Band 32, Heft 2

Background: Hearing loss (HL) is the most common sensory deficit from birth, with at least 50 % due to an underlying genetic etiology. A genetic evaluation is a recommended component to the medical workup for HL, and a genetic diagnosis can impact medical management and provide prognostic and recurrence risk information. The accuracy of a genetic diagnosis relies on the evidence supporting the gene–disease relationship, as well as the evidence supporting individual variant classifications. As such, the ClinGen Hearing Loss Working Group was formed and tasked with curating genes associated with genetic hearing loss and developing specifications of the ACMG/AMP variant interpretation guidelines with the goal of improving the genetic diagnosis of patients with HL. Objectives: To describe the prioritization and expert curation of genes and variants associated with HL performed under the purview of the ClinGen Hearing Loss Gene and Variant Expert Panels (HL GCEP and VCEP). Materials and methods: HL genes were taken from clinical testing panels in the Genetic Testing Registry and prioritized based on a nonsyndromic presentation. Variants were taken from ClinVar and those with diverse data types and medically significant conflicts were prioritized to test the specified variant interpretation guidelines and to resolve classification discrepancies, respectively. Conclusions: The ClinGen HL GCEP has curated 174 gene–disease pairs. The HL VCEP has submitted 77 variants, including the previously controversial p.Met34Thr and p.Val37Ile variants in GJB2 , into ClinVar, as an FDA-recognized database. Collaboration across clinics and laboratories were crucial to these curations and highlight the impact that data sharing can have on patient care.

Hereditary hearing loss is clinically and genetically heterogeneous. There are presently over 120 genes that have been associated with non-syndromic hearing loss and many more that are associated with syndromic forms. Despite an increasing number of genes that have been implemented into routine molecular genetic diagnostic testing, the diagnostic yield from European patient cohorts with hereditary hearing loss remains around the 50 % mark. This attests to the many gaps of knowledge the field is currently working toward resolving. It can be expected that many more genes await identification. However, it can also be expected, for example, that the mutational signatures of the known genes are still unclear, especially variants in non-coding or regulatory regions influencing gene expression. This review summarizes several challenges in the clinical and diagnostic setting for hereditary hearing loss with emphasis on syndromes that mimic non-syndromic forms of hearing loss in young children and other factors that heavily influence diagnostic rates. A molecular genetic diagnosis for patients with hearing loss opens several additional avenues, such as patient tailored selection of the best currently available treatment modalities, an understanding of the prognosis, and supporting family planning decisions. In the near future, a genetic diagnosis may enable patients to engage in preclinical trials for the development of therapeutics.

Usher syndrome (USH) manifests with congenital and apparently isolated hearing loss, followed by retinal degeneration in later life. Therefore, and because of its high prevalence in the congenitally hearing-impaired population, USH is one of the most relevant deafness syndromes. Next-generation sequencing (NGS)-based testing can now provide most analyzed USH patients with a molecular diagnosis, based on mutations in 11 genes. Given the availability of several excellent articles on the clinical and biochemical basis of USH, this short review focuses on critical assessment of new genes announced as USH genes, clinical and genetic differential diagnoses and therapeutic developments. Because obsolete loci, disproved USH genes and the inclusion of genes whose mutations cause similar phenotypes have increasingly blurred genetic classification, a revision based on phenotype restricted to genes related to the Usher protein complex is proposed.

Meniere disease (MD) represents a heterogeneous group of relatively rare disorders of the inner ear that causes vertigo attacks, fluctuating sensorineural hearing loss (SNHL) involving low and medium frequencies, tinnitus, and aural fullness. MD has been attributed to an accumulation of endolymph in the cochlear duct. The diagnosis of MD is based on the phenomenological association of clinical symptoms including SNHL during the vertigo attacks. At least two mechanisms are involved in MD: (a) a pro-inflammatory immune response mediated by interleukin-1 beta (IL-1β), tumor necrosis factor alpha (TNFα), and IL-6, and (b) nuclear factor-kappa B (NF-κB)-mediated inflammation in the carriers of the single nucleotide variant rs4947296. The majority of MD cases are considered sporadic, although familial aggregation has been recognized in European and East Asian populations in multiplex families, supporting a genetic contribution to the disease. In sporadic MD cases, the main genetic findings involve multiplex rare variants in several SNHL genes, such as GJB2, USH1G, SLC26A4, ESRRB , and CLDN14 , and axonal guidance signaling genes, such as NTN4 and NOX3 . Familial aggregation has been reported in 6–8 % of MD cases, and most families show an autosomal dominant inheritance. Few rare missense heterozygous variants have been described in simplex families in six genes ( COCH , FAM136A , DTNA , PRKCB , SEMA3D , and DPT ). Of note, 33 % of familial MD individuals show singleton and multiplex rare missense variants in the OTOG gene, suggesting a multiallelic inheritance. Moreover, potentially pathogenic rare variants in the familial genes FAM136A , DTNA , and DPT have been reported in Korean singletons with sporadic MD. Rare variants may have a significant contribution to sporadic and familial MD. The interaction of common cis-regulatory variants located in non-coding regions and rare variants in coding regions in one or more genes will determine the variation on the phenotype in MD. Further studies on genotype–phenotype correlations are required to improve the yield of genetic diagnosis, and different types of variants seem to contribute to the genetic structure of MD.

The process of hearing involves a series of events. The energy of sound is captured by the outer ear and further transferred through the external auditory canal to the middle ear. In the middle ear, sound waves are converted into movements of the tympanic membrane and the ossicles, thereby amplifying the pressure so that it is sufficient to cause movement of the cochlear fluid. The traveling wave within the cochlea leads to depolarization of the inner ear hair cells that, in turn, release the neurotransmitter glutamate. Thereby, the spiral ganglion neurons are activated to transfer the signals via the auditory pathway to the primary auditory cortex. This complex combination of mechanosensory and physiological mechanisms involves many distinct types of cells, the function of which are impacted by numerous proteins, including those involved in ion channel activity, signal transduction and transcription. In the last 30 years, pathogenic variants in over 150 genes were found to be linked to hearing loss. Hearing loss affects over 460 million people world-wide, and current treatment approaches, such as hearing aids and cochlear implants, serve to improve hearing capacity but do not address the underlying genetic cause of hearing loss. Therefore, therapeutic strategies designed to correct the genetic defects causative for hearing loss offer the possibility to treat these patients. In this review, we will discuss genetic causes of hearing loss, novel gene therapeutic strategies to correct hearing loss due to gene defects and some of the preclinical studies in hearing loss animal models as well as the clinical translation of gene therapy approaches to treat hearing loss patients.

The ongoing SARS-CoV-2 pandemic has triggered several months of global turmoil, and governments across the world are now actively attempting to develop strategies to combat both the virus and its societal impact. Since SARS-CoV-2 is a novel pathogen, basic research is essential, and manifold international efforts are now underway in order to elucidate the molecular mechanisms of both the SARS-CoV-2 infection process and the resulting disease, COVID-19. In this article we discuss how the field of Human Genetics can contribute to this endeavor, and summarize available findings from human genetic COVID-19 research. Finally, we briefly outline how through the use of existing national research infrastructure, German scientists can facilitate progress in this novel and fast-moving field.