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Hum Genet. 2018 May 12. doi: 10.1007/s00439-018-1880-5. [Epub ahead of print]

Heterozygous missense variants of LMX1A lead to nonsyndromic hearing impairment and vestibular dysfunction.

Author information

1
Department of Otorhinolaryngology, Hearing and Genes, Radboud University Medical Center, Internal Postal Code 377, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.
2
The Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
3
Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
4
Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
5
Centre for Molecular and Biomolecular Informatics, Radboud University Medical Center, Nijmegen, The Netherlands.
6
Department of Neurology, Radboud University Medical Center, Nijmegen, The Netherlands.
7
Department of Medical Psychology, Radboud University Medical Center, Nijmegen, The Netherlands.
8
Department of Dermatology, Radboud University Medical Center, Nijmegen, The Netherlands.
9
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
10
Department of Radiology, Radboud University Medical Center, Nijmegen, The Netherlands.
11
Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.
12
Department of Otolaryngology, Head and Neck Surgery, LUMC, Leiden, The Netherlands.
13
Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, The Netherlands.
14
Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
15
Department of Otorhinolaryngology, Hearing and Genes, Radboud University Medical Center, Internal Postal Code 377, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands. hannie.kremer@radboudumc.nl.
16
Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands. hannie.kremer@radboudumc.nl.
17
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands. hannie.kremer@radboudumc.nl.

Abstract

Unraveling the causes and pathomechanisms of progressive disorders is essential for the development of therapeutic strategies. Here, we identified heterozygous pathogenic missense variants of LMX1A in two families of Dutch origin with progressive nonsyndromic hearing impairment (HI), using whole exome sequencing. One variant, c.721G > C (p.Val241Leu), occurred de novo and is predicted to affect the homeodomain of LMX1A, which is essential for DNA binding. The second variant, c.290G > C (p.Cys97Ser), predicted to affect a zinc-binding residue of the second LIM domain that is involved in protein-protein interactions. Bi-allelic deleterious variants of Lmx1a are associated with a complex phenotype in mice, including deafness and vestibular defects, due to arrest of inner ear development. Although Lmx1a mouse mutants demonstrate neurological, skeletal, pigmentation and reproductive system abnormalities, no syndromic features were present in the participating subjects of either family. LMX1A has previously been suggested as a candidate gene for intellectual disability, but our data do not support this, as affected subjects displayed normal cognition. Large variability was observed in the age of onset (a)symmetry, severity and progression rate of HI. About half of the affected individuals displayed vestibular dysfunction and experienced symptoms thereof. The late-onset progressive phenotype and the absence of cochleovestibular malformations on computed tomography scans indicate that heterozygous defects of LMX1A do not result in severe developmental abnormalities in humans. We propose that a single LMX1A wild-type copy is sufficient for normal development but insufficient for maintenance of cochleovestibular function. Alternatively, minor cochleovestibular developmental abnormalities could eventually lead to the progressive phenotype seen in the families.

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