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

DOOFNL Consortium

Research output: Contribution to journalArticleAcademicpeer-review

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 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
Volume138
Issue number1
DOIs
Publication statusPublished - 11 Jan 2019

Cite this

@article{7398bc10c83f40a390b3f6c6bd4825e9,
title = "De novo and inherited loss-of-function variants of ATP2B2 are associated with rapidly progressive hearing impairment",
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 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.",
author = "{DOOFNL Consortium} and Smits, {Jeroen J.} and Jaap Oostrik and Beynon, {Andy J.} and Kant, {Sarina G.} and {de Koning Gans}, {Pia A.M.} and Rotteveel, {Liselotte J.C.} and {Klein Wassink-Ruiter}, {Jolien S.} and Free, {Rolien H.} and Maas, {Saskia M.} and {van de Kamp}, Jiddeke and Paul Merkus and Wouter Koole and Ilse Feenstra and Admiraal, {Ronald J.C.} and Lanting, {Cornelis P.} and Margit Schraders and Yntema, {Helger G.} and Pennings, {Ronald J.E.} and Hannie Kremer",
year = "2019",
month = "1",
day = "11",
doi = "10.1007/s00439-018-1965-1",
language = "English",
volume = "138",
pages = "61--72",
journal = "Human Genetics",
issn = "0340-6717",
publisher = "Springer Verlag",
number = "1",

}

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

In: Human Genetics, Vol. 138, No. 1, 11.01.2019, p. 61-72.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - De novo and inherited loss-of-function variants of ATP2B2 are associated with rapidly progressive hearing impairment

AU - DOOFNL Consortium

AU - Smits, Jeroen J.

AU - Oostrik, Jaap

AU - Beynon, Andy J.

AU - Kant, Sarina G.

AU - de Koning Gans, Pia A.M.

AU - Rotteveel, Liselotte J.C.

AU - Klein Wassink-Ruiter, Jolien S.

AU - Free, Rolien H.

AU - Maas, Saskia M.

AU - van de Kamp, Jiddeke

AU - Merkus, Paul

AU - Koole, Wouter

AU - Feenstra, Ilse

AU - Admiraal, Ronald J.C.

AU - Lanting, Cornelis P.

AU - Schraders, Margit

AU - Yntema, Helger G.

AU - Pennings, Ronald J.E.

AU - Kremer, Hannie

PY - 2019/1/11

Y1 - 2019/1/11

N2 - 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.

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U2 - 10.1007/s00439-018-1965-1

DO - 10.1007/s00439-018-1965-1

M3 - Article

VL - 138

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JF - Human Genetics

SN - 0340-6717

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