Development and validation of prediction model to estimate vertigo risk after endolymphatic sac decompression in Meniere's disease: a retrospective cohort study.

PURPOSE: To study the efficacy predictors of endolymphatic sac decompression (ESD) in Meniere's disease (MD), and to establish and verify the prediction model of vertigo after ESD in patients with MD. METHODS: The retrospective cohort data of 56 patients with unilateral MD who underwent ESD surgery were recorded. A stepwise regression method was used to select optimal modeling variables, and we established a logistic regression model with the outcome of vertigo after ESD. The bootstrap method was used for internal validation. RESULTS: Potential predictors included sex, age, follow-up duration, disease course, attack duration, frequency of attack, pure-tone threshold average (PTA) of the patient's speech frequency, audiogram type, glycerin test results, MD subtype, and 10-year atherosclerotic cardiovascular disease risk classification. Using the stepwise regression method, we found that the optimal modeling variables were the audiogram type and PTA of the patient's speech frequency. The prediction model based on these two variables exhibited good discrimination [area under the receiver operating characteristic curve: 0.72 (95% confidence interval: 0.57-0.86)] and acceptable calibration (Brier score 0.21). CONCLUSION: The present model based on the audiogram type and PTA of the patient's speech frequency was found to be useful in guidance of ESD efficacy prediction and surgery selection.

Resolving the genetic heterogeneity of prelingual hearing loss within one family: Performance comparison and application of two targeted next generation sequencing approaches.

Here, we report an unconventional Chinese pedigree consisting of three branches all segregating prelingual hearing loss (HL) with unclear inheritance pattern. After identifying the cause of one branch as maternally inherited aminoglycoside-induced HL, targeted next generation sequencing (NGS) was applied to identify the genetic causes for the other two branches. One affected subject from each branch was subject to targeted NGS whose genomic DNA was enriched either by whole-exome capture (Agilent SureSelect All Exon 50 Mb) or by candidate genes capture (Agilent SureSelect custom kit). By NGS analysis, we identified that patients from Branch A were compound heterozygous for p.E1006K and p.D1663V in the CDH23 (DFNB12) gene; and patients from Branch B were homozygous for IVS7-2A>G in the SLC26A4 (DFNB4) gene. Both CDH23 mutations altered conserved calcium binding sites of the extracellular cadherin domains. The co-occurrence of three different genetic causes in this family was exceedingly rare but fully compatible with the mutation spectrum of HL. Our study has also raised several technical and analytical issues when applying the NGS technique to genetic testing.

Radiotherapeutic treatment of a fighter pilot with nasopharyngeal carcinoma.

BACKGROUND: Radiotherapy is the standard and most effective treatment for nasopharyngeal carcinoma (NPC) in its early stages. However, its application in fighter pilots returning to flying duties with NPC has not been previously reported, presumably due to post-radiotherapeutic complications. CASE REPORT: A 36-yr-old male fighter pilot had a painless mass in the left neck for 5 mo. Pathological diagnosis demonstrated nonkeratinizing squamous cell carcinoma in the left nasopharynx which had metastasized to lymph nodes in the left side of the neck. He was diagnosed and staged with NPC (T1N2M0) before treatment with radiotherapy and adjuvant chemotherapy. The patient suffered from catarrhal otitis media and xerostomia after 3 mo of radiotherapy, but these symptoms resolved. After a total of 8 mo of radiotherapy, he was in remission with no evidence of tumor recurrence or metastasis. He had normal Eustachian tube, hearing, and vestibular function before and after hypobaric chamber testing and passed all flight-related physical examinations. Consequently, he was granted a medical waiver and returned to flying status in two-seat fighter aircraft, flying for 53 h in a 12-mo period. After passing all flight-related tests again, he was then allowed to fly in single-seat aircraft. At the time of submission of this article, he has flown for 147 h and remained on flying status for 26 mo. He will be monitored annually for long-term effects of radiotherapy and/or disease recurrence. CONCLUSIONS: Fighter pilots with NPC may be safely considered for medical waiver with appropriate monitoring after successful treatment.

Loss-of-function mutations in the PRPS1 gene cause a type of nonsyndromic X-linked sensorineural deafness, DFN2.

We report a large Chinese family with X-linked postlingual nonsyndromic hearing impairment in which the critical linkage interval spans a genetic distance of 5.41 cM and a physical distance of 15.1 Mb that overlaps the DFN2 locus. Mutation screening of the PRPS1 gene in this family and in the three previously reported DFN2 families identified four different missense mutations in PRPS1. These mutations result in a loss of phosphoribosyl pyrophosphate (PRPP) synthetase 1 activity, as was shown in silico by structural analysis and was shown in vitro by enzymatic activity assays in erythrocytes and fibroblasts from patients. By in situ hybridization, we demonstrate expression of Prps1 in murine vestibular and cochlea hair cells, with continuous expression in hair cells and postnatal expression in the spiral ganglion. Being the second identified gene associated with X-linked nonsyndromic deafness, PRPS1 will be a good candidate gene for genetic testing for X-linked nonsyndromic hearing loss.

The effect of vascular risk factors on the efficacy of endolymphatic sac decompression surgery for Meniere's disease: a retrospective cohort study.

Objectives: This study aimed to investigate the effect of vascular risk factors on the outcomes of endolymphatic sac decompression (ESD) surgery in patients with Meniere's disease. Methods: The study included 56 patients with Meniere's disease, who had undergone unilateral ESD surgery. The patients' vascular risk factors were assessed based on the preoperative 10-year atherosclerotic cardiovascular diseases risk classification. Those with no or low risk were defined as the low-risk group, while those with medium, high, or very high risk were defined as the high-risk group. The correlation between the vascular risk factors and ESD efficacy was evaluated by the comparison of vertigo control grade between the two groups. The functional disability score was also assessed to investigate whether ESD improved the quality of life in Meniere's disease patients with vascular risk factors. Results: After ESD, 78.95 and 81.08% of patients from the low-risk and high-risk groups, respectively, demonstrated at least grade B vertigo control; no statistically significant difference was observed (p = 0.96). The postoperative functional disability scores in both groups were significantly lower compared with those before surgery (p < 0.01), with a median decrease of two (1, 2) points in both groups. No statistically significant difference between the two groups was observed (p = 0.65). Conclusion: Vascular risk factors have little effect on the efficacy of ESD in patients with Meniere's disease. Patients with one or more vascular risk factors can still experience a not poor vertigo control and improved quality of life after ESD.

Qualification of Pilots with Aero-Otitis Media After Balloon Eustachian Tuboplasty.

BACKGROUND: Aero-otitis media (AOM), also known as aural barotrauma or barotitis media, is categorized into primary AOM and secondary AOM. Because conservative treatment was ineffective, primary AOM was one of the main reasons for grounding. In 2014, the team successfully treated a pilot with primary AOM using balloon Eustachian tuboplasty (BET). Now, this case is reported.CASE REPORT:The patient was a 40-yr-old male transport pilot who joined a flight after catching a cold. During the descent, the right ear appeared to have stuffiness and hearing loss, accompanied by tinnitus and ear pain. The local hospital's acoustic immittance test showed an "A" curve in the left ear and a "B" curve in the right ear. According to "secretory otitis media", right tympanic membrane puncture and drugs were performed. After he recovered, he continued to fly, and the symptoms reappeared again. Then he was transferred to our hospital, and right BET was performed. Equalization of ear pressure in the hypobaric chamber returned to normal 2 mo after the operation. The pilot was found fit to fly. The pilot is still qualified, with more than 6000 h of flight time.DISCUSSION: AOM is linked to Eustachian tube dysfunction. BET has been a minimally invasive treatment of Eustachian tube lesions in recent years. If conservative treatments for primary AOM are ineffective, BET can be selected. While the postoperative symptoms disappeared, pure tone audiometry, tympanometry, and ear pressure function tests met the standards for the physical examination of pilots, allowing the determination of flight qualification.Zhang M, Liu X, Wang B, Jin Z, Xu X. Qualification of pilots with aero-otitis media after balloon Eustachian tuboplasty. Aerosp Med Hum Perform. 2023; 94(8):629-633.

Pilots' Spatial Visualization Ability Assessment Based on Virtual Reality.

BACKGROUND: The aim of this study was to investigate the effectiveness of the mental rotation test (MRT) based on virtual reality (VR) in predicting pilots' spatial visualization ability (SVA).METHODS: Based on VR, 118 healthy pilots' SVA were evaluated by MRT. The pilot flight ability evaluation scale was used as the criterion of test validity. According to the scale score, pilots were divided into high, middle, or low spatial ability groups pursuant to the 27% allocation principle. Differences in reaction time (RT), correct rate (CR), and correct number per second (CNPS) of MRT between groups were compared. Correlations between scale scores and MRT scores were analyzed. RT, CR, and CNPS of MRT among different age groups and between genders were also compared.RESULTS: The RT of the high spatial ability group was remarkably slower than that of the low spatial ability group (363.4 ± 140.2 s, 458.1 ± 151.7 s). The CNPS of the high spatial ability group was dramatically higher than that of the low spatial ability group (0.111 ± 0.045 s, 0.086 ± 0.001 s). There were no significant differences in RT, CR, and CNPS between different genders. Pilots in the 29-35 yr old age group had considerably slower RT than those in the 22-28 yr old age group (330.8 ± 140.3 s, 417.2 ± 132.7 s). Pilots in the 29-35 yr old age group had conspicuously higher CNPS than pilots in the 22-28 yr old age group (0.119 ± 0.040 s, 0.096 ± 0.036 s). All pilots' scale scores were positively correlated with CNPS (r = 0.254) and negatively correlated with RT (r = -0.234).DISCUSSION: MRT based on VR has a good discrimination efficacy for SVA of pilots and is a good indicator for the SVA component measurement.Zhang M, Wang M, Feng H, Liu X, Zhai L, Xu X, Jin Z. Pilots' spatial visualization ability assessment based on virtual reality. Aerosp Med Hum Perform. 2023; 94(6):422-428.

Predictive accuracy of machine learning for radiation-induced temporal lobe injury in nasopharyngeal carcinoma patients: a systematic review and meta-analysis.

Background: Radiotherapy is a common treatment for nasopharyngeal carcinoma (NPC) but can cause radiation-induced temporal lobe injury (RTLI), resulting in irreversible damage. Predicting RTLI at the early stage may help with that issue by personalized adjustment of radiation dose based on the predicted risk. Machine learning (ML) models have recently been used to predict RTLI but their predictive accuracy remains unclear because the reported concordance index (C-index) varied widely from around 0.31 to 0.97. Therefore, a meta-analysis was needed. Methods: The PubMed, Web of Science, Embase, and Cochrane Library databases were searched from inception to November 2022. Studies that fully develop one or more ML risk models of RTLI after radiotherapy for NPC were included. The Prediction model Risk Of Bias Assessment Tool (PROBAST) was used to assess the risk of bias in the included research. The primary outcome of this review was the C-index, specificity (Spe), and sensitivity (Sen). Results: The meta-analysis included 14 studies with 15,573 NPC patients reporting a total of 72 prediction models. Overall, 94.44% of models were found to have a high risk of bias. Radiomics was included in 57 models, dosimetric predictors in 28, and clinical data in 27. The pooled C-index for ML models predicting RTLI was 0.77 [95% confidence interval (CI): 0.75-0.79] in the training set and 0.78 (95% CI: 0.75-0.81) in the validation set. The pooled Sen was 0.75 (95% CI: 0.69-0.80) in the training set and 0.70 (95% CI: 0.66-0.73) in the validation set and the pooled Spe was 0.78 (95% CI: 0.73-0.82) in the training set and 0.79 (95% CI: 0.75-0.82) in the validation set. Models with radiomics and clinical data achieved the most excellent discriminative performance, with a pooled C-index of 0.895. Conclusions: ML models can accurately predict RTLI at an early stage, allowing for timely interventions to prevent further damage. The kind of ML methods and the selection of predictors may influence the predictive accuracy.

Identification of a novel DFNA5 mutation, IVS7-2 a > G, in a Chinese family with non-syndromic sensorineural hearing loss.

BACKGROUND: To date, seven DFNA5 mutations have been reported in families with autosomal dominant non-syndromic hearing loss worldwide. All the mutations cause exon 8 skipping at the mRNA level, that led to the protein truncated and the protein could exert a gain of ototoxic function. OBJECTIVE: In this study, we found an autosomal-dominant non-syndromic hearing loss Chinese pedigree which spanned four generations and comprised 43 members. We want to identify the causative gene and mutation. METHODS: Application of microsatellite markers on DFNA 23 loci preliminary screening of 25 genes, data were analyzed by linkage analysis. RESULTS: We mapped the locus to the region between D7S629 and D7S516 (two-point lod-score of 5.39) with the application of 8 microsatellite markers. By direct sequencing of candidate genes in mapping region, we identified a novel missense mutation ivs7-2 A > G in DFNA5 gene, which was faithfully cosegregated with hearing loss in the family. CONCLUSION AND SIGNIFICANCE: The missense mutation in intron 7 of DFNA5 causes skipping of exon 8, resulting in premature termination of the open reading frame. This type of mutation has repeatedly confirmed that it provides more evidence for the previous view and provides a more solid foundation for future research.

Novel missense mutations in MYO7A underlying postlingual high- or low-frequency non-syndromic hearing impairment in two large families from China.

The myosin VIIA (MYO7A) gene encodes a protein classified as an unconventional myosin. Mutations within MYO7A can lead to both syndromic and non-syndromic hearing impairment in humans. Among different mutations reported in MYO7A, only five led to non-syndromic sensorineural deafness autosomal dominant type 11 (DFNA11). Here, we present the clinical, genetic and molecular characteristics of two large Chinese DFNA11 families with either high- or low-frequency hearing loss. Affected individuals of family DX-J033 have a sloping audiogram at young ages with high frequency are most affected. With increasing age, all test frequencies are affected. Affected members of family HB-S037 present with an ascending audiogram affecting low frequencies at young ages, and then all frequencies are involved with increasing age. Genome-wide linkage analysis mapped the disease loci within the DFNA11 interval in both families. DNA sequencing of MYO7A revealed two novel nucleotide variations, c.652G > A (p.D218N) and c.2011G > A (p.G671S), in the two families. It is for the first time that the mutations identified in MYO7A in the present study are being implicated in DFNA11 in a Chinese population. For the first time, we tested electrocochleography (ECochG) in a DFNA11 family with low-frequency hearing loss. We speculate that the low-frequency sensorineural hearing loss in this DFNA11 family was not associated with endolymphatic hydrops.

[Comparative study on the clinical features of familial clustered and sporadic vestibular migraine].

Objective:To compare and analyze the clinical features of family clustered vestibular migraine（FCVM） and sporadic vestibular migraine（SVM）. Methods:A total of 118 patients with vestibular migraine were selected and divided into FCVM group（66 cases） and SVM group（52 cases）, and the clinical features such as age, the form of symptoms, provoking and relieving factors, audiological manifestations, sequelae and complications, were compared and analyzed. Results:The onset of headache in FCVM group was earlier than that in SVM group （[23.88±11.45] years old and [28.77±11.85] years old, χ²=2.267, P=0.025） with a longer interval between headache and vertigo attack （[13.11±10.08] years old and [8.50±9.26] years old, χ²=2.554, P=0.012）.Patients with positional vertigo in the FCVM group were more than those in the SVM group （12[18.2%] and 0[0], χ²=3.171, P=0.002）. Mental anxiety（P<0.001）, neck stiffness（P=0.028）, and concentration difficulties（P=0.001） were more common in patients with FCVM at the end of the episode than in patients with SVM. Comorbid primary motion sickness combined was more common in FCVM group than in SVM group（49 cases[74.2%] and 25 cases[48.1%], χ²=2.906, P=0.004）. Conclusion:The onset of FCVM is earlier and the prognosis is often poor. Primary motion sickness can be used as a reference for the early diagnosis of FCVM.

Carotid imaging changes and serum IL-1ß, sICAM-1, and sVAP-1 levels in benign paroxysmal positional vertigo.

Benign paroxysmal positional vertigo (BPPV) is the most common cause of vertigo. This study was performed to evaluate serum levels of inflammatory factors and changes in B-mode carotid ultrasound findings in patients with BPPV. The study population consisted of 90 BPPV patients and 90 age- and sex-matched controls. ELISA was used to compare the levels of inflammatory factors, such as interleukin-1ß (IL-1ß), tumor necrosis factor-alpha (TNF-α), soluble intercellular adhesion molecule-1 (sICAM-1), prostaglandin-E2 (PG-E2), and soluble vascular adhesion protein-1 (sVAP-1), between BPPV patients and controls. In addition, the results of ultrasonographic imaging to determine carotid intima-media thickness (C-IMT), carotid atheromatous plaque, and vertebral artery stenosis were also compared between the BPPV and control groups. Serum levels of IL-1ß, sICAM-1, and sVAP-1 were significantly higher in BPPV patients than controls (P < 0.001, P < 0.05, and P < 0.001, respectively). C-IMT and vertebral artery stenosis were significantly different in BPPV patients compared to controls (both P < 0.05). There were no significant relations between other parameters and BPPV. IL-1ß, sICAM-1, and sVAP-1 are potentially associated with the pathogenesis of BPPV, and C-ITM and carotid vertebral stenosis may be useful reference imaging findings for the diagnosis of BPPV.

[Analysis of clinical features of vestibular migraine].

Objective:To analyze the clinical features of Vestibular migraine（VM） and provide evidence for its accurate diagnosis and medical identification of flight personnel. Method:A total of 490 samples of VM patients were collected. Among them, 88 samples were secondary to benign paroxysmal positional vertigo（BPPV）, and 11 samples were co-occurring with Meniere's disease（MD）. All patients received drugs, lifestyle management, vestibular rehabilitation and other comprehensive treatment, and analyzed the clinical features and effect within 6 months. Result:①The male-female ratio of VM patients was 1∶1.95, the average age was （50.2±14.3） years old, （48.7±15.0） years old for males and （51.0±13.9） years old for females. No statistically significant differences were found（P>0.05）. The average duration was（54.5±84.8） months, （35.0±59.0） months for males and（64.7±94.0） months for females. The difference was statistically significant（P<0.05）. ②The main clinical symptoms are dizziness, migraine or previous history of migraine, fear of sound/noisy environment sensitivity, photophobia/visual sensitivity, nausea/vomiting, vestibular posture symptoms, tinnitus, hearing loss, etc. , diarrhea during dizziness or headache was one special symptom of VM; ③The abnormal rate of vestibular autorotation test（VAT） in 118 VM patients was 72.3%, while the abnormal rate of caloric test in 170 VM patients was 32.9%; ④The effective remission rate within 6 months of VM patients with secondary BPPV and MD was 78.6% and 83.4%, while the VM patients without secondary benign paroxysmal positional vertigo（BPPV） and Meniere's disease（MD） was 93.3%. The difference was statistically significant（P<0.05）. Conclusion:The clinical manifestations of VM patients were various. Female VM patients had higher incidence, the course of disease than male VM patients, diarrhea can be regarded as one of the clinical features distinguished from MD. The abnormal rate of VAT was higher in the common clinical examiniations of VM patients. VM patients treatment should focus on personalized prescription and lifestyle management, vestibular rehabilitation, and corresponding treatment at the same time should be given to patients with secondary BPPV and MD to improve the efficacy. The medical identification of flight personnel VM patients should be strictly controlled, pilots should be grounded, while flight combat personnel and flight technical personnel need chartered medical identification.

Dynamic Rabbit Model of Ear Barotrauma.

BACKGROUND: Establishing animal models of ear barotrauma (EB) to provide evaluation criteria for Eustachian tube dysfunction.METHODS: Using expansive sponges, 70 rabbits' right pharyngeal openings of the auditory tubes were blocked to cause dysfunction in the right Eustachian tubes. The right tympanic cavities of 65 rabbits were the Model Group (Subgroups 1-13) and these rabbits' left tympanic cavities were the Nonblockage Group. Hypobaric chamber tests (HCTs) at various vertical speeds (100 m · s-1, 75 m · s-1, 50 m · s-1, and 15 m · s-1) and altitudes (13,123 ft and 6562 ft) were conducted. The remaining five rabbits' right tympanic cavities were the Control Group and no HCTs were conducted. After HCTs, observations were made on rabbits' behavioral changes, oto-endoscope and tympanometry results, and pathological changes of the tympanic mucosae.RESULTS: 1) Rabbits in Subgroups 1-12 demonstrated EB, while Subgroup 13 and the Control Group did not. 2) Histopathology showed EB caused by rapid ascent/descent at 100 m · s-1 was more severe than that of 75 m · s-1 and 50 m · s-1 (P < 0.01), and that there were no significant differences in EB caused by rapid ascent/descent at 75 m · s-1 and 50 m · s-1 (P > 0.05). There were no significant differences in pathological injuries at the altitudes of 6562 ft and 13,123 ft (P > 0.05). 3) Based on tympanic membrane structures, tympanometry, and histopathological results, rabbits' EB can be classified into mild, moderate, and severe.DISCUSSION: EB's dynamic models could be established through HCTs on rabbits with Eustachian tube dysfunction.Wang B, Xu X, Lin J, Jin Z. Dynamic rabbit model of ear barotrauma. Aerosp Med Hum Perform. 2019; 90(8):696-702.

The epigenetically-regulated miR-34a targeting c-SRC suppresses RAF/MEK/ERK signaling pathway in K-562 cells.

Previous reports show that miR-34a suppressed K-562 cell proliferation and contributed to megakaryocytic differentiation of K-562 cells. Here, we reported that miR-34a, a tumor suppressor gene, is down-regulated in the K-562 cells and chronic myeloid leukemia (CML) patients due to aberrant DNA hypermethylation. c-SRC is a target of miR-34a. Restoring miR-34a expression resulted in down-regulation of c-SRC and phosphorylated (Tyr416) c-SRC protein in K-562 cells, which consequently triggered suppression of the RAF/MEK/ERK signaling pathway to decrease cell proliferation.

A Dynamic Rabbit Model of Sinus Barotrauma and Its Related Pathology.

BACKGROUND: This study was undertaken to establish a dynamic animal model of sinus barotrauma (SB). METHODS: The right nasal cavities of 65 rabbits were filled with sponges to obstruct the right ostiomeatal complex (OMC), while in the left nasal cavities, the left OMC was kept clear. The rabbits were exposed to hypobaric chamber simulation. The right sinuses were assigned as the model group, randomly divided into 13 subgroups with 5 in each subgroup, while the left sinuses were assigned as the control group. The hypobaric chamber simulation involved 6 pairs of ascending/descending speeds (100 m · s(-1), 75 m · s(-1), 50 m · s(-1)) to 2 altitudes (13,123 ft or 6562 ft). The ascending/descending speed for Model Group 13 was 15 m · s(-1) to an altitude of 13,123 ft. The control group was not exposed to hypobaric chamber simulation or obstruction of the OMC. All rabbits were monitored for behavior and via nasal endoscopy, MRI, and mucosal pathology, and statistically analyzed. RESULTS: SB appeared at the ascending/descending speeds of 50 m · s(-1), 75 m · s(-1), and 100 m · s(-1). SB was more obvious at 100 m · s(-1) than at 50 m · s(-1) and 75 m · s(-1), and SB happened mainly at altitudes between 0-6562 ft. Based on behavior during hypobaric chamber simulation and the results of endoscopic morphology, imaging, and cell pathology, SB could be divided into mild, moderate, and severe. DISCUSSION: By obstructing the OMC and using hypobaric chamber simulation at high ascending/descending speeds and altitude, a dynamic rabbit model of SB at various degrees was established. The severity of SB was proportional to the ascending/descending speeds and mainly seen below 6562 ft.

Variants in the KCNE1 or KCNE3 gene and risk of Ménière's disease: A meta-analysis.

BACKGROUND: Ménière's disease (MD) is defined as an idiopathic disorder of the inner ear characterized by the triad of tinnitus, vertigo, and sensorineural hearing loss. Although many studies have evaluated the association between variants in the KCNE1 or KCNE3 gene and MD risk, debates still exist. OBJECTIVE: Our aim is to evaluate the association between KCNE gene variants, including KCNE1 rs1805127 and KCNE3 rs2270676, and the risk of MD by a systematic review. METHODS: We searched the literature in PubMed, SCOPUS and EMBASE through May 2015. We calculated pooled odds ratios (OR) and 95% confidence intervals (CIs) using a fixed-effects model or a random-effects model for the risk to MD associated with different KCNE gene variants. The heterogeneity assumption decided the effect model. RESULTS: A total of three relevant studies, with 302 MD cases and 515 controls, were included in this meta-analysis. The results indicated that neither the KCNE1 rs1805127 variant (for G vs. A: OR = 0.724, 95%CI 0.320, 1.638, P= 0.438), nor the KCNE3 rs2270676 variant (for T vs. C: OR = 0.714, 95%CI 0.327, 1.559, P = 0.398) was associated with MD risk. CONCLUSIONS: Based on current evidence from published studies, neither of the two variants from KCNE was significantly associated with the risk of MD. Larger studies with mixed ethnicity subjects and stratified by clinical and sub-clinical characteristics are needed to validate our findings.

Identification of a Novel TECTA mutation in a Chinese DFNA8/12 family with prelingual progressive sensorineural hearing impairment.

Tectorial membrane, an extracellular matrix of the cochlea, plays a crucial role in the transmission of sound to the sensory hair cells. Alpha-tectorin is the most important noncollagenous component of the tectorial membrane and the otolith membrane in the maculae of the vestibular system. Defects in TECTA, the gene encodes alpha-tectorin, are cause of both dominant (DFNA8/12) and recessive (DFNB21) forms of deafness. Here, we report a three-generation Chinese family characterized by prelingual progressive sensorineural hearing impairment. We mapped the disease locus to chromosome 11q23-24 region, overlapping with the DFNA8/12 locus. Sequencing of candidate gene TECTA revealed a heterozygous c.5945C>A substitution in exon 19, causing amino acid substitution of Ala to Asp at a conservative position 1982. The A1982D substitution is consistent with hearing loss in this Chinese family and has not been found in 200 random control chromosomes. To our knowledge, this is the first TECTA mutation identified in Chinese population. Our data provides additional molecular and clinical information for establishing a better genotype-phenotype understanding of DFNA8/12.

Preimplantation genetic diagnosis for a Chinese family with autosomal recessive Meckel-Gruber syndrome type 3 (MKS3).

Meckel-Gruber syndrome type 3 is an autosomal recessive genetic defect caused by mutations in TMEM67 gene. In our previous study, we have identified a homozygous TMEM67 mutation in a Chinese family exhibiting clinical characteristics of MKS3, which provided a ground for further PGD procedure. Here we report the development and the first clinical application of the PGD for this MKS3 family. Molecular analysis protocol for clinical PGD procedure was established using 50 single cells in pre-clinical set-up. After whole genomic amplification by multiple displacement amplification with the DNA from single cells, three techniques were applied simultaneously to increase the accuracy and reliability of genetic diagnosis in single blastomere, including real-time PCR with Taq Man-MGB probe, haplotype analysis with polymorphic STR markers and Sanger sequencing. In the clinical PGD cycle, nine embryos at cleavage-stage were biopsied and subjected to genetic diagnosis. Two embryos diagnosed as free of TMEM67 mutation were transferred and one achieving normal pregnancy. Non-invasive prenatal assessment of trisomy 13, 18 and 21 by multiplex DNA sequencing at 18 weeks' gestation excluded the aneuploidy of the analyzed chromosomes. A healthy boy was delivered by cesarean section at 39 weeks' gestation. DNA sequencing from his cord blood confirmed the result of genetic analysis in the PGD cycle. The protocol developed in this study was proved to be rapid and safe for the detection of monogenic mutations in clinical PGD cycle.