Publications by authors named "Barbara Vona"

35 Publications

A biallelic variant in CLRN2 causes non-syndromic hearing loss in humans.

Hum Genet 2021 Jan 26. Epub 2021 Jan 26.

Department of Genetics, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran.

Deafness, the most frequent sensory deficit in humans, is extremely heterogeneous with hundreds of genes involved. Clinical and genetic analyses of an extended consanguineous family with pre-lingual, moderate-to-profound autosomal recessive sensorineural hearing loss, allowed us to identify CLRN2, encoding a tetraspan protein, as a new deafness gene. Homozygosity mapping followed by exome sequencing identified a 14.96 Mb locus on chromosome 4p15.32p15.1 containing a likely pathogenic missense variant in CLRN2 (c.494C > A, NM_001079827.2) segregating with the disease. Using in vitro RNA splicing analysis, we show that the CLRN2 c.494C > A variant leads to two events: (1) the substitution of a highly conserved threonine (uncharged amino acid) to lysine (charged amino acid) at position 165, p.(Thr165Lys), and (2) aberrant splicing, with the retention of intron 2 resulting in a stop codon after 26 additional amino acids, p.(Gly146Lysfs*26). Expression studies and phenotyping of newly produced zebrafish and mouse models deficient for clarin 2 further confirm that clarin 2, expressed in the inner ear hair cells, is essential for normal organization and maintenance of the auditory hair bundles, and for hearing function. Together, our findings identify CLRN2 as a new deafness gene, which will impact future diagnosis and treatment for deaf patients.
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http://dx.doi.org/10.1007/s00439-020-02254-zDOI Listing
January 2021

Expanding the phenotype of PIGS-associated early onset epileptic developmental encephalopathy.

Epilepsia 2021 Feb 7;62(2):e35-e41. Epub 2021 Jan 7.

Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, University College London, London, UK.

The phosphatidylinositol glycan anchor biosynthesis class S protein (PIGS) gene has recently been implicated in a novel congenital disorder of glycosylation resulting in autosomal recessive inherited glycosylphosphatidylinositol-anchored protein (GPI-AP) deficiency. Previous studies described seven patients with biallelic variants in the PIGS gene, of whom two presented with fetal akinesia and five with global developmental delay and epileptic developmental encephalopathy. We present the molecular and clinical characteristics of six additional individuals from five families with unreported variants in PIGS. All individuals presented with hypotonia, severe global developmental delay, microcephaly, intractable early infantile epilepsy, and structural brain abnormalities. Additional findings include vision impairment, hearing loss, renal malformation, and hypotonic facial appearances with minor dysmorphic features but without a distinctive facial gestalt. Four individuals died due to neurologic complications. GPI anchoring studies performed on one individual revealed a significant decrease in GPI-APs. We confirm that biallelic variants in PIGS cause vitamin pyridoxine-responsive epilepsy due to inherited GPI deficiency and expand the genotype and phenotype of PIGS-related disorder. Further delineation of the molecular spectrum of PIGS-related disorders would improve management, help develop treatments, and encourage the expansion of diagnostic genetic testing to include this gene as a potential cause of neurodevelopmental disorders and epilepsy.
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http://dx.doi.org/10.1111/epi.16801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898547PMC
February 2021

Revisiting multiple erroneous genetic testing results and clinical misinterpretations in a patient with Li-Fraumeni syndrome: lessons for translational medicine.

Hered Cancer Clin Pract 2021 Jan 6;19(1). Epub 2021 Jan 6.

N.N. Petrov Institute of Oncology, Pesochniy, Saint-Petersburg, 197758, Russia.

Background: Many cancer patients undergo sophisticated laboratory testing, which requires proper interpretation and interaction between different specialists.

Case Presentation: We describe a patient with an extensive family history of cancer, who was diagnosed with bilateral breast cancer and two lung cancer lumps by the age of 40 years. She submitted a lung cancer specimen to a genetic profiling service, which reported the presence of the EGFR mutation (a combination of G719S and L833V substitutions) and the TP53 с.322_327del (p.G108_F109del) mutation in the tumor tissue. Possible therapeutic options were discussed at a medical conference, where one of the discussants raised a concern that the identified TP53 mutation may not necessarily be somatic, but reflect the germ-line status of the gene. Review of clinical records and follow-up dialog with the patient revealed, that she previously provided her blood for DNA analysis in two laboratories. The first laboratory utilized a custom NGS assay and did not detect the TP53 mutation, instead pointed to a potential pathogenic significance of the MSH6 c.2633 T > C (p.V878A) allele. The second laboratory revealed the TP53 с.322_327del (p.G108_F109del) allele but stated in the written report that it has an unknown pathogenic significance. To resolve the possible uncertainty regarding the role of the TP53 с.322_327del (p.G108_F109del) variant, we suggested that the patient invite her second cousin for genetic testing, as she was affected by neuroblastoma at the age of 3 years. This analysis revealed the presence of the same TP53 variant.

Conclusion: We provide point-by-point discussion, reviewing multiple laboratory mistakes and clinical misinterpretations occurred with this patient. This case report exemplifies the need to involve rigorous clinical expertise in the daily practice of medical laboratory facilities.
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http://dx.doi.org/10.1186/s13053-020-00157-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789132PMC
January 2021

Radixin modulates the function of outer hair cell stereocilia.

Commun Biol 2020 Dec 23;3(1):792. Epub 2020 Dec 23.

Department of Biomedical and Clinical Sciences, Linköping University, SE-581 83, Linköping, Sweden.

The stereocilia of the inner ear sensory cells contain the actin-binding protein radixin, encoded by RDX. Radixin is important for hearing but remains functionally obscure. To determine how radixin influences hearing sensitivity, we used a custom rapid imaging technique to visualize stereocilia motion while measuring electrical potential amplitudes during acoustic stimulation. Radixin inhibition decreased sound-evoked electrical potentials. Other functional measures, including electrically induced sensory cell motility and sound-evoked stereocilia deflections, showed a minor amplitude increase. These unique functional alterations demonstrate radixin as necessary for conversion of sound into electrical signals at acoustic rates. We identified patients with RDX variants with normal hearing at birth who showed rapidly deteriorating hearing during the first months of life. This may be overlooked by newborn hearing screening and explained by multiple disturbances in postnatal sensory cells. We conclude radixin is necessary for ensuring normal conversion of sound to electrical signals in the inner ear.
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http://dx.doi.org/10.1038/s42003-020-01506-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758333PMC
December 2020

Age-related hearing loss pertaining to potassium ion channels in the cochlea and auditory pathway.

Pflugers Arch 2020 Dec 17. Epub 2020 Dec 17.

Translational Hearing Research, Tübingen Hearing Research Center, Department of Otolaryngology, Head and Neck Surgery, University of Tübingen, 72076, Tübingen, Germany.

Age-related hearing loss (ARHL) is the most prevalent sensory deficit in the elderly and constitutes the third highest risk factor for dementia. Lifetime noise exposure, genetic predispositions for degeneration, and metabolic stress are assumed to be the major causes of ARHL. Both noise-induced and hereditary progressive hearing have been linked to decreased cell surface expression and impaired conductance of the potassium ion channel K7.4 (KCNQ4) in outer hair cells, inspiring future therapies to maintain or prevent the decline of potassium ion channel surface expression to reduce ARHL. In concert with K7.4 in outer hair cells, K7.1 (KCNQ1) in the stria vascularis, calcium-activated potassium channels BK (KCNMA1) and SK2 (KCNN2) in hair cells and efferent fiber synapses, and K3.1 (KCNC1) in the spiral ganglia and ascending auditory circuits share an upregulated expression or subcellular targeting during final differentiation at hearing onset. They also share a distinctive fragility for noise exposure and age-dependent shortfalls in energy supply required for sustained surface expression. Here, we review and discuss the possible contribution of select potassium ion channels in the cochlea and auditory pathway to ARHL. We postulate genes, proteins, or modulators that contribute to sustained ion currents or proper surface expressions of potassium channels under challenging conditions as key for future therapies of ARHL.
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http://dx.doi.org/10.1007/s00424-020-02496-wDOI Listing
December 2020

SCUBE3 loss-of-function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signaling.

Am J Hum Genet 2021 01 11;108(1):115-133. Epub 2020 Dec 11.

Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy. Electronic address:

Signal peptide-CUB-EGF domain-containing protein 3 (SCUBE3) is a member of a small family of multifunctional cell surface-anchored glycoproteins functioning as co-receptors for a variety of growth factors. Here we report that bi-allelic inactivating variants in SCUBE3 have pleiotropic consequences on development and cause a previously unrecognized syndromic disorder. Eighteen affected individuals from nine unrelated families showed a consistent phenotype characterized by reduced growth, skeletal features, distinctive craniofacial appearance, and dental anomalies. In vitro functional validation studies demonstrated a variable impact of disease-causing variants on transcript processing, protein secretion and function, and their dysregulating effect on bone morphogenetic protein (BMP) signaling. We show that SCUBE3 acts as a BMP2/BMP4 co-receptor, recruits the BMP receptor complexes into raft microdomains, and positively modulates signaling possibly by augmenting the specific interactions between BMPs and BMP type I receptors. Scube3 mice showed craniofacial and dental defects, reduced body size, and defective endochondral bone growth due to impaired BMP-mediated chondrogenesis and osteogenesis, recapitulating the human disorder. Our findings identify a human disease caused by defective function of a member of the SCUBE family, and link SCUBE3 to processes controlling growth, morphogenesis, and bone and teeth development through modulation of BMP signaling.
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http://dx.doi.org/10.1016/j.ajhg.2020.11.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820739PMC
January 2021

The Many Faces of DFNB9: Relating Variants to Hearing Impairment.

Genes (Basel) 2020 Nov 26;11(12). Epub 2020 Nov 26.

Tübingen Hearing Research Centre, Department of Otolaryngology, Head & Neck Surgery, University of Tübingen Medical Center, 72076 Tübingen, Germany.

The gene encodes otoferlin, a critical protein at the synapse of auditory sensory cells, the inner hair cells (IHCs). In the absence of otoferlin, signal transmission of IHCs fails due to impaired release of synaptic vesicles at the IHC synapse. Biallelic pathogenic and likely pathogenic variants in predominantly cause autosomal recessive profound prelingual deafness, DFNB9. Due to the isolated defect of synaptic transmission and initially preserved otoacoustic emissions (OAEs), the clinical characteristics have been termed "auditory synaptopathy". We review the broad phenotypic spectrum reported in patients with variants in that includes milder hearing loss, as well as progressive and temperature-sensitive hearing loss. We highlight several challenges that must be addressed for rapid clinical and genetic diagnosis. Importantly, we call for changes in newborn hearing screening protocols, since OAE tests fail to diagnose deafness in this case. Continued research appears to be needed to complete otoferlin isoform expression characterization to enhance genetic diagnostics. This timely review is meant to sensitize the field to clinical characteristics of DFNB9 and current limitations in preparation for clinical trials for gene therapies that are projected to start in 2021.
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http://dx.doi.org/10.3390/genes11121411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768390PMC
November 2020

Genetic Spectrum of Syndromic and Non-Syndromic Hearing Loss in Pakistani Families.

Genes (Basel) 2020 Nov 11;11(11). Epub 2020 Nov 11.

Institute of Human Genetics, Julius Maximilians University Würzburg, 97074 Würzburg, Germany.

The current molecular genetic diagnostic rates for hereditary hearing loss (HL) vary considerably according to the population background. Pakistan and other countries with high rates of consanguineous marriages have served as a unique resource for studying rare and novel forms of recessive HL. A combined exome sequencing, bioinformatics analysis, and gene mapping approach for 21 consanguineous Pakistani families revealed 13 pathogenic or likely pathogenic variants in the genes , , , , , , and , with an overall resolve rate of 61.9%. and were the most frequently involved genes in this cohort. All the identified variants were either homozygous or compound heterozygous, with two of them not previously described in the literature (15.4%). Overall, seven missense variants (53.8%), three nonsense variants (23.1%), two frameshift variants (15.4%), and one splice-site variant (7.7%) were observed. Syndromic HL was identified in five (23.8%) of the 21 families studied. This study reflects the extreme genetic heterogeneity observed in HL and expands the spectrum of variants in deafness-associated genes.
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http://dx.doi.org/10.3390/genes11111329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7709052PMC
November 2020

Aberrant COL11A1 splicing causes prelingual autosomal dominant nonsyndromic hearing loss in the DFNA37 locus.

Hum Mutat 2021 Jan 11;42(1):25-30. Epub 2020 Nov 11.

Department of Otolaryngology-Head & Neck Surgery, Tübingen Hearing Research Centre, Eberhard Karls University Tübingen, Tübingen, Germany.

Alpha-chain collagen molecules encoded by genes that include COL11A1 are essential for skeletal, ocular, and auditory function. COL11A1 variants have been reported in syndromes involving these organ systems. However, a description of the complete clinical spectrum is lacking, as evidenced by a recent association of autosomal dominant nonsyndromic hearing loss due to a splice-altering variant in COL11A1, mapping the DFNA37 locus. Here, we describe two German families presenting prelingual autosomal dominant nonsyndromic hearing loss with novel COL11A1 heterozygous splice-altering variants (c.652-1G>C and c.4338+2T>C) that were molecularly characterized. Interestingly, the c.652-1G>C variant affects the same intron 4 canonical splice site originally reported in the DFNA37 family (c.652-2A>C) but elicits a different splicing outcome. Furthermore, the c.4338+2T>C variant originated de novo. We provide clinical and molecular genetic evidence to unambiguously confirm that COL11A1 splice-altering variants cause DFNA37 hearing loss and affirm that COL11A1 be included in the genetic testing of patients with nonsyndromic deafness.
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http://dx.doi.org/10.1002/humu.24136DOI Listing
January 2021

The First Inherited Retinal Disease Registry in Iran: Research Protocol and Results of a Pilot Study.

Arch Iran Med 2020 07 1;23(7):445-454. Epub 2020 Jul 1.

Ophthalmic Research Center, Research Institute for Ophthalmology and Vision Science, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Background: To describe the protocol for developing a national inherited retinal disease (IRD) registry in Iran and present its initial report.

Methods: This community-based participatory research was approved by the Ministry of Health and Medical Education of Iran in 2016. To provide the minimum data set (MDS), several focus group meetings were held. The final MDS was handed over to an engineering team to develop a web-based software. In the pilot phase, the software was set up in two referral centers in Iran. Final IRD diagnosis was made based on clinical manifestations and genetic findings. Ultimately, patient registration was done based on all clinical and non-clinical manifestations.

Results: Initially, a total of 151 data elements were approved with Delphi technique. The registry software went live at www. IRDReg.org based on DHIS2 open source license agreement since February 2016. So far, a total of 1001 patients have been registered with a mean age of 32.41±15.60 years (range, 3 months to 74 years). The majority of the registered patients had retinitis pigmentosa (42%, 95% CI: 38.9% to 45%). Genetic testing was done for approximately 20% of the registered individuals.

Conclusion: Our study shows successful web-based software design and data collection as a proof of concept for the first IRD registry in Iran. Multicenter integration of the IRD registry in medical centers throughout the country is well underway as planned. These data will assist researchers to rapidly access information about the distribution and genetic patterns of this disease.
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http://dx.doi.org/10.34172/aim.2020.41DOI Listing
July 2020

A novel missense variant in MYO3A is associated with autosomal dominant high-frequency hearing loss in a German family.

Mol Genet Genomic Med 2020 08 10;8(8):e1343. Epub 2020 Jun 10.

Institute of Human Genetics, Julius Maximilians University, Würzburg, Germany.

Background: MYO3A, encoding the myosin IIIA protein, is associated with autosomal recessive and autosomal dominant nonsyndromic hearing loss. To date, only two missense variants located in the motor-head domain of MYO3A have been described in autosomal dominant families with progressive, mild-to-profound sensorineural hearing loss. These variants alter the ATPase activity of myosin IIIA.

Methods: Exome sequencing of a proband from a three-generation German family with prelingual, moderate-to-profound, high-frequency hearing loss was performed. Segregation analysis confirmed a dominant inheritance pattern. Regression analysis of mean hearing level thresholds per individual and ear was performed at high-, mid-, and low-frequencies.

Results: A novel heterozygous missense variant c.716T>C, p.(Leu239Pro) in the kinase domain of MYO3A was identified that is predicted in silico as disease causing. High-frequency, progressive hearing loss was identified.

Conclusion: Correlation analysis of pure-tone hearing thresholds revealed progressive hearing loss, especially in the high-frequencies. In the present study, we report the first dominant likely pathogenic variant in MYO3A in a European family and further support MYO3A as an autosomal dominant hearing loss gene.
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http://dx.doi.org/10.1002/mgg3.1343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7434730PMC
August 2020

Biallelic mutations cause a novel syndromal disease due to hampered cellular collagen secretion.

Elife 2020 Feb 26;9. Epub 2020 Feb 26.

Institute of Human Genetics, Julius Maximilians University Würzburg, Würzburg, Germany.

The transport and Golgi organization 1 (TANGO1) proteins play pivotal roles in the secretory pathway. Full length TANGO1 is a transmembrane protein localised at endoplasmic reticulum (ER) exit sites, where it binds bulky cargo within the ER lumen and recruits membranes from the ER Golgi intermediate compartment to create an exit route for their export. Here we report the first TANGO1-associated syndrome in humans. A synonymous substitution that results in exon eight skipping in most mRNA molecules, ultimately leading to a truncated TANGO1 protein was identified as disease-causing mutation. The four homozygously affected sons of a consanguineous family display severe dentinogenesis imperfecta, short stature, various skeletal abnormalities, insulin-dependent diabetes mellitus, sensorineural hearing loss, and mild intellectual disability. Functional studies in HeLa and U2OS cells revealed that the corresponding truncated TANGO1 protein is dispersed in the ER and its expression in cells with intact endogenous TANGO1 impairs cellular collagen I secretion.
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http://dx.doi.org/10.7554/eLife.51319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062462PMC
February 2020

Small fish, big prospects: using zebrafish to unravel the mechanisms of hereditary hearing loss.

Hear Res 2020 Nov 6;397:107906. Epub 2020 Feb 6.

Genes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, United States. Electronic address:

Over the past decade, advancements in high-throughput sequencing have greatly enhanced our knowledge of the mutational signatures responsible for hereditary hearing loss. In its present state, the field has a largely uncensored view of protein coding changes in a growing number of genes that have been associated with hereditary hearing loss, and many more that have been proposed as candidate genes. Sequencing data can now be generated using methods that have become widespread and affordable. The greatest hurdles facing the field concern functional validation of uncharacterized genes and rapid application to human diseases, including hearing and balance disorders. To date, over 30 hearing-related disease models exist in zebrafish. New genome editing technologies, including CRISPR/Cas9 will accelerate the functional validation of hearing loss genes and variants in zebrafish. Here, we discuss current progress in the field and recent advances in genome editing approaches.
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http://dx.doi.org/10.1016/j.heares.2020.107906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415493PMC
November 2020

Novel Loss-of-Function Variants in are Associated with Recessive Sensorineural Hearing Loss in Iranian and Pakistani Patients.

Int J Mol Sci 2020 Jan 2;21(1). Epub 2020 Jan 2.

Institute of Human Genetics, Julius Maximilians University, 97074 Würzburg, Germany.

encodes the Cell Division Cycle 14A protein and has been associated with autosomal recessive non-syndromic hearing loss (DFNB32), as well as hearing impairment and infertile male syndrome (HIIMS) since 2016. To date, only nine variants have been associated in patients whose initial symptoms included moderate-to-profound hearing impairment. Exome analysis of Iranian and Pakistani probands who both showed bilateral, sensorineural hearing loss revealed a novel splice site variant (c.1421+2T>C, p.?) that disrupts the splice donor site and a novel frameshift variant (c.1041dup, p.Ser348Glnfs*2) in the gene , respectively. To evaluate the pathogenicity of both loss-of-function variants, we analyzed the effects of both variants on the RNA-level. The splice variant was characterized using a minigene assay. Altered expression levels due to the c.1041dup variant were assessed using RT-qPCR. In summary, cDNA analysis confirmed that the c.1421+2T>C variant activates a cryptic splice site, resulting in a truncated transcript (c.1414_1421del, p.Val472Leufs*20) and the c.1041dup variant results in a defective transcript that is likely degraded by nonsense-mediated mRNA decay. The present study functionally characterizes two variants and provides further confirmatory evidence that is associated with a rare form of hereditary hearing loss.
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http://dx.doi.org/10.3390/ijms21010311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6982189PMC
January 2020

Exome-wide copy number variation analysis identifies a COL9A1 in frame deletion that is associated with hearing loss.

Eur J Med Genet 2019 Oct 14;62(10):103724. Epub 2019 Jul 14.

Institute of Human Genetics, Julius Maximilians University, Würzburg, Germany; Department of Otorhinolaryngology-Head and Neck Surgery, Tübingen Hearing Research Centre, Eberhard Karls University Tübingen, Tübingen, Germany. Electronic address:

Pathogenic variants in COL9A1 are primarily associated with autosomal recessive Stickler syndrome. Patients with COL9A1-associated Stickler syndrome (STL) present hearing loss (HL), ophthalmic manifestations and skeletal abnormalities. However, the clinical spectrum of patients with COL9A1 variants can also include multiple epiphyseal dysplasia, as well as non-syndromic HL that was observed in one previously reported proband. Exome sequencing was performed on the genomic DNA of an Iranian patient and his affected brother who both report non-syndromic HL. A 44.6 kb homozygous in-frame deletion spanning exons 6 to 33 of COL9A1 was detected via exome-based copy number variation analysis. The deleted exons were confirmed by PCR in the patient and his affected brother, who both have non-syndromic HL. Segregation analysis via qPCR confirmed the parents as heterozygous deletion carriers. Breakpoint analysis mapped the homozygous deletion spanning introns 5 to 33 (g.70,948,188_70,997,277del, NM_001851.4(COL9A1):c.697-3754_2112+769del, p.(Phe233_Ser704del), with an additional 67 bp of inserted intronic sequence that may have originated due to a fork stalling and template switching/microhomology-mediated break-induced replication (FoSTeS/MMBIR) mechanism. This mechanism has not been previously implicated in HL or STL. This is also the first reported copy number variation in COL9A1 that was identified through an exome data set in an Iranian family with apparent non-syndromic HL. The present study emphasizes the importance of exome-wide copy number variation analysis in molecular diagnosis and provides supporting evidence to associate COL9A1 with autosomal recessive non-syndromic HL.
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http://dx.doi.org/10.1016/j.ejmg.2019.103724DOI Listing
October 2019

Unbalanced segregation of a paternal t(9;11)(p24.3;p15.4) translocation causing familial Beckwith-Wiedemann syndrome: a case report.

BMC Med Genomics 2019 06 7;12(1):83. Epub 2019 Jun 7.

Institute of Human Genetics, Julius Maximilians University Würzburg, Biozentrum, Am Hubland, 97074, Würzburg, Germany.

Background: The vast majority of cases with Beckwith-Wiedemann syndrome (BWS) are caused by a molecular defect in the imprinted chromosome region 11p15.5. The underlying mechanisms include epimutations, uniparental disomy, copy number variations, and structural rearrangements. In addition, maternal loss-of-function mutations in CDKN1C are found. Despite growing knowledge on BWS pathogenesis, up to 20% of patients with BWS phenotype remain without molecular diagnosis.

Case Presentation: Herein, we report an Iranian family with two females affected with BWS in different generations. Bisulfite pyrosequencing revealed hypermethylation of the H19/IGF2: intergenic differentially methylated region (IG DMR), also known as imprinting center 1 (IC1) and hypomethylation of the KCNQ1OT1: transcriptional start site (TSS) DMR (IC2). Array CGH demonstrated an 8 Mb duplication on chromosome 11p15.5p15.4 (205,827-8,150,933) and a 1 Mb deletion on chromosome 9p24.3 (209,020-1,288,114). Chromosome painting revealed that this duplication-deficiency in both patients is due to unbalanced segregation of a paternal reciprocal t(9;11)(p24.3;p15.4) translocation.

Conclusions: This is the first report of a paternally inherited unbalanced translocation between the chromosome 9 and 11 short arms underlying familial BWS. Copy number variations involving the 11p15.5 region are detected by the consensus diagnostic algorithm. However, in complex cases which do not only affect the BWS region itself, characterization of submicroscopic chromosome rearrangements can assist to estimate the recurrence risk and possible phenotypic outcomes.
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http://dx.doi.org/10.1186/s12920-019-0539-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555757PMC
June 2019

A Big Data Perspective on the Genomics of Hearing Loss.

Laryngorhinootologie 2019 Mar 3;98(S 01):S32-S81. Epub 2019 Apr 3.

Klinik für Hals-, Nasen- und Ohrenheilkunde, Eberhard Karls Universität, Universitätsklinik Tübingen.

The completion of the human genome, the most fundamental example of big data in science and medicine, is the remarkable product of multidisciplinary collaboration and is regarded as one of the largest and most successful undertakings in human history. Unravelling the human genome means not only identifying the sequence of its more than 3.2 billion nucleotide bases, but also understanding disease-associated variations and applying this knowledge to patient-tailored precision medicine approaches. Genomics has moved at a remarkable pace, with much of the propelling forces behind this credited to technological developments in sequencing, computing, and bioinformatics, that have given rise to the term "big genomics data." The analysis of genetics data in a disease context involves the use of several big data resources that take the form of clinical genetics data repositories, in silico prediction tools, and allele frequency databases. These exceptional developments have cultivated high-throughput sequencing technologies that are capable of producing affordable high-quality data ranging from targeted gene panels to exomes and genomes. These new advancements have revolutionized the diagnostic paradigm of hereditary diseases including genetic hearing loss.Dissecting hereditary hearing loss is exceptionally challenging due to extensive genetic and clinical heterogeneity. There are presently over 150 genes involved in non-syndromic and common syndromic forms of hearing loss. The mutational spectrum of a single hearing loss associated-gene can have several tens to hundreds of pathogenic variants. Moreover, variant interpretation of novel variants can pose a challenge when conflicting information is deposited in valuable databases. Harnessing the power that comes from detailed and structured phenotypic information has proven promising for some forms of hearing loss, but may not be possible for all genetic forms due to highly variable clinical presentations. New knowledge in both diagnostic and scientific realms continues to rapidly accumulate. This overwhelming amount of information represents an increasing challenge for medical specialists. As a result, specialist medical care may evolve to take on new tasks and facilitate the interface between the human genetic diagnostic laboratory and the patient. These tasks include genetic counselling and the inclusion of genetics results in patient care.This overview is intended to serve as a reference to otolaryngologists who wish to gain an introduction to the molecular genetics of hearing loss. Key concepts of molecular genetic diagnostics will be presented. The complex processes underlying the identification and interpretation of genetic variants in particular would be inconceivable without the enormous amount of data available. In this respect, "big data" is an indispensable prerequisite for filtering genetic data in specific individual cases and making it clear and useful, especially for clinicians in contact with patients.
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http://dx.doi.org/10.1055/a-0803-6149DOI Listing
March 2019

Cardiomyopathy with lethal arrhythmias associated with inactivation of KLHL24.

Hum Mol Genet 2019 06;28(11):1919-1929

Genetics Research Centre, Molecular and Clinical Sciences Institute, St George's University of London, Cranmer Terrace, London, UK.

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disorder, yet the genetic cause of up to 50% of cases remains unknown. Here, we show that mutations in KLHL24 cause HCM in humans. Using genome-wide linkage analysis and exome sequencing, we identified homozygous mutations in KLHL24 in two consanguineous families with HCM. Of the 11 young affected adults identified, 3 died suddenly and 1 had a cardiac transplant due to heart failure. KLHL24 is a member of the Kelch-like protein family, which acts as substrate-specific adaptors to Cullin E3 ubiquitin ligases. Endomyocardial and skeletal muscle biopsies from affected individuals of both families demonstrated characteristic alterations, including accumulation of desmin intermediate filaments. Knock-down of the zebrafish homologue klhl24a results in heart defects similar to that described for other HCM-linked genes providing additional support for KLHL24 as a HCM-associated gene. Our findings reveal a crucial role for KLHL24 in cardiac development and function.
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http://dx.doi.org/10.1093/hmg/ddz032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6812045PMC
June 2019

Heritability and Tinnitus.

Authors:
Barbara Vona

JAMA Otolaryngol Head Neck Surg 2019 03;145(3):229-230

Tübingen Hearing Research Centre, Department of Otorhinolaryngology-Head and Neck Surgery, Eberhard Karls University Tübingen, Tübingen, Germany.

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http://dx.doi.org/10.1001/jamaoto.2018.3946DOI Listing
March 2019

Phenotypic Characterization of DFNB16-associated Hearing Loss.

Otol Neurotol 2019 01;40(1):e48-e55

Department of Oto-Rhino-Laryngology, Head and Neck Surgery "Otto Körner", University Hospital Rostock, Rostock, Germany.

Hypothesis: We hypothesized that patients with DFNB16 caused hearing loss show characteristical audiological findings depending on genetic results.

Background: Hearing loss belongs to the most frequent congenital diseases. In 50-70% of individuals, hearing loss is caused by genetic defects. DFNB1 (deafness, neurosensory, autosomal-recessive) is the most frequently affected locus. Despite its great genetic heterogeneity, comprehensive analysis of genes like STRC, encoding stereocilin (DFNB16) is possible. The genetic architecture of the DFNB16 locus is challenging and requires a unique molecular genetic testing assay. The aim of the study is a systematic characterization of the audiological phenotype in DFNB16-positive patients.

Methods: Since 2011, 290 patients with suspicion of inherited hearing loss received a human genetic exploration. Eighty two DFNB1-negative patients advanced to further testing in the DFNB16 locus. STRC-positive patients obtained complete audiological diagnostic workup. Additionally, epidemiological data was collected.

Results: Nine of 82 (11%) of the examined patients (mean age 5 yr) showed mutations in the STRC (3 homozygous, 6 compound heterozygous). Aside from a moderate hearing loss in the pure tone audiogram, auditory brainstem response thresholds were 40-50 dB nHL. Otoacoustic emissions were detectable in only one patient.

Conclusions: Examination of the DFNB16-locus should be a standard diagnostic test after negative DFNB1-gene screening result. Notably, DFNB16-associated hearing loss can be audiologically characterized as moderate sensorineural hearing loss in the main speech field with absent otoacoustic emissions. Our study is the first to correlate audiological findings with genetic results in patients with hearing loss due to STRC.
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http://dx.doi.org/10.1097/MAO.0000000000002059DOI Listing
January 2019

Expanding the clinical phenotype of IARS2-related mitochondrial disease.

BMC Med Genet 2018 11 12;19(1):196. Epub 2018 Nov 12.

Genetics and Molecular Cell Sciences Research Centre, St George's, University of London, Cranmer Terrace, London, SW17 0RE, UK.

Background: IARS2 encodes a mitochondrial isoleucyl-tRNA synthetase, a highly conserved nuclear-encoded enzyme required for the charging of tRNAs with their cognate amino acid for translation. Recently, pathogenic IARS2 variants have been identified in a number of patients presenting broad clinical phenotypes with autosomal recessive inheritance. These phenotypes range from Leigh and West syndrome to a new syndrome abbreviated CAGSSS that is characterised by cataracts, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, and skeletal dysplasia, as well as cataract with no additional anomalies.

Methods: Genomic DNA from Iranian probands from two families with consanguineous parental background and overlapping CAGSSS features were subjected to exome sequencing and bioinformatics analysis.

Results: Exome sequencing and data analysis revealed a novel homozygous missense variant (c.2625C > T, p.Pro909Ser, NM_018060.3) within a 14.3 Mb run of homozygosity in proband 1 and a novel homozygous missense variant (c.2282A > G, p.His761Arg) residing in an ~ 8 Mb region of homozygosity in a proband of the second family. Patient-derived fibroblasts from proband 1 showed normal respiratory chain enzyme activity, as well as unchanged oxidative phosphorylation protein subunits and IARS2 levels. Homology modelling of the known and novel amino acid residue substitutions in IARS2 provided insight into the possible consequence of these variants on function and structure of the protein.

Conclusions: This study further expands the phenotypic spectrum of IARS2 pathogenic variants to include two patients (patients 2 and 3) with cataract and skeletal dysplasia and no other features of CAGSSS to the possible presentation of the defects in IARS2. Additionally, this study suggests that adult patients with CAGSSS may manifest central adrenal insufficiency and type II esophageal achalasia and proposes that a variable sensorineural hearing loss onset, proportionate short stature, polyneuropathy, and mild dysmorphic features are possible, as seen in patient 1. Our findings support that even though biallelic IARS2 pathogenic variants can result in a distinctive, clinically recognisable phenotype in humans, it can also show a wide range of clinical presentation from severe pediatric neurological disorders of Leigh and West syndrome to both non-syndromic cataract and cataract accompanied by skeletal dysplasia.
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http://dx.doi.org/10.1186/s12881-018-0709-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6233262PMC
November 2018

MPZL2 is a novel gene associated with autosomal recessive nonsyndromic moderate hearing loss.

Hum Genet 2018 Jul 7;137(6-7):479-486. Epub 2018 Jul 7.

John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, 1501 NW 10th Avenue, BRB-610 (M-860), Miami, FL, 33136, USA.

While recent studies have revealed a substantial portion of the genes underlying human hearing loss, the extensive genetic landscape has not been completely explored. Here, we report a loss-of-function variant (c.72delA) in MPZL2 in three unrelated multiplex families from Turkey and Iran with autosomal recessive nonsyndromic hearing loss. The variant co-segregates with moderate sensorineural hearing loss in all three families. We show a shared haplotype flanking the variant in our families implicating a single founder. While rare in other populations, the allele frequency of the variant is ~ 0.004 in Ashkenazi Jews, suggesting that it may be an important cause of moderate hearing loss in that population. We show that Mpzl2 is expressed in mouse inner ear, and the protein localizes in the auditory inner and outer hair cells, with an asymmetric subcellular localization. We thus present MPZL2 as a novel gene associated with sensorineural hearing loss.
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http://dx.doi.org/10.1007/s00439-018-1901-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6478175PMC
July 2018

Hereditary hearing loss SNP-microarray pilot study.

BMC Res Notes 2018 Jun 14;11(1):391. Epub 2018 Jun 14.

Institute of Human Genetics, Julius Maximilians University, Würzburg, Germany.

Objectives: Despite recent advancements in diagnostic tools, the genomic landscape of hereditary hearing loss remains largely uncharacterized. One strategy to understand genome-wide aberrations includes the analysis of copy number variation that can be mapped using SNP-microarray technology. A growing collection of literature has begun to uncover the importance of copy number variation in hereditary hearing loss. This pilot study underpins a larger effort that involves the stage-wise analysis of hearing loss patients, many of whom have advanced to high-throughput sequencing analysis.

Data Description: Our data originate from the Infinium HumanOmni1-Quad v1.0 SNP-microarrays (Illumina) that provide useful markers for genome-wide association studies and copy number variation analysis. This dataset comprises a cohort of 108 individuals (99 with hearing loss, 9 normal hearing family members) for the purpose of understanding the genetic contribution of copy number variations to hereditary hearing loss. These anonymized SNP-microarray data have been uploaded to the NCBI Gene Expression Omnibus and are intended to benefit other investigators interested in aggregating platform-matched array patient datasets or as part of a supporting reference tool for other laboratories to better understand recurring copy number variations in other genetic disorders.
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http://dx.doi.org/10.1186/s13104-018-3466-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6003021PMC
June 2018

Recommendations on Collecting and Storing Samples for Genetic Studies in Hearing and Tinnitus Research.

Ear Hear 2019 Mar/Apr;40(2):219-226

Otology & Neurotology Group CTS495, Department of Genomic Medicine, Centro de Genómica e Investigación Oncológica, Pfizer/Universidad de Granada/Junta de Andalucía (GENyO), Granada, Spain.

Objectives: Research on the genetic basis of tinnitus is still in its first steps. A group of scientists dedicated to tinnitus genetics within European Tinnitus Network (TINNET) network recognize that further progress requires multicenter collaborative efforts for defining contributing genes. The purpose of the present work is to provide instructions regarding collection, processing, storage, and shipment of samples intended for genetic studies in auditory research.

Design: One part of the recommendations has a general character; another part is of particular importance for auditory healthcare practitioners such as otolaryngology physicians, audiologists, and general practitioners.

Results: We provide a set of instructions and various options for obtaining samples. We give advice regarding sample processing, storage, and shipment and define the minimal and essential clinical information that should accompany the samples collected for genetic processing.

Conclusions: These recommendations offer a basis to standardize and optimize collaborations between geneticists and healthcare practitioners specialized in tinnitus and hearing disorders.
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http://dx.doi.org/10.1097/AUD.0000000000000614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6400449PMC
August 2019

The conserved p.Arg108 residue in S1PR2 (DFNB68) is fundamental for proper hearing: evidence from a consanguineous Iranian family.

BMC Med Genet 2018 05 18;19(1):81. Epub 2018 May 18.

Institute of Human Genetics, Julius Maximilians University, Würzburg, Germany.

Background: Genetic heterogeneity and consanguineous marriages make recessive inherited hearing loss in Iran the second most common genetic disorder. Only two reported pathogenic variants (c.323G>C, p.Arg108Pro and c.419A>G, p.Tyr140Cys) in the S1PR2 gene have previously been linked to autosomal recessive hearing loss (DFNB68) in two Pakistani families. We describe a segregating novel homozygous c.323G>A, p.Arg108Gln pathogenic variant in S1PR2 that was identified in four affected individuals from a consanguineous five generation Iranian family.

Methods: Whole exome sequencing and bioinformatics analysis of 116 hearing loss-associated genes was performed in an affected individual from a five generation Iranian family. Segregation analysis and 3D protein modeling of the p.Arg108 exchange was performed.

Results: The two Pakistani families previously identified with S1PR2 pathogenic variants presented profound hearing loss that is also observed in the affected Iranian individuals described in the current study. Interestingly, we confirmed mixed hearing loss in one affected individual. 3D protein modeling suggests that the p.Arg108 position plays a key role in ligand receptor interaction, which is disturbed by the p.Arg108Gln change.

Conclusion: In summary, we report the third overall mutation in S1PR2 and the first report outside the Pakistani population. Furthermore, we describe a novel variant that causes an amino acid exchange (p.Arg108Gln) in the same amino acid residue as one of the previously reported Pakistani families (p.Arg108Pro). This finding emphasizes the importance of the p.Arg108 amino acid in normal hearing and confirms and consolidates the role of S1PR2 in autosomal recessive hearing loss.
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http://dx.doi.org/10.1186/s12881-018-0598-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5960148PMC
May 2018

Dual Diagnosis of Ellis-van Creveld Syndrome and Hearing Loss in a Consanguineous Family.

Mol Syndromol 2017 Dec 22;9(1):5-14. Epub 2017 Sep 22.

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Multilocus analysis of rare or genetically heterogeneous diseases is a distinct advantage of next-generation sequencing (NGS) over conventional single-gene investigations. Recent studies have begun to uncover an under-recognized prevalence of dual molecular diagnoses in patients with a "blended" phenotype that is the result of 2 clinical diagnoses involving 2 separate genetic loci. This blended phenotype could be mistakenly interpreted as a novel clinical extension of a single-gene disorder. In this study, we ascertained a proband from a large consanguineous Iranian family who manifests postlingual, progressive, moderate hearing loss in addition to suspected Ellis-van Creveld syndrome phenotype. NGS with a customized skeletal dysplasia panel containing over 370 genes and subsequent bioinformatics analysis disclosed 2 homozygous mutations in (c.2653C>T; p.Arg885*) and (c.966dup; p.Thr323His*19), respectively. This study highlights a dual molecular diagnosis in a patient with a blending of 2 distinct phenotypes and illustrates the advantage and importance of this staple technology to facilitate rapid and comprehensive genetic dissection of a heterogeneous phenotype. The differentiation between phenotypic expansion of a genetic disorder and a blended phenotype that is due to more than one distinct genetic aberration is essential in order to reduce the diagnostic odyssey endured by patients.
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http://dx.doi.org/10.1159/000480458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5803684PMC
December 2017

The CAPOS mutation in ATP1A3 alters Na/K-ATPase function and results in auditory neuropathy which has implications for management.

Hum Genet 2018 Feb 5;137(2):111-127. Epub 2018 Jan 5.

North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, WC1N 3JH, UK.

Cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing impairment (CAPOS) is a rare clinically distinct syndrome caused by a single dominant missense mutation, c.2452G>A, p.Glu818Lys, in ATP1A3, encoding the neuron-specific alpha subunit of the Na+/K+-ATPase α3. Allelic mutations cause the neurological diseases rapid dystonia Parkinsonism and alternating hemiplegia of childhood, disorders which do not encompass hearing or visual impairment. We present detailed clinical phenotypic information in 18 genetically confirmed patients from 11 families (10 previously unreported) from Denmark, Sweden, UK and Germany indicating a specific type of hearing impairment-auditory neuropathy (AN). All patients were clinically suspected of CAPOS and had hearing problems. In this retrospective analysis of audiological data, we show for the first time that cochlear outer hair cell activity was preserved as shown by the presence of otoacoustic emissions and cochlear microphonic potentials, but the auditory brainstem responses were grossly abnormal, likely reflecting neural dyssynchrony. Poor speech perception was observed, especially in noise, which was beyond the hearing level obtained in the pure tone audiograms in several of the patients presented here. Molecular modelling and in vitro electrophysiological studies of the specific CAPOS mutation were performed. Heterologous expression studies of α3 with the p.Glu818Lys mutation affects sodium binding to, and release from, the sodium-specific site in the pump, the third ion-binding site. Molecular dynamics simulations confirm that the structure of the C-terminal region is affected. In conclusion, we demonstrate for the first time evidence for auditory neuropathy in CAPOS syndrome, which may reflect impaired propagation of electrical impulses along the spiral ganglion neurons. This has implications for diagnosis and patient management. Auditory neuropathy is difficult to treat with conventional hearing aids, but preliminary improvement in speech perception in some patients suggests that cochlear implantation may be effective in CAPOS patients.
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http://dx.doi.org/10.1007/s00439-017-1862-zDOI Listing
February 2018

Genetics of Tinnitus: Still in its Infancy.

Front Neurosci 2017 8;11:236. Epub 2017 May 8.

Institute of Human Genetics, Julius Maximilians University WürzburgWürzburg, Germany.

Tinnitus is the perception of a phantom sound that affects between 10 and 15% of the general population. Despite this considerable prevalence, treatments for tinnitus are presently lacking. Tinnitus exhibits a diverse array of recognized risk factors and extreme clinical heterogeneity. Furthermore, it can involve an unknown number of auditory and non-auditory networks and molecular pathways. This complex combination has hampered advancements in the field. The identification of specific genetic factors has been at the forefront of several research investigations in the past decade. Nine studies have examined genes in a case-control association approach. Recently, a genome-wide association study has highlighted several potentially significant pathways that are implicated in tinnitus. Two twin studies have calculated a moderate heritability for tinnitus and disclosed a greater concordance rate in monozygotic twins compared to dizygotic twins. Despite the more recent data alluding to genetic factors in tinnitus, a strong association with any specific genetic locus is lacking and a genetic study with sufficient statistical power has yet to be designed. Future research endeavors must overcome the many inherent limitations in previous study designs. This review summarizes the previously embarked upon tinnitus genetic investigations and summarizes the hurdles that have been encountered. The identification of candidate genes responsible for tinnitus may afford gene based diagnostic approaches, effective therapy development, and personalized therapeutic intervention.
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http://dx.doi.org/10.3389/fnins.2017.00236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5421307PMC
May 2017

Confirmation of PDZD7 as a Nonsyndromic Hearing Loss Gene.

Ear Hear 2016 Jul-Aug;37(4):e238-46

1Institute of Human Genetics, Julius Maximilians University Würzburg, Würzburg, Germany; 2Institute of Human Genetics, 3Department of Ophthalmology, University Medical Centre, Johannes Gutenberg University, Mainz, Germany; and 4Division of Communication Disorders, Department of Otorhinolaryngology, University Medical Centre, Mainz, Germany.

Objective: PDZD7 was identified in 2009 in a family with apparent nonsyndromic sensorineural hearing loss. However, subsequent clinical reports have associated PDZD7 with digenic Usher syndrome, the most common cause of deaf-blindness, or as a modifier of retinal disease. No further reports have validated this gene for nonsyndromic hearing loss, intuitively calling correct genotype-phenotype association into question. This report describes a validating second case for biallelic mutations in PDZD7 causing nonsyndromic mild to severe sensorineural hearing loss. It also provides detailed audiometric and ophthalmologic data excluding Usher syndrome in both the present proband (proband 1) and the first proband described in 2009 (proband 2).

Design: Proband 1 was sequenced using a custom-designed next generation sequencing panel consisting of 151 deafness genes. Bioinformatics analysis and filtering disclosed two PDZD7 sequence variants (c.1648C>T, p.Q550* and c.2107del, p.S703Vfs*20). Segregation testing followed in the family. For both probands, audiograms were collected and analyzed for progressive hearing loss and detailed ophthalmic evaluations were performed including electroretinography.

Results: Proband 1 demonstrated a prelingual, nonsyndromic, sensorineural hearing loss that progressed in the higher frequencies between 4 and 9 years old. PDZD7 segregation analysis confirmed biallelic inheritance (compound heterozygosity). Mutation analysis determined the c.1648C>T mutation as novel and reported the c.2107del deletion as rs397516633 with a calculated minor allele frequency of 0.000018. Clinical evaluation spanning well over a decade in proband 2 disclosed bilateral, nonprogressive hearing loss. Both probands showed healthy retinas, excluding Usher syndrome-like changes in the eye.

Conclusions: PDZD7 is confirmed as a bona fide autosomal recessive nonsyndromic hearing loss gene. In both probands, there was no evidence of impaired vision or ophthalmic pathology. As the current understanding of PDZD7 mutations bridge Mendelian and complex phenotypes, the authors recommend careful variant interpretation, since PDZD7 is one of many genes associated with both Usher syndrome and autosomal recessive nonsyndromic hearing loss. Additional reports are required for understanding the complete phenotypic spectrum of this gene, including the possibility of high-frequency progression, as well as noise-induced hearing loss susceptibility in adult carriers. This report rules out all forms of Usher syndrome with an onset before 12 and 15 years old in probands 1 and 2, respectively. However, due to the young ages of the probands, this report is uninformative regarding older patients.
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http://dx.doi.org/10.1097/AUD.0000000000000278DOI Listing
January 2018