De novo and inherited loss-of-function variants of ATP2B2 are associated with rapidly progressive hearing impairment

Jeroen J. Smits, Jaap Oostrik, Andy J. Beynon, Sarina G. Kant, Pia A.M. de Koning Gans, Liselotte J.C. Rotteveel, Jolien S. Klein Wassink-Ruiter, Rolien H. Free, Saskia M. Maas, Jiddeke van de Kamp, Paul Merkus, Wouter Koole, Ilse Feenstra, Ronald J.C. Admiraal, Cornelis P. Lanting, Margit Schraders, Helger G. Yntema, Ronald J.E. Pennings, Hannie Kremer*, DOOFNL Consortium

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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 screening, 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.

Original languageEnglish
Pages (from-to)61-72
Number of pages12
JournalHuman Genetics
Issue number1
Publication statusPublished - 11 Jan 2019

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