PMC9478892_01
Phenotypes of three patients with WS and exotropia. All patients had an large angle exotropia (A-C). They were diagnosed as WS by dystopia canthorum, broad nasal root, synophrys (A-C), and hypopigmented fundus (D-F). Their fovea structure were normal (G-I).
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F1
He was diagnosed as Waardenburg syndrome type 1 in terms of his dystopia canthorum, broad nasal root, synophrys, depigmented irides, and hypopigmented fundus (Figures 1C,F,I).
Clinical features of Patient 01. He had deformity of the fingers (A) and heterochromia irides (B). The audiograms showed that his hearing was severely reduced on the left more than the right side (C). X-axis, frequency in hertz (Hz); Y-axis, hearing level in decibels (dB).
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F2
He was diagnosed as Waardenburg syndrome type 3 based on his dystopia canthorum, broad nasal root, synophrys, heterochromia irides, hypopigmented fundus appearance, normal fovea and malformed fingers, and hearing loss (Figures 1A, D, G; Figures 2A-C).
PMC9478892_02
Phenotypes of three patients with WS and exotropia. All patients had an large angle exotropia (A-C). They were diagnosed as WS by dystopia canthorum, broad nasal root, synophrys (A-C), and hypopigmented fundus (D-F). Their fovea structure were normal (G-I).
fgene-13-969680-g001.jpg
PMC9478892_03_fgene-13-969680-g001.jpg
F1
He was diagnosed as Waardenburg syndrome type 1 in terms of his dystopia canthorum, broad nasal root, synophrys, depigmented irides, and hypopigmented fundus (Figures 1C,F,I).
PMC9478892_03
Phenotypes of three patients with WS and exotropia. All patients had an large angle exotropia (A-C). They were diagnosed as WS by dystopia canthorum, broad nasal root, synophrys (A-C), and hypopigmented fundus (D-F). Their fovea structure were normal (G-I).
fgene-13-969680-g001.jpg
PMC9478892_03_fgene-13-969680-g001.jpg
F1
He was diagnosed as Waardenburg syndrome type 1 in terms of his dystopia canthorum, broad nasal root, synophrys, depigmented irides, and hypopigmented fundus (Figures 1C,F,I).
Four novel variants were identified from three WS patients in this study. A double gene variant in the PAX3 and COL11A2 was detected in Patient 01. Cloning sequencing showed that a single nucleotide deletion of c.136del A was detected in the PAX3, and a single nucleotide duplication of c.709dupC was found in the COL11A2 gene (A). A heterozygote missense variation of c.426G>A in SOX10 was detected in the Patient 02 (B). This variant resulted in an amino acid of Tryptophan (W) at Codon 142 replaced by a premature terminate codon. A novel heterozygote missense variation of c.668G>T in PAX3 was detected in Patient 03 (C). The variant led to an amino acid of Arginine at Codon 223 replaced by Leucine. Mutant type (upper row), wide type (lower row); the arrows denote the locations of the indel mutations.
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F3
Both of these variations were novel identified in this study, and predicted to produce an abnormal mRNA with a premature termination codon (PTC), which would be probably degraded due to the nonsense mediated decay (NMD) mechanism (Figure 3A). A novel heterozygous variation of c.426G>A (p.Trp142X) in the SOX10 gene was detected in Patient 02 (Figure 3B). Tryptophan at Codon 142 replaced by a premature termination codon, which would be degraded due to NMD mechanism. The novel identified pathogenic variation of c.668G>T (p.Arg223Leu) in PAX3 (Figure 3C) was detected in Patient 03.
A 3-D model construction showed that the novel missense variation of c .668G>T in PAX3 resulted in a large and positively charged amino acid of Arginine (R) at codon 223 being replaced by small and uncharged nonpolar amino acid of Leucine (L). The wild-type Arginine formed a hydrogen bond with R221 (A), while Leucine could form hydrogen bonds with R221 and T224 (B), which would damage the stability of the protein structure and function.
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F4
Argnine at codon 223 replaced by a nonpolar Leucine would be predicted to damage the stability of the protein structure and function, which was proven in the 3-D model construction using the PyMOL program (Figure 4). All above four variations were not detected in 100 ethnically matched control individuals through the Sanger sequencing.