Dominant deafness-onychodystrophy syndrome (DDOD) and hypokalemic periodic paralysis (HypoPP) are distinct autosomal dominant disorders caused by mutations in ATP6V1B2 and CACNA1S, respectively. We describe an eight-year-old female with congenital deafness, nail dysplasia, enamel hypoplasia, and recurrent episodes of hypokalemia-induced muscle weakness. Whole-exome sequencing (WES) revealed a de novo ATP6V1B2 nonsense variant (c.1516C>T, p.Arg506Ter) and a maternally inherited CACNA1S missense variant (c.1583G>A, p.Arg528His). The proband's mother and maternal grandfather carried the same CACNA1S variant with milder periodic weakness, indicating intrafamilial variability and reduced penetrance. This dual diagnosis broadens the phenotypic spectrum of both DDOD and HypoPP and illustrates how comprehensive genomic testing can elucidate complex, blended phenotypes. Although no direct mechanistic link between ATP6V1B2 and CACNA1S has been demonstrated, their coexistence highlights the importance of considering multilocus genetic etiologies in rare diseases and supports precision medicine approaches integrating genomic diagnostics and individualized management.

Objective: To explore the perioperative precautions, rehabilitation effect, and affecting factors in cochlear implantation (CI) among patients with hereditary syndromic hearing loss. Methods: This was a retrospective cohort study. 47 patients diagnosed as hereditary syndromic deafness were treated in the Department of Otolaryngology-Head and Neck Surgery of the Chinese PLA General Hospital from 2010 to 2021, including 26 males and 21 females, aged 0.9-25 years. All patients received unilateral or bilateral CI. Clinical manifestation combined with genetic testing was used to diagnose syndromic hearing loss. The risks and precautions of CI in these patients were summarized from preoperative imaging, intraoperative observations, and postoperative complications. Single factor linear regression and multiple linear regression models in SPSS 26.0 software were used to evaluate the effects of various factors on auditory and speech rehabilitation after CI for syndromic hearing loss. The postoperative outcomes were analyzed through aided hearing thresholds, categories of auditory performance (CAP) scale, and speech intelligibility rate (SIR) scale. Results: Thirteen kinds of syndromes, totally 47 cases, including CHARGE (20 cases), Waardenburg (9 cases), Autosomal dominant deafness-onychodystrophy (DDOD, 4 cases), Pendred (3 cases), Noonan Syndrome with Multiple Lentigines (NSML, 2 cases), Branchio-Oto-Renal (BOR, 2 cases), Bart-Pumphery (1 case), Perrault (1 case), Kabuki (1 case), Frontometaphyseal dysplasia type 2 (FMD 2, 1 case), Mandibulofacial dysostosis Guion-Almeida type (MFDGA, 1 case), Coffin-Siris (1 case), and 10q26.12-q26.3 del (1 case), were enrolled. The perioperative special management included the following measures. For patients with cardiac and/or cartilage development issues, preoperative assessments of cardiac function and/or laryngeal cartilage development were performed to minimize anesthetic risks. For patients with mild intellectual disability and/or an auditory neuropathy phenotype, preoperative communication with the patients' families was conducted to explain the limitations of CI and assist in setting reasonable expectations. For syndromic hearing loss patients who commonly present with inner ear malformations, facial nerve anomalies, and/or intraoperative cerebrospinal fluid leakage, appropriate electrodes were selected prior to surgery, intraoperative facial nerve monitoring and careful cerebrospinal fluid leak repair were conducted, respectively. For patients with NSML accompanied by coagulation issues, the postoperative compression bandaging duration was extended to reduce the risk of hematoma formation. The daily duration of cochlear implant use, the presence of cochlear malformation, and developmental delay were independent factors influencing postoperative CAP scores. The daily duration of cochlear implant use, developmental delay, and unilateral or bilateral CI were independent factors influencing postoperative SIR scores. Conclusions: Hereditary syndrome deafness is a rare disease that affects multiple organs and causes extensive functional impairment. Before CI, a comprehensive evaluation of major affected organ functions is required to assess anesthetic and surgical risks. Genetic diagnosis not only identifies the molecular etiology of patients with syndromic hearing loss and reveals rare phenotypes, but also aids in prognostic evaluation. The main factors affecting CI outcomes in patients with syndromic hearing loss include the presence of cochlear malformations, developmental delays, daily duration of cochlear implant use, and bilateral implantation status. 目的： 分析遗传性综合征型聋患者人工耳蜗植入的围手术期注意事项、术后效果及其影响因素。 方法： 本研究为回顾性队列研究，研究对象为2010—2021年间在中国人民解放军总医院耳鼻咽喉头颈外科就诊的综合征型聋患者47例，其中男26例、女21例，年龄0.9~25岁。所有患者均接受单侧或双侧人工耳蜗植入。通过表型评估结合基因检测进行综合征型聋的诊断；从术前影像、术中所见及并发症处理等方面总结综合征型聋患者人工耳蜗植入的风险及注意事项；用助听听阈、听觉行为分级（Categories of Auditory Performance，CAP）量表和言语可懂度分级（Speech Intelligibility Rating，SIR）量表评价术后效果。应用SPSS 26.0软件通过单因素线性回归和多重线性回归模型评估各因素对综合征型聋患者人工耳蜗植入术后效果的影响。 结果： 47例综合征型聋患者中CHARGE综合征20例，Waardenburg综合征9例，耳聋甲发育不全综合征4例，Pendred综合征3例，多痣Noonan综合征2例，鳃耳（肾）综合征2例，Bart-Pumphrey综合征、Perrault综合征、Kabuki综合征、额骨骺发育不良2型、Guion-Almeida型下颌面骨发育不全、Coffin-Siris综合征、10号染色体12.7 Mb区带缺失各1例。围手术期特殊处理包括：对累及心脏和/或软骨发育的患者，术前行心功能和/或喉软骨发育评估以减低麻醉风险；对伴有轻度智力障碍和/或听神经病表型的患者，术前与患者家属沟通人工耳蜗植入效果的局限性以帮助其建立合理预期；针对综合征型聋患者进行人工耳蜗植入术较常遇到的内耳畸形、面神经畸形、脑脊液漏等情况，在术前选择合适的电极，术中进行面神经监测、妥善修补脑脊液漏；对累及凝血功能的多痣Noonan综合征患者，延长术后加压包扎时间以减少血肿发生。人工耳蜗每日佩戴时长、是否有耳蜗畸形、是否有发育迟缓是术后CAP分级的独立影响因素；人工耳蜗每日佩戴时长、是否有发育迟缓、单双侧植入是术后SIR分级的独立影响因素。 结论： 遗传性综合征型聋属于罕见病，累及多器官，功能损伤广泛。人工耳蜗植入前需要全面评估主要受累脏器功能以明确麻醉和手术风险。基因诊断除了明确综合征型聋患者的分子病因、提示罕见表型，还能辅助预后判断。是否伴耳蜗畸形、是否伴发育迟缓、人工耳蜗每日佩戴时长、单双侧植入是影响综合征型聋患者人工耳蜗植入效果的主要因素。. TBC1D24-related disorders comprise a continuum of features that were originally described as distinct, recognized phenotypes: DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures), with profound sensorineural hearing loss, onychodystrophy, osteodystrophy, intellectual disability / developmental delay, and seizures; familial infantile myoclonic epilepsy (FIME), with early-onset myoclonic seizures, focal epilepsy, dysarthria, and mild-to-moderate intellectual disability; progressive myoclonus epilepsy (PME), with action myoclonus, tonic-clonic seizures, ataxia, and progressive neurologic decline; rolandic epilepsy with paroxysmal exercise-induced dystonia and writer's cramp (EPRPDC); developmental and epileptic encephalopathy (DEE), including epilepsy of infancy with migrating focal seizures (EIMFS); autosomal recessive nonsyndromic hearing loss (DFNB); and autosomal dominant nonsyndromic hearing loss (DFNA). The diagnosis of a TBC1D24-related disorder is established in an individual with suggestive findings biallelic TBC1D24 pathogenic variants when the mode of inheritance is autosomal recessive (i.e., DOORS syndrome, FIME, PME, EPRPDC, DEE, and DFNB), and in an individual with suggestive findings and a heterozygous TBC1D24 pathogenic variant when the mode of inheritance is autosomal dominant (DFNA). Treatment of manifestations: Hearing aids or cochlear implants as needed for hearing loss; early educational intervention and physical, occupational, and speech therapy for developmental delay; symptomatic pharmacologic management for seizures; standard treatment for tremors, dystonic attacks, or other neurologic manifestations; routine management of visual impairment and renal, cardiac, dental, orthopedic, and endocrine issues. Surveillance: Neurologic evaluations with EEGs depending on seizure frequency and/or progression; annual audiologic evaluations to assess for possible progression of hearing loss and/or the efficacy of hearing aids; annual dental evaluations; annual endocrine evaluations. Agents/circumstances to avoid: Excessive ambient noise, which may exacerbate hearing loss in individuals with a heterozygous TBC1D24 pathogenic variant that causes autosomal dominant hearing loss (DFNA). Evaluation of relatives at risk: Molecular genetic testing for the familial TBC1D24 pathogenic variant(s) in older and younger sibs of a proband is appropriate in order to identify as early as possible those who would benefit from early treatment of seizures and/or hearing loss. Most TBC1D24-related disorders are inherited in an autosomal recessive manner (DOORS syndrome, FIME, PME, EPRPDC, and DEE [including EIMFS]). TBC1D24-related nonsyndromic hearing loss can be inherited in an autosomal recessive (DFNB) or autosomal dominant (DFNA) manner. Autosomal recessive inheritance: If both parents are known to be heterozygous for a TBC1D24 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial TBC1D24 pathogenic variants. Heterozygotes (carriers) are typically asymptomatic. Carrier testing for at-risk relatives requires prior identification of the TBC1D24 pathogenic variants in the family. Once the TBC1D24 pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

The vacuolar H+-ATPase is a multisubunit enzyme which plays an essential role in the acidification and functions of lysosomes, endosomes, and synaptic vesicles. Many genes encoding subunits of V-ATPases, namely ATP6V0C, ATP6V1A, ATP6V0A1, and ATP6V1B2, have been associated with neurodevelopmental disorders and epilepsy. The autosomal dominant ATP6V1B2 p.Arg506* variant can cause both congenital deafness with onychodystrophy, autosomal dominant (DDOD) and deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures syndromes (DOORS). Some but not all individuals with this truncating variant have intellectual disability and/or epilepsy, suggesting incomplete penetrance and/or variable expressivity. To further explore the impact of the p.Arg506* variant in neurodevelopment and epilepsy, we generated Atp6v1b2emR506* mutant mice and performed standardized phenotyping using the International Mouse Phenotyping Consortium (IMPC) pipeline. In addition, we assessed the EEG profile and seizure susceptibility of Atp6v1b2emR506* mice. Behavioral tests revealed that the mice present locomotor hyperactivity and show less anxiety-associated behaviors. Moreover, EEG analyses indicate that Atp6v1b2emR506* mutant mice have interictal epileptic activity and that both heterozygous (like patients) and homozygous mice have reduced seizure thresholds to pentylenetetrazol. Our results confirm that variants in ATP6V1B2 can cause seizures and that the Atp6v1b2emR506* heterozygous mouse model is a valuable tool to further explore the pathophysiology and potential treatments for vacuolar ATPases-associated epilepsy and disorders.

ATP6V1B2 pathogenic variants are linked with variable phenotypes, such as dominant deafness-onychodystrophy syndrome (DDOD), autosomal dominant Zimmermann-Laband syndrome type 2 (ZLS2), and some cases of DOORS (deafness, onychodystrophy, osteodystrophy, intellectual disability [ID], and seizures). Epilepsy was first linked to ATP6V1B2, when the p.(Glu374Gln) missense variant was detected in a patient with ID and seizures, but without characteristic features of DDOD or ZLS2 syndromes. We herein report a novel pathogenic ATP6V1B2:p.Glu374Gly variant detected in an adult patient with ID and myoclonic-atonic seizures. The (re)occurrence of different variants affecting the same highly conserved hydrophilic glutamic acid on position 374 of the V-proton ATPase subunit B, indicates a potential novel pathogenic hotspot and a critical role for the specific residue in the development of epilepsy. ATP6V1B2 gene defects should be considered when analyzing patients with epilepsy, even in the absence of most cardinal features of DDOD, DOORS, or ZLS such as deafness, onychodystrophy, and osteodystrophy.

Dominant deafness-onychodystrophy (DDOD) syndrome is a rare autosomal dominant disorder caused by mutations in ATP6V1B2 gene. We previously generated an induced pluripotent stem cell (iPSC) line (CPGHi002-A) from a DDOD patient with a heterozygous c.1516 C>T mutation in the ATP6V1B2 gene. Here we genetically corrected the c.1516 C>T mutation in the ATP6V1B2 gene using CRISPR/Cas9 technology to generate an isogenic control, CPGHi002-A-1. The characterization of CPGHi002-A-1 demonstrates normal karyotype, pluripotent state, and potential to differentiate in vitro towards endoderm, mesoderm, and ectoderm.