Clinical Features and Molecular Characteristics of Korean Patients with Congenital Aniridia

In Kyun Hahn; Dae Hee Kim; Hyun Taek Lim

doi:10.3341/jkos.2016.57.9.1441

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Hahn, Kim, and Lim: Clinical Features and Molecular Characteristics of Korean Patients with Congenital Aniridia

Original Article

J Korean Ophthalmol Soc 2016;57(9):1441-1450.

Published online: 25 September 2016

DOI: https://doi.org/10.3341/jkos.2016.57.9.1441

Clinical Features and Molecular Characteristics of Korean Patients with Congenital Aniridia

In Kyun Hahn, MD¹, Dae Hee Kim, MD², Hyun Taek Lim, MD, PhD¹

¹Department of Ophthalmology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

²Department of Ophthalmology, Myongji Hospital, Seonam University College of Medicine, Goyang, Korea

Address reprint requests to Hyun Taek Lim, MD, PhD Department of Ophthalmology, Asan Medical Center, #88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea Tel: 82-2-3010-3680, Fax: 82-2-470-6440 E-mail: htlim@amc.seoul.kr

Received 16 June 2016 Revised 6 July 2016 Accepted 18 August 2016

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Purpose

To introduce clinical features and molecular characteristics of Korean patients with congenital aniridia.

Methods

Patients with iris hypoplasia were diagnosed clinically as congenital aniridia and were included in the study. Best corrected visual acuity (BCVA) and associated ocular abnormalities (including severity of iris hypoplasia, nystagmus, keratopathy, and foveal hypoplasia), and findings in optical coherence tomography were analyzed. PAX6 analysis, multiplex ligation-depend-ent probe amplification (MLPA), genomic molecular karyotyping, and candidate gene sequencing were performed to detect genetic abnormalities.

Results

28 patients from 18 families were included in the study. BCVA varied from hand motion to 20/25. No manifest nystagmus was found in 3 patients, but the rest of the patients had pendular horizontal nystagmus. Keratopathy was found in 23 patients, cataracts in 12 patients, and glaucoma in 4 patients. All patients had foveal hypoplasia, including one case with a subtle phenotype. The PAX6 mutation was detected in 13 families out of 18;2 (p.Trp162Leufs*38, p.Gly409Arg) were novel, 3 families had the miss ensemutation, and 3 families had alargedeletion in the PAX6 gene.

Conclusions

This study adds 2 novel PAX6 mutations related to congenital aniridia to those previously reported. Congenital aniridia is a serious, sight-threatening ocular malformation, but central vision and the degree of iris hypoplasia were highly variable. The PAX6 mutation was detected in 72% of the patients in this study, and there were no specific clinical features differentiating aniridia with and without PAX6 mutations.

Keywords: Aniridia, Foveal hypoplasia, Iris hypoplasia, Mutation, PAX6

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Figure 1.

Patients with PAX6 mutation. (A-C) Case 10B carries a run-on mutation of PAX6. (A) Anterior segment image showing iris hypoplasia, about 20% of iris remnants, but no significant keratopathy and cataract. (B) Fundus image showing marked foveal hypoplasia. (C) Loss of foveal depression is seen in optical coherence tomography. (D, E) Case 9B carries a run-on mutation of PAX6. (D) Anterior segment image showing subtle iris hypoplasia. (E) But fundus image demonstrates moderate degree of foveal hypoplasia.

Figure 2.

Patients without PAX6 mutation. (A-C) Case 18. (A) Anterior segment image showing mild degree of iris hypoplasia. (B) Subtle foveal hypoplasia was seen in fundus image. (C) Near normal foveal depression was also demonstrated in optical coherence tomography. (D-F) Case 17B. (D) Anterior segment image showing complete abscence of iris. (E) Fundus image showing moderate degree of foveal hypoplasia. (F) Loss of foveal depression was seen in optical coherence tomography.

Figure 3.

Familial patients with missense mutation of PAX6. (A, B) Case 8A. (A) Anterior segment image showing moderate degree of iris hypoplasia, peripheral corneal opacity and cataract. (B) Fundus image showing moderate degree of foveal hypoplasia. (C-E) Case 8B (mother of 8A). (C) Anterior segment image showing mild degree of iris hypoplasia and cataract, but no definite corneal opacity. (D) Fundus image showing moderate degree of foveal hypoplasia. (E) Optical coherence tomography also showing flat foveal contour.

Table 1.

PAX6 gene analysis in 18 probands

Case	PAX6 mutation	Consequence	Exon/Intron	Domain	Status/Reference
1A	c.128C>T	p.Ser43Phe	Exon 5	PD	Previously reported¹⁷
2A	c.399 + 1G>A (IVS3 [+1] G>A)	Splice defect	Intron 7	Linker	Previously reported²³
3	c.484_485insT	p.Trp162Leufs*38	Exon 7	Linker	Novel
4A	c.622C>T	p.Arg208Trp	Exon 8	HD	Previously reported²⁴
5	c.683–9C>G (IVS8–9C>G)	Splice defect	Intron 8	HD	Previously reported¹⁷
6	c.718C>T	p.Arg240X	Exon 9	HD	Previously reported⁵
7	c.949C>T	p.Arg317X	Exon 11	PST	Previously reported⁴
8A	c.1225G>C	p.Gly409Arg	Exon 13	PST	Novel
9A	c.1268A>T	p.X423Leu	Exon 13	3' Untranslated Region	Previously reported²⁵
10A	c.1268A>T	p.X423Leu*15	Exon 13	3' Untranslated Region	Previously reported²⁵
11	Exon 1–4 deletion				MLPA kit P219
12	Whole exon deletion	WAGR			MLPA kit P219
13	Whole exon deletion	WAGR			MLPA kit P219
14A	No mutation found
15	No mutation found
16	No mutation found
17A	No mutation found
18	No mutation found

PD = paired domain; HD = homeodomain; PST = proline-serine-threonine-rich domain; MLPA = multiplex ligation-dependent probe am-plification; WAGR = Wilms tumor, aniridia, genitourinary anomalies, and mental retardation.

Table 2.

Phenotypic data of the 20 patients having PAX6 mutation

Case	Age/ Sex	Inheritance	Mutation type	BCVA	Iris anomaly	Nystagmus	Foveal hypoplasia	Keratopathy	Others	Severity
1A	0.4/F	AD	Missense	FF	Iris remnant, ∼70%	++	+	+/−	Ectropion uvea, corectopia	Severe
1B	30/F	Mother of 1A	Missense	20/80	Iris remnant, ∼50%	+++	+	+++	Ectropion uvea, corectopia, cataract	Moderate
2A	0.4/F	AD	Splice defect	FF	Thin rim of iris, ∼10%	+	+	+	–	Moderate
2B	30/F	Mother of 2A	Splice defect	20/80	Thin rim of iris, ∼10%	+	+	++	Cataract, glaucoma	Moderate
3	3.5/F	Sporadic	Frameshift	20/200	Near-total absence of iris	++	++	+/−	Null zone nystagmus with face turn	Severe
4A	25/F	AD	Missense	20/300	Iris remnant, ∼80%	++	+	+++	Cataract, microcornea	Severe
4B	54/F	Mother of 4A	Missense	20/100	Iris remnant, ∼80%	+	+	++	Microcornea	Moderate
5	4/F	Sporadic	Splice defect	20/160	Iris remnant, ∼80% OD; thin rim, ∼20% OS	+/−	+	+	Ectropion uvea, corectopia	Mild
6	3/F	Sporadic	Nonsense	20/400	Near-total absence of iris	+	++	+		Severe
7	18/F	Sporadic	Nonsense	20/200	Thin rim of iris, ∼10%	+	+	+	Cataract	Severe
8A	1/M	AD	Missense	FF	Iris remnant, ∼50%	++	++	+++	Ectropion uvea, corneal opacity, cataract	Severe
8B	42/F	Mother of 8A	Missense	20/160	Iris remnant, ∼80%	++	++	+	Cataract, glaucoma	Severe
9A	3/M	AD	Run-on	20/400	Near-total absence of iris	++	++	+	Cataract	Severe
9B	26/M	Father of 9A	Run-on	20/125	Near-full iris	++	++	++	Cataract	Moderate
10A	2.5/M	AD	Run-on	FF	Iris remnant, ∼80%	+	++	+/−	Iridocorneal adhesion, hearing loss	Severe
10B	9/F	Sister of 10A	Run-on	20/80	Iris remnant, ∼80%	+	++	+/−	High myopia, hearing loss	Moderate
10C	43/M	Father of 10A	Run-on	20/100	Iris remnant, ∼80%	+	++	+	Cataract	Moderate
11	0.5/M	Sporadic	Large deletion	FF	No iris	++	++	–	Glaucoma	Severe
12	0.5/F	Sporadic	Large deletion	FF	No iris	++	++	–	WAGR	Severe
13	0.3/M	Sporadic	Large deletion	FF	Near-total absence of iris	++	++	+++	WAGR, cataract, glaucoma	Severe

BCVA = best corrected visual acuity; AD = autosomal dominant; FF = fix and follow; +++ = severe; ++ = moderate; + = mild; +/− = very subtle or minimal; – = none; WAGR = Wilms tumor, aniridia, genitourinary anomalies, and mental retardation.

Table 3.

Phenotypic data of the 8 patients without PAX6 mutation

Case	Age/ Sex	Inheritance	BCVA	Iris anomaly	Nystagmus	Foveal hypoplasia	Keratopathy	Others	Severity
14A	2/F	AD	FF	No iris	+++	++	–	Developmental delay	Severe
14B	27/F	Mother of 14A	20/200	Thin rim of iris, ∼5%	+++	++	++	Cataract, optic atrophy	Severe
15	5/F	Sporadic	20/25	No iris	+/−	+	–		Very mild
16	4/M	Sporadic	20/400	No iris	++	++	–		Severe
17A	1/F	AD	FF	Iris remnant, ∼80%	++	++	–		Severe
17B	3/M	Brother of 17A	20/200	No iris	++	++	+/−		Severe
17C	31/F	Mother of 17A	20/160	Near-total absence of iris	++	++	++	Cataract	Severe
18	3/M	Sporadic	20/200	Iris remnant, ∼80%	+/−	+/−	–		Mild

BCVA = best corrected visual acuity; AD = autosomal dominant; FF = fix and follow; +++ = severe; ++ = moderate; + = mild; +/− = very subtle or minimal; – = none.

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