Authors:Gu Liang, Gao Fengjie, Guan Huaijin, Ji Min
Corresponding author:Ji Min, Email:amyji1234@hotmail.com
Published:2026-08-10
DOI:10.3760/cma.j.cn115989-20250303-00063
ABSTRACT
Objective To analyze the clinical and genetic characteristics of a family with Waardenburg syndrome type Ⅰ (WS1) .
Methods A pedigree investigation was conducted. Clinical data from 3 generations of 7 people from a family with WS1 in the Nantong area of China, Jiangsu Province, who visited the Department of Ophthalmology at the Affiliated Hospital of Nantong University in April 2024, including 3 patients. Proband and her parents underwent comprehensive ophthalmic examinations, including slit-lamp examination, color fundus photography, optical coherence tomography, anterior segment photography, pure-tone audiometry, and general physical examination. Peripheral blood samples were obtained for whole-exome sequencing and subsequent data analysis. The pathogenic variants from members were analyzed according to the ACMG guidelines. This study adhered to the Declaration of Helsinki and was approved by the institutional Ethical Committee Review Board of Affiliated Hospital of Nantong University (No. 2024-L080). All subjects were informed of the purpose of this study and signed informed consent forms.
Results The proband, a 12-year-old girl, presented with dystopia canthorum, wide nasion, thick and connected eyebrows, bright blue irises, and diffuse hypopigmentation of the fundus with exposure of choroidal vessels in both eyes. The choroid was significantly thickened in both eyes, reaching a thickness of 509 µm in the right eye and 514 µm in the left eye. She also had moderate hearing loss in the left ear and severe hearing loss in the right ear. Physical examination of the proband’s mother showed premature gray hair, lateral deviation of the inner canthus of both eyes, wide nasion, and thick eyebrows. The left eye iris was bright blue, and the fundus was diffusely hypomelanotic with choroidal vessels exposed, showing a sunset glow-like fundus. The left eye choroid was significantly thickened to 558 µm. No obvious abnormalities were noted in the right eye. Audiometric testing revealed severe impairment in both ears. Whole exome sequencing showed that the proband and her mother carried a heterozygous nonsense variation c.667C>T (p.Arg223Ter) in the PAX3 gene, which caused premature termination of protein translation. This variant is classified as pathogenic according to ACMG guidelines. The inheritance pattern in this family is consistent with autosomal dominant inheritance.
Conclusions The c.667C>T mutation in the PAX3 gene is a pathogenic variant site in this WS1 family. The special manifestation of iris heterochromia accompanied by ipsilateral choroid thickening in this family has been reported for the first time in WS1.
KEYWORDS：
Waardenburg syndrome type Ⅰ;PAX3 gene ;Heterochromic iris;Choroidal thickening;c.667C>T (p.Arg223Ter)
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Authors Info & Affiliations
Gu Liang
Department of Ophthalmology, Affiliated Hospital of Nantong University, Nantong 226001, China
Gao Fengjie
Department of Ophthalmology, Affiliated Hospital of Nantong University, Nantong 226001, China
Guan Huaijin
Department of Ophthalmology, Affiliated Hospital of Nantong University, Nantong 226001, China
Ji Min
Department of Ophthalmology, Affiliated Hospital of Nantong University, Nantong 226001, China
Figures & Tables
Figure 1 Pedigree map of type Ⅰ Waardenburg syndrome □: normal male; ○: normal female; ■: affected male; ●: affected female; ↗: proband
Figure 2 Facial and ocular clinical features of the proband The proband exhibited lateral deviation of the inner canthi of both eyes, a wide nasion, thick and prominent eyebrows, and vivid blue irises A: Face B: Right eye C: Left eye
Figure 3 Fundus photographs of the proband’s eyes The retinas of both eyes appeared flat, exhibiting diffuse hypopigmentation and exposed choroidal vessels, which resulted in a sunset-like glow of the fundus A: Right eye B: Left eye
Figure 4 Optical coherence tomography images of the macular region in both eyes of the proband Significant thickening of the choroidal layer in both eyes A: Right eye B: Left eye
Figure 5 Comparison of choroidal thickness measured by optical coherence tomography angiography between the two eyes of the proband The choroidal thickness was 509 μm in the right eye and 514 μm in the left eye of the proband A: Right eye B: Left eye
Figure 6 Binaural pure tone audiometry results of the proband and her mother A: The proband showed severe impairment in the right ear and moderate impairment in the left ear B: The proband’s mother showed bilateral severe impairment
Figure 7 Facial and ocular clinical features of the proband’s mother Notable characteristics included bilateral lateral canthus, wide nasion, thick eyebrows, and a bright blue iris in the left eye of the proband’s mother A: Face B: Right eye C: Left eye
Figure 8 Fundus photography of the proband’s mother The fundus of both eyes of the proband’s mother appeared flat, exhibiting diffuse hypopigmentation and exposed choroidal vessels, which resulted in a sunset-like glow of the fundus A: Right eye B: Left eye
Figure 9 Optical coherence tomography examination of the binocular macula of the proband’s mother Significant thickening of the choroidal layer in the left eye A: Right eye B: Left eye
Figure 10 Comparison of choroidal thickness between the two eyes of the proband’s mother under optical coherence tomography angiography The left eye of proband’s mother exhibited a choroidal thickness of 558 μm, while the right eye had a choroidal thickness of 327 μm A: Right eye B: Left eye
Figure 11 Sanger sequencing results A: Heterozygous mutation (c.667C>T) in the proband B: Heterozygous mutation (c.667C>T) in the proband’s mother C: Wild-type sequence in the proband’s father The arrow pointed to the variant site
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