Summary of Clinical Data for 20 Chinese WS2 Patients.

<p>A, complete heterochromia iridis; B, partial or segmental heterochromia iridis; C, brilliant blue iris; Skin, numerous brown freckles on the face, trunk, and limb extremities; W, W index; HL, hearing loss; +, sign present; −, sign absent.</p

Genetic and Phenotypic Heterogeneity in Chinese Patients with Waardenburg Syndrome Type II

<div><p>Waardenburg Syndrome (WS) is an autosomal-dominant disorder characterized by sensorineural hearing loss and pigmentary abnormalities of the eyes, hair, and skin. Microphthalmia-associated transcription factor (<i>MITF</i>) gene mutations account for about 15% of WS type II (WS2) cases. To date, fewer than 40 different <i>MITF</i> gene mutations have been identified in human WS2 patients, and few of these were of Chinese descent. In this study, we report clinical findings and mutation identification in the <i>MITF</i> gene of 20 Chinese WS2 patients from 14 families. A high level of clinical variability was identified. Sensorineural hearing loss (17/20, 85.0%) and heterochromia iridum (20/20, 100.0%) were the most commonly observed clinical features in Chinese WS2 patients. Five affected individuals (5/20, 25.0%) had numerous brown freckles on the face, trunk, and limb extremities. Mutation screening of the <i>MITF</i> gene identified five mutations: c.20A>G, c.332C>T, c.647_649delGAA, c.649A>G, and c.763C>T. The total mutational frequency of the <i>MITF</i> gene was 21.4% (3/14), which is significantly higher than the 15.0% observed in the fair-skinned WS2 population. Our results indicate that <i>MITF</i> mutations are relatively common among Chinese WS2 patients.</p></div

Mutation analyses of Chinese WS2 families WS01, WS02, WS04, WS08, and WS09.

<p>A. DNA sequence chromatograms showing heterozygous missense c.20A>G mutation identified in family WS02, compared with wild-type controls. The structure of MITF indicates the position of c.20A>G mutation in exon 1 and p. Y7C outside the HLH domain. B. DNA sequence chromatograms showing heterozygous missense c.332C>T mutation identified in family WS09, compared with wild-type controls. The structure of MITF indicates the position of c.332C>T mutation in exon 3 and p. A111V outside the HLH domain. C. DNA sequence chromatograms showing heterozygous c.647_649delGAA deletion mutation identified in family WS04, compared with wild-type controls. The structure of MITF indicates the position of c.647_649delGAA mutation in exon 7 and p. R217del in the HLH domain. D. DNA sequence chromatograms showing heterozygous missense c.649A>G mutation identified in family WS08, compared with wild-type controls. The structure of MITF indicates the position of c.649A>G mutation in exon 7 and p. R217G in the HLH domain. E. DNA sequence chromatograms showing heterozygous nonsense c.763C>T mutation identified in family WS01, compared with wild-type controls. The structure of MITF indicates the position of c.763C>T mutation in exon 8 and p. R255X in the HLH domain. F. Conservation analysis shows that the Arg residue at 217 in MITF is conserved across human, Pan troglodytes, macaca, canis, bos, Mus musculus, Rattus norvegicus, gallus, and Danio rerio. G. Schematic illustration of <i>MITF</i> gene structure showing the position of the mutations. AD1-3, transactivation domains; b, basic domain; HLH, helix-loop-helix domain; LZ, leucine zipper domain.</p

Pedigrees of the Chinese WS2 families WS01, WS02, and WS03, and audiograms of some affected male and female subjects.

<p>High clinical variability was observed even within the same family. Not all affected persons manifested all clinical features. Circle, female; square, male; filled quadrants indicate phenotype associated with WS, upper left, premature graying hair; lower left, freckles on the skin; upper right, hearing loss; lower right, heterochromia iridis; arrow, the proband; *, DNA samples available.</p

Summary of <i>MITF</i> Gene Mutations Identified in Chinese WS2 Patients.

<p>a. Description of the mutations is based on the GenBank reference sequence for the <i>M</i> isoform of the <i>MITF</i> gene: NM_000248.3.</p><p>b. Amino acid numbering is based on GenBank Reference Sequence: NP_000239.1.</p>*<p>, mutations first described in a Chinese population.</p><p>The English in this document has been checked by at least two professional editors, both native speakers of English. For a certificate, please see: <a href="http://www.textcheck.com/certificate/O0uNHd" target="_blank">http://www.textcheck.com/certificate/O0uNHd</a>.</p

Stepwise hierarchic assessment of efficacy of cochlear implantation.

<p>★, subject in this row has approached the level of the current column; ○, subjects in this row is not approaching the level of the current column.</p><p>Stepwise hierarchic assessment of efficacy of cochlear implantation.</p

Progress according to IT-MAIS/MAIS scores.

<p>(<b>a</b>) ANCI_01, IT-MAIS/MAIS score; (<b>b</b>) ANCI_02, IT-MAIS/MAIS score; (<b>c</b>) ANCI_03, MAIS score; (<b>d</b>) ANCI_04, MAIS score; (<b>e</b>) ANCI_05, IT-MAIS/MAIS score; (<b>f</b>) ANCI_07, IT-MAIS/MAIS score; (<b>g</b>) ANCI_09, MAIS score; (<b>h</b>) ANCI_10, MAIS score. MAIS, Meaningful Auditory Integration Scale; IT-MAIS, Infant-Toddler Meaningful Auditory Integration Scale.</p

The Prestin-CreER^T2 knockin homozygous mice exhibit fewer threshold shifts in the acute phase of cochlear pathogenesis (2 h after the noise exposure).

<p><b>A</b> Elevation of ABR thresholds at 2 h after the noise exposure. <b>B</b> Comparison of the percentages of the average detectable ABRs among the three groups (the Prestin-CreER^T2 homozygous, heterozygous and wild-type groups). Detectable ABRs were defined as ABRs that could be visually identified within the intensity range of the stimuli. The percentage of detection is 100% for the homozygous mice. By contrast, the values are 40.6±45.9% for the wild-type mice and 60.8±42.8% for the heterozygous mice. Both are significantly lower than that of homozygous mice (one-way ANOVA; <i>F_2,65</i> = 23.039, <i>P</i><0.001; *** indicates <i>P</i><0.001 tested by Tukey test). In addition, the heterozygous mice had a greater detectable rate than that observed for the wild-type mice (* indicates <i>P</i> = 0.045 tested by Tukey test). <b>C</b> Comparison of the ABR threshold shifts among the Prestin-CreER^T2 mice (+/+ and +/-) and wild-type mice. The levels of the threshold shift of the homozygous mice are significantly smaller than those of the heterozygous and wild-type mice (two-way ANOVA, two-way ANOVA, <i>F_{2, 244}</i> = 56.11, <i>P</i><0.001; *** indicates <i>P</i><0.001 tested by Tukey test). These results indicate that the Prestin-CreER^T2 knockin homozygous mice have a reduced level of hearing loss at the early phase of acoustic trauma.</p

Preoperative and postoperative audiograms.

<p>(<b>a</b>) ANCI_01, preoperative and 10 months postoperative; (<b>b</b>) ANCI_04, preoperative and 7 months postoperative; (<b>c</b>) ANCI_05, preoperative and 48 months postoperative; (<b>d</b>) ANCI_09, preoperative and 11 months postoperative; (<b>e</b>) ANCI_10 preoperative and 12 months postoperative.</p

Progress according to MESP performance.

<p>(<b>a</b>) ANCI_01, MESP performance; (<b>b</b>) ANCI_02, MESP performance; (<b>c</b>) ANCI_03, MESP performance; (<b>d</b>) ANCI_04, MESP and Mandarin Pediatric Speech Intelligibility Test performance; (<b>e</b>) ANCI_05, MESP performance; (<b>f</b>) ANCI_09, MESP performance; (<b>g</b>) ANCI_10, MESP performance. MESP, Mandarin Early Speech Perception Test.</p