to the USH2A CNV is predicted to be benign and has a high MAF (>1%). This patient carries either a second yet unidentified USH2A mutation, or is a heterozygous carrier of the USH2A CNV and has another underlying disease gene.
  3. Reference sequences: BEST1: NM_004183.3, EYS: NM_001292009.1, KCNV2: NM_133497.3, MERTK: NM_006343.2, OPA1: NM_015560.2, PCDH15: NM_033056.3, PDE6G: NM_002602.3, PRPH2: NM_000322.4, SPATA7: NM_018418.4, USH2A: NM_206933.2.
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