Mutational and phenotypic spectrum of OTOF-related auditory neuropathy in Koreans: eliciting reciprocal interaction between bench and clinics

Kim, Bong Jik; Jang, Jeong Hun; Han, Jin Hee; Park, Hye-Rim; Oh, Doo Yi; Lee, Seungmin; Kim, Min Young; Kim, Ah Reum; Lee, Chung; Kim, Nayoung K. D.; Park, Woong-Yang; Choung, Yun-Hoon; Choi, Byung Yoon

doi:10.1186/s12967-018-1708-z

Table 1 Mutational spectrum of 11 subjects from 10 families with DFNB9

From: Mutational and phenotypic spectrum of OTOF-related auditory neuropathy in Koreans: eliciting reciprocal interaction between bench and clinics

Family ID	Variant (OTOF) NM_001287489 NP_001274418	State	Prediction algorithm			Conservation score		MAF		Classification of pathogenic variants [31]	References
Family ID	Variant (OTOF) NM_001287489 NP_001274418	State	Mutation taster	PolyPhen-2	SIFT	PhyloP	GERP++	Global MAF	KRGDB (n = 1722)	Classification of pathogenic variants [31]	References
SB10-23	c.5816G > A: p.Arg1939Gln rs201326023	Hom	DC	PD	D	2.261	2.28	T = 0.00003/1 (ExAC) T = 0.0002/1 (1000 Genomes)	T = 0.001452/5	Pathogenic (PS4, PM2, PM3 PP1, PP3, PP4)	[31]
SH132-273	c.5816G > A: p.Arg1939Gln rs201326023	Hom	DC	PD	D	2.261	2.28	T = 0.00003/1 (ExAC) T = 0.0002/1 (1000 Genomes)	T = 0.001452/5	Pathogenic	[31]
SB22-51	c.5816G > A: p.Arg1939Gln rs201326023	Het	DC	PD	D	2.261	2.28	T = 0.00003/1 (ExAC) T = 0.0002/1 (1000 Genomes)	T = 0.001452/5	Pathogenic	[31]
SB22-51	Large genomic deletion Chr2:26710657 ~ 26706557	Het	NA	NA	NA	NA	NA			Pathogenic (PVS1, PP1, PP4)	[16]
SB204-398	c.5816G > A: p.Arg1939Gln rs201326023	Het	DC	PD	D	2.261	2.28	T = 0.00003/1 (ExAC) T = 0.0002/1 (1000 Genomes)	T = 0.001452/5	Pathogenic	[31]
SB204-398	c.5566C > T: p.Arg1856Trp rs368155547	Het	DC	PD	D	2.963	2.84	A = 0.00004/5 (ExAC) A = 0.00008/1 (GO-ESP)	A = 0.000871/3	Pathogenic (PS4, PM2, PM3 PP1, PP3, PP4)	[10]
SH81-185	c.5816G > A: p.Arg1939Gln rs201326023	Het	DC	PD	D	2.261	2.28	T = 0.00003/1 (ExAC) T = 0.0002/1 (1000 Genomes)	T = 0.001452/5	Pathogenic	[31]
SH81-185	c.2521G > A: p.Glu841Lys rs772729658	Het	DC	PD	D	5.523	5	T = 0.00003/3 (ExAC)	ND	Pathogenic (PS4, PM2, PM3 PP1, PP3, PP4)	[16]
SB239-465	c.5816G > A: p.Arg1939Gln rs201326023	Het	DC	PD	D	2.261	2.28	T = 0.00003/1 (ExAC) T = 0.0002/1 (1000 Genomes)	T = 0.001452/5	Pathogenic	[31]
SB239-465	c.3032T > C: p.Leu1011Pro rs80356596	Het	DC	PD	D	5.012	4.64	ND	ND	Pathogenic (PS4, PM2, PM3 PP1, PP3, PP4)	[32]
SB239-466	^ac.5791C > A: p.Pro1931Thr rs537706054	Het	DC	PD	D	5.867	5.22	T = 0.000008/1 (ExAC)	ND	Pathogenic (PM2, PM3, PP1, PP3, PP4)	This study
SB239-466	c.2521G > A: p.Glu841Lys rs772729658	Het	DC	PD	D	5.523	5	T = 0.00003/3 (ExAC)	ND	Pathogenic	[16]
SH195-443	c.3192C > G: p.Tyr1064Ter rs766819324	Hom	DC	NA	NA	1.937	2.78	C = 0.000008/1 (ExAC)	C = 0.00029/1	Pathogenic (PVS1, PM2, PP1, PP3, PP4)	[15]
SH234-547	c.5816G > A: p.Arg1939Gln rs201326023	Het	DC	PD	D	2.261	2.28	T = 0.00003/1 (ExAC) T = 0.0002/1 (1000 Genomes)	T = 0.001452/5	Pathogenic	[31]
SH234-547	c.5566C > T: p.Arg1856Trp rs368155547	Het	DC	PD	D	2.963	2.84	A = 0.00004/5 (ExAC) A = 0.00008/1 (GO-ESP)	A = 0.000871/3	Pathogenic	[10]
AJ2-3	^ac.5534G > A: p.Gly1845Glu dbSNP ID:ND	Het	DC	PD	D	5.739	4.97	ND	ND	Pathogenic (PM2, PM3 PP1, PP3, PP4)	This study
AJ2-3	c.3032T > C: p.Leu1011Pro rs80356596	Het	DC	PD	D	5.012	4.64	ND	ND	Pathogenic	[32]
SH230-538	c.2521G > A: p.Glu841Lys rs772729658	Het	DC	PD	D	5.523	5	T = 0.00003/3 (ExAC)	ND	Pathogenic	[16]
SH230-538	^ac.4227 + 5G > C rs571671530	Het	DC	NA	NA	1.616	3.95	G = 0.00006/7 (ExAC) G = 0.0002/1 (1000 Genomes)	ND	Likely pathogenic (PM2, PM3 PP1, PP3, PP4)	This study

Splice site variant prediction tools by ESEfinder, NNSplice, and NetGene2: splice site broken. Normal score (10.34940) and mutant score (6.54650) by ESEfinder, Normal score (0.99) and mutant score (0.50) by NNSplice, Normal score (0.997) and mutant score (0.685) by NetGene2
In silico prediction Algorithm: Polyphen-2 (http://genetics.bwh.harvard.edu/pph2/index.shtml); SIFT (http://sift.jcvi.org/www/SIFT_chr_coords_submit.html) or SIFT-indels2 (http://sift.bii.a-star.edu.sg/www/SIFT_indels2.html)
Conservation tools: GERP++ score in the UCSC Genome Browser (http://genome-asia.ucsc.edu/); PhyloP score from the Mutation Taster (http://www.mutationtaster.org/)
Splice site prediction tools: ESEfinder (http://rulai.cshl.edu/cgi-bin/tools/ESE3/esefinder.cgi?process=home); NNSplice (http://www.fruitfly.org/seq_tools/splice.html); NetGene2 (http://www.cbs.dtu.dk/services/NetGene2/)
ExAC, Exome Aggregation Consortium (http://exac.broadinstitute.org/)
1000 Genomes (https://www.ncbi.nlm.nih.gov/variation/tools/1000genomes/)
KRGDB, Korean Reference Genome DB (http://152.99.75.168/KRGDB/)
Het, heterozygote mutant; Hom, homozygote mutant; DC, disease causing; PD, probably damaging; D, damaging; ND, not detected; NA, not applicable
^aNovel variant

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