Development and application of a next-generation-sequencing (NGS) approach to detect known and novel gene defects underlying retinal diseases

Audo, Isabelle; Bujakowska, Kinga M; Léveillard, Thierry; Mohand-Saïd, Saddek; Lancelot, Marie-Elise; Germain, Aurore; Antonio, Aline; Michiels, Christelle; Saraiva, Jean-Paul; Letexier, Mélanie; Sahel, José-Alain; Bhattacharya, Shomi S; Zeitz, Christina

doi:10.1186/1750-1172-7-8

Orphanet Journal of Rare Diseases

Table 6 Patients with unsolved genotype and unlikely disease causing mutations

From: Development and application of a next-generation-sequencing (NGS) approach to detect known and novel gene defects underlying retinal diseases

Index	Phenotype	Pre-screening	Gene	Mutation	Allele State	Read reference NGS	Read variant NGS	Mutation verified by Sanger and co-segregation	Comment
CIC03282, F1388	Stargardt	ABCA4 microarray	*ABCA4*	c.1268A > G p.H423R	het	77	61	yes	but reported as polymorphism [71]
				c.6764G > T p.S2255I no additional variants in lower covered exons	het	2	7	yes	but reported as polymorphism [72]
			*CFH*	c.3482C > A p.P1161Q	het	77	52	yes	conserved, probably damaging
				c.1204C > T p.H402Y	het	94	87	yes	AMD
CIC01269, F761	adRP	-	*RP1L1*	c.5959C > T p.Q1987X	het	145	150	yes, did not co-segregate	pass to whole exome sequencing
CIC01312, F795	adCD with post-receptoral defects	RHO, PDE6B, GNAT1 adRP chip	*CUBN*	c.127C > T p.R43X	het	139	102	yes, did not co-segregate	pass to whole exome sequencing
			*CUBN*	c.9340G > A p.G3114S	het	61	44	yes, did not co-segregate
			*GUCY2D*	c.1499C > T p.P500L	het	41	34	yes, did not co-segregate
			*TRPM1*	c.3904T > C p.C1302R	het	102	99	yes, did not co-segregate
CIC03225, F1362	arRP consang.	arRP chip	*PROM1*	c.314A > G p.Y105C	het	120	115	yes, but no additional mutation	no homo, no compound hets, pass to whole exome sequencing
			*GUCY2D*	c.2917G > A p.V973L	het	6	2	false positive, not found by Sanger
			*DSCAML1*	c.592C > T p.R198C	het	70	81	yes, but no additional mutation
			*TBC1D24*	c.641G > A p.R214H	het	27	12	yes, but no additional mutation
			*TMEM67*	c.1700A > G p.Y567C	het	80	58	yes, but no additional mutation
CIC04757 F2364	Index and affected sister early onset arCD, macro-cephaly and mental retardation in affected sister consang.	-	*IMPG2*	c.3439C > T p.P1147S	homo	0	140	no	Polyphen and Sift benign, not conserved
			*PKD2L1*	c.1027C > T p.R343C	het	63	68
				c.1202T > G p.V401G	het	25	19		appeared also het in 11 of our samples appeared also het in affected sister but no other mutation in less covered exons
			*DFNB31*	c.1943C > A p.S648Y	het	7	7	yes	affected sister also both variants but both come from father, no other variant in lower covered region.
				c.2644C > A p.R882S	het	27	14	yes
			*EYS*	c.7597A > G p.K2533E	het	151	149	yes	Affected sister does not carry this variant
			*RPGRIP1*	c.2417C > T p.T806I	het	138	132	no	not conserved
CIC04152, F1955	male x-linked cCSNB, has affected nephew	NYX	*TRPM1*	c.470C > T p.S157F	het	118	130	yes, no other het mutation.	x-linked inheritance and phenotype verification

Index patients and respective gene defect are highlighted in bold. In some cases also family members were used for NGS.

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ISSN: 1750-1172

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