A recurrent variant in LIM2 causes an isolated congenital sutural/lamellar cataract in a Japanese family

Figures & data

Figure 1. (a) Abridged pedigree with lamellar/sutural congenital cataract. Squares and circles symbolize males and females, respectively. Open and filled symbols indicate unaffected and affected individuals, respectively. The arrows indicate the family members who participated in the WES analysis and were sequenced to show segregation; (b) (I) III:2 depicts bilateral lamellar cataract and in (II) III-3 with sutural cataract in left eye and lamellar cataract in the right eye.

Figure 2. Sequence analysis—(a) LIM2–missense variant c.388c>t in affected member, (b) LIM2 wild type, (c) COL11A1-missense variant at c.3788c>t in affected and unaffected family members, and (d) wild-type COL11A1.

Table 1. Pathogenicity scores of variants in COL11A1 and LIM2 genes causing sutural/lamellar cataract.

Genes	Genomic pos./Exon	HGVSp	MutationTaster/verdict	PROVEAN	REVEL	GERP	CADD	SIFT	DANN
LIM2	Chr19q13.4/Ex-4/5	p.R130C	Disease-causing/0.81-Pathogenic	Damaging /0.74	Pathogenic/0.96	4.73	35.1	Damaging	0.999
COL11A1	Chr1p21.1/Ex-50/67	p.P1263L	Uncertain Significance/0.81	Damaging /0.9	Pathogenic/0.89	5.4	32.0	Damaging	0.997

Protein Variation Effect Analyzer (PROVEAN) is to predict the functional consequences of amino acid substitutions and indels; Rare Exome Variant Ensemble Learner (REVEL) tool is to predict the pathogenicity of missense variants based on a combination of scores from 13 individual tools; Genomic Evolutionary Rate Profiling (GERP) NR corresponds to the neutral rate conservation score of the site; Combined Annotation Dependent Depletion (CADD) is a score for the deleteriousness of a variant. A CADD score >15 is considered damaging; Sorting Intolerant From Tolerant (SIFT) score (0.0–0.05) to check the deleteriousness of the amino acid substitution on the protein function; * indicates the truncated protein.

Table 2. LIM2 Variants causing cataractogenesis to date.

No.	Exon	HGVSc	HGVSp	Inheritance	Origin	Phenotype	Ocular defects	Reference
1.	Ex2/5	c.57G>A	p.L19L	Complex	China	Age-related cortical		(10)
2.	Ex2/5	c.67A>C	p.M23L	Complex	China	Age-related cortical		(10)
3.	Ex3/5	c.233 G>A	p.G78D	AR	Pakistan	Nuclear		(11)
4.	Ex3/5	c.313T>G	p.F105V	AR	Iraq	Presenile, cortical, sutural		(12)
5.	Ex4/5	c.385C>T	p.R129C	AD	Spain	-		(13)
6.	Ex4/5	c.388C>T	p.R130C	AD	UK/Czechia	Nuclear pulverulent		(3)
7.	Ex4/5	c.388C>T	p.R130C	AD	China	Membranous	Nystagmus, amblyopia	(14)
8.	Ex4/5	c.388C>T	p.R130C	AD	China	Variable (nuclear, lamellar, pulverulent)	Elongated Axial Length, Myopia	(15)
9.	Ex4/5	c.388C>T	p.R130C	AD	Spain	Nuclear		(13)
10.	Ex4/5	c.388C>T	p.R130C	AD	Spain	Lamellar		(13)
11.	Ex4/5	c.388C>T	p.R130C	AD	Japan	sutural/Lamellar		Present Study
12.	Ex4/5	c.462G>A	p.G154E	AR	India	Congenital	Nystagmus, amblyopia	(16)

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