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De Novo and Inherited Loss-Of-Function Variants of ATP2B2 Are Associated with Rapidly Progressive Hearing Impairment DOOFNL Consortium

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De Novo and Inherited Loss-Of-Function Variants of ATP2B2 Are Associated with Rapidly Progressive Hearing Impairment DOOFNL Consortium University of Groningen De novo and inherited loss-of-function variants of ATP2B2 are associated with rapidly progressive hearing impairment DOOFNL Consortium Published in: HUMAN GENETICS DOI: 10.1007/s00439-018-1965-1 IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2019 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): DOOFNL Consortium (2019). De novo and inherited loss-of-function variants of ATP2B2 are associated with rapidly progressive hearing impairment. HUMAN GENETICS, 138(1), 61-72. https://doi.org/10.1007/s00439-018-1965-1 Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date: 24-09-2021 Human Genetics (2019) 138:61–72 https://doi.org/10.1007/s00439-018-1965-1 ORIGINAL INVESTIGATION De novo and inherited loss-of-function variants of ATP2B2 are associated with rapidly progressive hearing impairment Jeroen J. Smits1,2 · Jaap Oostrik1,2 · Andy J. Beynon1 · Sarina G. Kant3 · Pia A. M. de Koning Gans3 · Liselotte J. C. Rotteveel4 · Jolien S. Klein Wassink‑Ruiter5 · Rolien H. Free6 · Saskia M. Maas7 · Jiddeke van de Kamp7 · Paul Merkus8 · DOOFNL Consortium · Wouter Koole9 · Ilse Feenstra9 · Ronald J. C. Admiraal1 · Cornelis P. Lanting1 · Margit Schraders1,9 · Helger G. Yntema2,9 · Ronald J. E. Pennings1,2 · Hannie Kremer1,2,9 Received: 12 October 2018 / Accepted: 30 November 2018 / Published online: 8 December 2018 © The Author(s) 2018 Abstract ATP2B2 encodes the PMCA2 Ca2+ pump that plays an important role in maintaining ion homeostasis in hair cells among others by extrusion of Ca2+ from the stereocilia to the endolymph. Several mouse models have been described for this gene; mice heterozygous for loss-of-function defects display a rapidly progressive high-frequency hearing impairment. Up to now ATP2B2 has only been reported as a modifier, or in a digenic mechanism with CDH23 for hearing impairment in humans. Whole exome sequencing in hearing impaired index cases of Dutch and Polish origins revealed five novel heterozygous (predicted to be) loss-of-function variants of ATP2B2. Two variants, c.1963G>T (p.Glu655*) and c.955delG (p.Ala319fs), occurred de novo. Three variants c.397+1G>A (p.?), c.1998C>A (p.Cys666*), and c.2329C>T (p.Arg777*), were identified in families with an autosomal dominant inheritance pattern of hearing impairment. After normal newborn hearing screen- ing, a rapidly progressive high-frequency hearing impairment was diagnosed at the age of about 3–6 years. Subjects had no balance complaints and vestibular testing did not yield abnormalities. There was no evidence for retrocochlear pathology or structural inner ear abnormalities. Although a digenic inheritance pattern of hearing impairment has been reported for heterozygous missense variants of ATP2B2 and CDH23, our findings indicate a monogenic cause of hearing impairment in cases with loss-of-function variants of ATP2B2. Introduction Ronald J.E. Pennings and Hannie Kremer contributed equally to this work. Hearing impairment (HI) is an important cause of social bur- den worldwide (WHO 2008). The reported incidence in early Electronic supplementary material The online version of this article (https ://doi.org/10.1007/s0043 9-018-1965-1) contains childhood varies from 1 to 3/1000 (Wroblewska-Seniuk supplementary material, which is available to authorized users. * Hannie Kremer 6 Department of Otorhinolaryngology, Head and Neck [email protected] Surgery, University Medical Center Groningen, Groningen, The Netherlands 1 Hearing and Genes, Department of Otorhinolaryngology, 7 Department of Clinical Genetics, Amsterdam UMC, Vrije Head and Neck Surgery, Radboud University Medical Universiteit Amsterdam, Amsterdam, The Netherlands Center, Nijmegen, The Netherlands 8 Department of Otolaryngology, Head and Neck Surgery, 2 Donders Institute for Brain, Cognition and Behaviour, Ear and Hearing, Amsterdam Public Health Research Radboud University Medical Center, Nijmegen, Institute, Amsterdam UMC, Vrije Universiteit Amsterdam, The Netherlands Amsterdam, The Netherlands 3 Department of Clinical Genetics, Leiden University Medical 9 Hearing and Genes, Department of Human Genetics, Center, Leiden, The Netherlands Radboud University Medical Center, Internal postal code 4 Department of Otorhinolaryngology, Head and Neck 855, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands Surgery, LUMC, Leiden, The Netherlands 5 Department of Clinical Genetics, University Medical Center Groningen, Groningen, The Netherlands Vol.:(0123456789)1 3 62 Human Genetics (2019) 138:61–72 et al. 2017). It is estimated that early onset sensorineural HI of the families, the variants are de novo. All variants affect (SNHI) is hereditary in about 50% of the cases and in 20% exons, or their splice sites, that encode the ortholog of the of the cases nonsyndromic SNHI is inherited in an autoso- rat PMCA2 w/a isoform. This isoform is highly abundant in mal dominant pattern (Smith et al. 2005). Until now, more stereocilia of outer hair cells (OHC) and to a lesser extent at than 60 loci and 37 genes have been identified for autoso- the apical surface of inner hair cells (IHC) (Hill et al. 2006). mal dominant nonsyndromic SNHI (Hereditary Hearing loss Homepage). Still, for many subjects with congenital or childhood-onset HI, a genetic diagnosis cannot be provided Materials and methods (Zazo Seco et al. 2017). For several of the genes (recently) described to be associated with early onset HI, defects have Clinical examination so far been found in only a few or one single family. To confirm the association of such genes with HI, additional This study was approved by the medical ethics committee supportive data are required. Mouse models have contrib- of the Radboud University Medical Center in Nijmegen, the uted such evidence for several genes and have been of great Netherlands and was carried out according to the Decla- significance by providing candidate genes for HI in humans ration of Helsinki. Written informed consent was obtained (Brown et al. 2008; Friedman et al. 2007; Wesdorp et al. from all participants or their legal representatives. Medical 2018). history was taken from all participants, with special atten- The plasma membrane Ca 2+ ATPase 2 (PMCA2), tion paid to (acquired) HI and vestibular symptoms. Affected encoded by Atp2b2, has already been known for 2 decades individuals underwent general ear, nose and throat (ENT) to be essential for hearing and balance in mouse (e.g. the examinations in the Radboud University Medical Center or deafwaddler mouse) (Street et al. 1998). It is one of the findings of ENT examination were taken from their medical two PMCAs with a tissue-specific expression; PMCA2 is history. Pure tone audiometry (PTA) was performed accord- mainly expressed in the inner ear, the cerebellum and the ing to current standards in a sound-attenuating booth, where mammary gland. Alternative splicing of Atp2b2 transcripts air conduction hearing thresholds for the frequencies from results in several PMCA2 isoforms, e.g. PMCA2 w/a, or z/a 250 Hz to 8 kHz were measured. Bone conduction thresh- [for review (Strehler and Zacharias 2001)]. Isoform PMCA2 olds were measured for the frequencies 500 Hz–8 kHz. w/a is the major PMCA2 isoform in the organ of Corti and The age- and gender-specific 95th percentile thresholds for is encoded by a transcript with three alternatively spliced individual hearing levels for each frequency were derived exons at the first alternative splice site, site A (Grati et al. from the International Organisation for Standardization; ISO 2006; Hill et al. 2006). Given the structural and functional 7029:2017. Individuals were considered affected when pure homology of the inner ear in mice, rat and human, PMCA2 tone thresholds for at least three frequencies were below the was anticipated to be critical for hearing in humans as well, 95th percentile (P95) for the better hearing ear. The GEN- and indications for that have already been reported. A hypo- DEAF guidelines for the description of audiological data functional variant of PMCA2 (p.Val586Met) was found to were applied in this study (Mazzoli et al. 2003). GraphPad aggravate HI in a family with a homozygous CDH23 vari- Prism 6.0 (GraphPad, San Diego, CA, USA) was used to ant (Schultz et al. 2005). Moreover, digenic inheritance of calculate an age-related typical audiogram (ARTA), based SNHI was suggested in an isolated case with heterozygous on linear regression, for the ages of 10–70 years as described missense variants in both ATP2B2 and CDH23 (Ficarella (Huygen et al. 2003). Speech perception was assessed in et al. 2007). Furthermore, SNHI in cases with the 3p dele- a sound-attenuating booth with standard monosyllabic tion syndrome (MIM 613792) was suggested to be cor- consonant–vowel–consonant Dutch word lists (Bosman related with haploinsufficiency of ATP2B2 (McCullough and Smoorenburg 1995). Otoacoustic emissions and click- et al. 2007). A heterozygous missense variant in ATP2B2 evoked brainstem-evoked response audiometric (BERA) has recently been associated with ataxia but without HI; the measurements were performed according to current stand- identified variant functionally affected a PMCA2 isoform ards. In the Netherlands, the first step of newborn hearing that is expressed in the cerebellum but not prominently in screening is carried out by the detection of transient evoked the inner ear (Vicario et al.
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