Prescreening whole exome sequencing results from patients with retinal degeneration for variants in genes associated with retinal degeneration

Figures & data

Table 1 Breakdown of diagnoses included in this study

Incoming clinical diagnosis	Number of patients
autosomal dominant retinitis pigmentosa	5
Cone dystrophy	3
Cone-rod dystrophy	2
Leber’s congenital amaurosis	24
Macular dystrophy	1
Nanophthalmos	1
Retinitis pigmentosa	15
Stargardt	11
Usher syndrome	2
Achromatopsia	1
Vitreoschisis	1
Retinal degeneration (unspecified)	2

Table 2 Pathogenic and probable pathogenic variants in known disease-causing genes identified in subjects in this study

Subject	Dx	Gene	Nucleotide change	Protein change	dbSNP	Reference
JB260	Stargardt	ABCA4	c.6119G>A	p.Arg2040Gln	rs148460146	Zernant et al (2014)^Citation50
			c.2879del	p.Ala960Aspfs*17	N/A
JB333	Stargardt	ABCA4	c.4363T>C	p.Cys1455Arg	rs758835368	Fujinami et al (2013)^Citation51
			c.4666del	p.Arg1556Glyfs*25	N/A
JB358	Stargardt	ABCA4	c.2588G>C	p.Gly863Ala	rs76157638	Maugeri et al (2000)^Citation52
			c.3984_3987del	p.His1328Glnfs^*60	N/A
JB16	Stargardt	ABCA4	c.5917del	p.Val1973^*	rs61751389	Kitiratschky et al (2008)^Citation53
			c.5917del	p.Val1973^*	rs61751389	Kitiratschky et al (2008)^Citation53
JB320	Stargardt	ABCA4	c.1749G>C	p.Lys583Asn	rs145265791	Fujinami et al (2013)^Citation51
			c.4594G>A	p.Asp1532Asn	rs62642574	Briggs et al (2001)^Citation54
JB249	LCA	AIPL1	c.834G>A	p.Trp278^*	rs62637014	Sohocki et al (2000)^Citation55
			c.404_405insA	p.Glu135fs^*23	N/A
JB319	RP (BBS)	BBS4	c.513_514insA	p.Ile172Asnfs*18	rs779047261	Mykytyn et al (2001)^Citation26
			c.883C>G	p.Arg295Gly	N/A	Priya et al (2016)^Citation27
JB42	ADRP	CA4	c.761A>C	p.Gln254Pro	rs150432787	Yang et al (2005)^Citation49
JB165	LCA	CEP290	c.2991+1655A>G	Splice mutation	rs281865192	den Hollander et al (2006)^Citation41
			c.3461+2TA>GT	Splice mutation	N/A
JB290	LCA	CEP290	c.2390del	p.Lys797Serfs^*2	rs781670422	Cideciyan et al (2011)^Citation56
			c.2390del	p.Lys797Serfs^*2	rs781670422	Cideciyan et al (2011)^Citation56
JB9	Retinal degeneration (Batten disease)	CLN3	c.597C>A	p.Tyr199^*	rs267606737	Sarpong et al (2009)^Citation57
			c.597C>A	p.Tyr199^*	rs267606737	Sarpong et al (2009)^Citation57
JB255	LCA (Batten disease)	CLN3	c.883G>A CNV suspected~	p.Glu295Lys	rs121434286	Munroe et al (1997)^Citation58
JB426	CORD (achromatopsia)	CNGB3	c.1148del	p.Thr383Ilefs^*13	rs397515360	Kohl et al (2005)^Citation59
			c.1306A>C	p.Ser436Arg	rs748354081
JB274	LCA	CRB1	c.2300T>C	p.Leu767Pro	N/A
			c.2300T>C	p.Leu767Pro	N/A
JB375	RP	CRB1	c.1576C>T	p.Arg526^*	rs114342808	Seong et al (2008)^Citation60
			c.1429G>A	p.Gly477Arg	rs866822473	Abu-Safieh et al (2013)^Citation61
JB402	LCA	CRB1	c.2843G>A	p.Cys948Tyr	rs62645748	den Hollander et al (1999)^Citation62
			c.3988G>T	p.Glu1330^*	N/A
JB38	RP	FAM161A	c.1355_1356del	p.Thr452Serfs*3	rs397704718	Bandah-Rozenfeld et al (2010)^Citation63
			c.1355_1356del	p.Thr452Serfs	rs397704718	Bandah-Rozenfeld et al (2010)^Citation63
JB301	Achromatopsia	GNAT2	c.896C>A	p.Ala299Glu	N/A	Nishiguchi et al (2005),^Citation32 Jobling et al (2013),^Citation33 and Kuniyoshi et al (2016)^Citation34
			c.720+2T>C	Splice mutation	N/A
JB324	Usher	GPR98	c.14767del	p.Thr4923Profs^*8	rs747459491	Weston et al (2004)^Citation28
			c.17668_17669del	p.Met5890Valfs^*10	rs757696771
JB185	Cone dystrophy (ad)	GUCA1A	c.296A>G	p.Tyr99Cys	rs104893967	Payne et al (1998)^Citation14
JB282	LCA	GUCY2D	c.2080C>T	p.Gln694^*	rs61750164	Eisenberger et al (2013)^Citation64
			c.1009_1010insCAGCAGCT	p.Asp337Alafs^*61 (p.Pro335_Ser336 insSer in cis)
JB307	Cone dystrophy	KIF7	c.A2501A>G	p.Gln834Arg	rs138354681	Putoux et al (2011)^Citation20
			c.3345C>G	p.His1115Gln	rs142032413	Putoux et al (2011)^Citation20
JB32	RP	NR2E3	c.119-2A>C	Splice mutation	rs2723341	Bandah et al (2009)^Citation65
			c.932G>A	p.Arg311Gln	rs28937873	Haider et al (2000)^Citation66
JB181	Nanophthalmos, maculopathy	NR2E3	c.767C>A	p.Ala256Glu	rs377257254	Sharon et al (2003)^Citation67
			c.119-2A>C	Splice mutation	rs2723341	Bandah et al (2009)^Citation65
JB48	RP (ad)	NR2E3	c.166G>A	p.Gly56Arg	rs121912631	Coppieters et al (2007)^Citation68
JB275	LCA (ad retinal degeneration)	OTX2	c.527del	p.Pro177^*	N/A
JB28	LCA (EORD)	PDE6A	c.1705C>A	p.Gln569Lys	rs139444207	Dryja et al (1999)^Citation69
			c.1620+2T>A	Splice mutation
JB33	ADRP	PRPF31	c.590T>C	p.Leu197Pro	N/A
JB310	LCA	PRPH2	c.522G>A	p.Trp174^*	N/A
			c.522G>A	p.Trp174^*	N/A
JB167	AD retinal degeneration	PRPH2	c.136C>T	p.Arg46^*	rs61755771
JB46	CORD	PRPH2	c.514C>T	p.Arg172Trp	rs61755792	Conley et al (2014),^Citation42 Meins et al (1993),^Citation43 Wroblewski et al (1994),^Citation44 and Wang et al (2013)^Citation45
JB284	LCA	PROM1	c.2050C>T	p.R684^*	rs530749007
			c.2050C>T	p.R684^*	rs530749007
JB44	ADRP	RP1	c.2029C>T	p.Arg677^*	rs104894082	Payne et al (2000)^Citation70
JB372	RP	RP1L1	c.1138G>A	p.Gly380Arg	rs184332984	Tiwari et al (2016) (for macular dystrophy)^Citation71
			c.1138G>A	p.Gly380Arg	rs184332984	Tiwari et al (2016) (for macular dystrophy)^Citation71
JB47	RP	RP1L1	c.1270A>T	p.Lys424^*	rs770463388
			c.1270A>T	p.Lys424^*	rs770463388
JB283	LCA	RPE65	c.1067_1068insA	p.Asn356Lysfs*9	rs766074572
			c.1067_1068insA	p.Asn356Lysfs*9	rs766074572
JB357	LCA	RPE65	c.1249G>C	p.Glu417Gln	rs62636299	Simovich et al (2001)^Citation72
			c.1102T>C	p.Tyr368His	rs62653011	Yzer et al (2003)^Citation73
JB285	LCA	RPGRIP1	c.767C>G	p.Ser256^*	N/A
			c.1084_1087del	p.Arg363Leufs^*11	N/A
JB124	LCA	RPGRIP1	c.1180C>T	p.Gln394^*	N/A
			c.1180C>T	p.Gln394^*	N/A
JB43	RP	RPGRIP1L	c.171G>T	p.Leu57Phe	rs146925098
			c.628A>G	p.Asn210Asp	rs146584570
JB41	RP	USH2A	c.1036A>C	p.Asn346His	rs369522997	Weston et al (2000)^Citation74
			c.13335_13337del	p.Glu4445_Asn4446delinsAsp	rs775556188
JB49	RP	USH2A	c.13297G>T	p.Val4433Leu (benign?)	rs111033381	Dreyer et al (2008)^Citation75
			c.6713A>C	p.Glu2238Ala	rs41277212	Aller et al (2006)^Citation77 and McGee et al (2010)^Citation76
JB252	Usher	USH2A	c.13207_13208del	p.Gly4403Profs*15	rs746447649	Le Quesne Stabej et al (2012)^Citation78
			c.2299del	p.Glu767Serfs^*21	rs80338903	Eudy et al (1998),^Citation79 and Weston et al (2000)^Citation74

Note: Only variants that completely explain the disease phenotype have been included in this table.

Abbreviations: ADRP, autosomal dominant retinitis pigmentosa; BBS, Bardet–Biedl syndrome; CORD, cone–rod dystrophy; dbSNP, database of single nucleotide polymorphisms; Dx, diagnosis; EORD, early-onset retinal degeneration; LCA, Leber’s congenital amaurosis; NA, not applicable; RP, retinitis pigmentosa.

Table 3 Additional heterozygous variants of uncertain significance found in this study

Subject	Dx	Disease-causing gene	Other genes	Nucleotide change	Protein change	dbSNP	Reference
JB333	Stargardt	ABCA4	IQCB1	c.772delA	p.Arg258Aspfs*4	N/A
JB320	Stargardt	ABCA4	RD3	c.16T>C	p.Trp6Arg	rs35649846	Friedman et al (2006)^Citation80
				c.69G>C	p.Glu23Asp	rs34422496	Friedman et al (2006)^Citation80
JB9	Retinal degeneration (Batten disease)	CLN3	MKKS	c.1015A>G	p.Ile339Val (hom)	rs137853909	Slavotinek et al (2002)^Citation81
JB375	RP	CRB1	AHI1	c.653A>G	p.Tyr218Cys	rs183936286	Srour et al (2012)^Citation82 and Huang et al (2015)^Citation83
				c.3257A>G	p.Glu1086Gly	rs148000791	Kroes et al (2008)^Citation84 and Srour et al (2012)^Citation82
JB38	RP	FAM161A	RPGRIP1L	c.685G>A	p.Ala229Thr	rs61747071	Khanna et al (2009)^Citation24
JB301	LCA vs achromatopsia	GNAT2	GDF6	c.746C>A	p.Ala249Glu	rs121909352	Asai-Coakwell et al (2009)^Citation35 and (2013)^Citation36 and Tassabehji et al (2008)^Citation37
JB32	RP	NR2E3	USH2A	c.2137G>C	p.Gly713Arg	rs696723	Dreyer et al (2000)^Citation85
				c.10246T>G	p.Cys3416Gly	rs527236140	Huang et al (2013)^Citation86
JB181	Nanophthalmos, maculopathy	NR2E3	ABCA4	c.2828G>A	p.Arg943Gln	rs61749446	Yatsenko et al (2001)^Citation87 and Briggs et al (2001)^Citation54
JB184	Nanophthalmos, maculopathy	NR2E3	ABCA4	c.2828G>A	p.Arg943Gln	rs61749446	Yatsenko et al (2001)^Citation87 and Briggs et al (2001)^Citation54
JB48	ADRP	NR2E3	USH2A	c.10246T>G	p.Cys3416Gly	rs527236140	Huang et al (2013)^Citation86
				c.14419G>A	p.Ala4807Thr	rs534656527
JB275	LCA (ad retinal degeneration)	OTX2	RP1	c.5673G>T	p.Leu1891Phe	rs139088785
JB28	LCA (EORD)	PDE6A	IQCB1	c.962T>A	p.Val321Glu	N/A
JB284	LCA	RD3	USH2A	c.10451G>A	p.Arg3484Gln	rs771999994	McGee et al (2010)^Citation76
				c.13709G>A	p.Arg4570His	rs730254	McGee et al (2010)^Citation76
JB41	RP	USH2A	RP2	c.844C>T	p.Arg282Trp (hom)	rs1805147	Breuer et al (2002)^Citation88 and Sharon et al (2000)^Citation89
JB49	RP	USH2A	RP1	c.4875A>G	p.Ile1625Met	rs757644601
JB195	Stargardt	Unknown	CRX	c.724G>A	p.Val242Met	rs61748459	Swain et al (1997)^Citation29 and Chen et al (1997)^Citation30 and (2002)^Citation31
JB42	ADRP	CA4	ABCA4	c.1140T>A	p.Asn380Lys	rs61748549	Riveiro-Alvarez et al (2009)^Citation90
			BBS12	c.617T>G	p.Val206Gly	N/A
			CDH23	c.1096G>A	p.Ala366Thr	rs143282422	Ouyang et al (2005)^Citation91
			GPR98	c.6017G>A	p.Gly2006Asp	rs768201036
			USH2A	c.2276G>T	p.Cys759Phe	rs80338902	Dreyer et al (2000)^Citation85
JB307	Cone dystrophy	KIF7	BBS1	c.1169T>G	p.Met390Arg	rs113624356	Mykytyn et al (2003)^Citation92
			CEP164	c.4228C>T	p.Gln1410*	rs147398904
			RPGRIP1	c.1639G>T	p.Ala547Ser	rs10151259	Roepman et al (2000)^Citation93
			CLN3	c.1189G>A	p.Ala397Thr	rs754468227
			RP1l1	c.6359A>G	p.Glu2120Gly	N/A
JB284	LCA (RP)	PROM1	USH2A	c.13709G>A	p.Arg4570His	rs730254	McGee et al (2010)^Citation76
			USH2A	c.13297G>T	p.Val4433Leu	rs111033381	Dreyer et al (2008)^Citation75
			USH2A	c.10451G>A	p.Arg3484Gln	rs771999994
			RP1	c.5840T>G	p.Leu1947Trp	N/A
			RPGRIP1	c.3341A>G	p.Asp1114Gly	rs17103671	Gerber et al (2001)^Citation94
			BBS1	c.700G>A	p.Glu234Lys	rs35520756	Beales et al (2003)^Citation95
			ABCA4	c.3602G>T	p.Leu1201Arg	rs61750126	Briggs et al (2001)^Citation54
			RD3	c.69G>C	p.Glu23Asp	rs34422496	Friedman et al (2006)^Citation80
			RD3	c.16T>C	p.Trp6Arg	rs35649846	Friedman et al (2006)^Citation80
			WFS1	c.862G>A	p.Val288Met	rs71537685
			WFS1	c.1949A>G	p.Tyr650Cys	N/A
			WFS1	c.2008G>A	p.Gly670Ser	N/A
JB274	LCA	CRB1	KIF7	c.A2501A>G	p.Gln834Arg	rs138354681	Putoux et al (2011)^Citation20
			BBS1	c.1396G>A	p.Ala466Thr	N/A
			FAM161A	c.1133T>G	p.Leu378Arg	rs187695569	Langmann et al (2010)^Citation96
			MAK	c.112A>C	p.Lys38Gln	N/A
			RGS9	c.1351C>A	p.Gln451Lys	N/A

Note: These variants are unlikely to be pathogenic in the subjects, but we were unable to exclude the possibility that they act as modifying alleles.

Abbreviations: ADRP, autosomal dominant retinitis pigmentosa; BBS, Bardet–Biedl syndrome; CORD, cone–rod dystrophy; dbSNP, database of single nucleotide polymorphisms; Dx, diagnosis; EORD, early-onset reitnal degeneration; LCA, Leber’s congenital amaurosis; N/A, not applicable; RP, retinitis pigmentosa.

Table 4 Multiple compound heterozygous mutations identified in a subject with multiplex RP

Subject	Dx	Disease-causing gene	Other genes	Nucleotide change	Protein change	dbSNP	Reference
JB40	Multiplex RP	Unknown	RPGRIP1L	c.685G>A	p.Ala229Thr	rs61747071	Khanna et al (2009)^Citation24
			RPGRIP1L	c.2952G>C	p.Gln984His	rs775144757
			RPGRIP1L	c.196C>A	p.Gln66Lys	rs751444506
			CDH23	c.1096G>A	p.Ala366Thr	rs143282422	Ouyang et al (2005)^Citation91
			CDH23	c.3293A>G	p.Asn1098Ser	rs41281310	Oshima et al (2008)^Citation97
			FAM161A	c.977A>C	p.Lys326Thr	rs745318331
			GUCY2D	c.3247C>A	p.Leu1083Met	N/A
			USH2A	c.6713A>C	p.Glu2238Ala	rs41277212	Aller et al (2006)^Citation77
			USH2A	c.1434G>C	p.Glu478Asp	rs35730265	Seyedahmadi et al (2004)^Citation98

Notes: This family appears to have an unusually high number of recessive mutations rather than the single dominant mutation that was expected based on the family history. We were unable to perform segregation analysis. The CDH23 mutations and the RPGRIP1L mutations are the most likely to be pathogenic.

Abbreviations: dbSNP, database of single nucleotide polymorphisms; Dx, diagnosis; N/A, not applicable; RP, retinitis pigmentosa.

Figure 1 Final outcome of initial screening for variants in genes associated with retinal degeneration.

Notes: Of the initial cohort of 69 subjects with retinal degeneration, the pathogenic variants were identified in 44 subjects, heterozygous mutations consistent with the diagnosis were identified in 5 subjects, and 9 subjects had no obviously pathogenic variants and lacked relatives willing or able to enroll in the study to perform segregation analysis on potentially pathogenic variants. Eleven are good candidates for further analysis to find novel genes associated with retinal degeneration.

Table 5 Heterozygous variants identified in subjects with recessive disease

Subject	Dx	Gene	Nucleotide change	Protein change	dbSNP	Reference
JB200	Stargardt	ABCA4	c.2828G>A	p.Arg943Gln (probable polymorphism)	rs1801581	Briggs et al (2001)^Citation54
JB188	Stargardt	CNGB3	c.2139_2160del	p.Lys714_Gln720del (p.Lys804*in cis)	(rs151039691in cis)	Kohl et al (2005)^Citation59
JB23	LCA	KCNJ13	c.458C>T	p.Thr153Ile	rs863224884
JB189	Stargardt	PROM1	c.303+1G>A	Splice mutation	rs777673930
JB241	Cone dystrophy	PROM1	c.1623_1624del	p.Y541fs	N/A

Notes: The variant is most likely pathogenic and is consistent with the diagnosis, but we were unable to identify the second mutation. These subjects should be screened for copy number variants and intronic variants.

Abbreviations: dbSNP, database of single nucleotide polymorphisms; Dx, diagnosis; LCA, Leber’s congenital amaurosis; N/A, not applicable.

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