Autosomal Dominantly Inherited GREB1L Variants in Individuals with Profound Sensorineural Hearing Impairment
Congenital hearing impairment is a sensory disorder that is genetically highly heterogeneous. By performing exome sequencing in two families with congenital nonsyndromic profound sensorineural hearing loss (SNHL), we identified autosomal dominantly inherited missense variants [p.(Asn283Ser); p.(Thr1...
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MDPI AG
2020-06-01
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| Series: | Genes |
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| Online Access: | https://www.mdpi.com/2073-4425/11/6/687 |
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| author | Isabelle Schrauwen Khurram Liaqat Isabelle Schatteman Thashi Bharadwaj Abdul Nasir Anushree Acharya Wasim Ahmad Guy Van Camp Suzanne M. Leal |
| author_facet | Isabelle Schrauwen Khurram Liaqat Isabelle Schatteman Thashi Bharadwaj Abdul Nasir Anushree Acharya Wasim Ahmad Guy Van Camp Suzanne M. Leal |
| author_sort | Isabelle Schrauwen |
| collection | DOAJ |
| description | Congenital hearing impairment is a sensory disorder that is genetically highly heterogeneous. By performing exome sequencing in two families with congenital nonsyndromic profound sensorineural hearing loss (SNHL), we identified autosomal dominantly inherited missense variants [p.(Asn283Ser); p.(Thr116Ile)] in <i>GREB1L</i>, a neural crest regulatory molecule. The p.(Thr116Ile) variant was also associated with bilateral cochlear aplasia and cochlear nerve aplasia upon temporal bone imaging, an ultra-rare phenotype previously seen in patients with de novo <i>GREB1L</i> variants. An important role of GREB1L in normal ear development has also been demonstrated by <i>greb1l</i><sup>−/−</sup> zebrafish, which show an abnormal sensory epithelia innervation. Last, we performed a review of all disease-associated variation described in <i>GREB1L</i>, as it has also been implicated in renal, bladder and genital malformations. We show that the spectrum of features associated with <i>GREB1L</i> is broad, variable and with a high level of reduced penetrance, which is typically characteristic of neurocristopathies. So far, seven <i>GREB1L</i> variants (14%) have been associated with ear-related abnormalities. In conclusion, these results show that autosomal dominantly inherited variants in <i>GREB1L</i> cause profound SNHL. Furthermore, we provide an overview of the phenotypic spectrum associated with <i>GREB1L</i> variants and strengthen the evidence of the involvement of <i>GREB1L</i> in human hearing. |
| first_indexed | 2024-03-10T18:57:11Z |
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| institution | Directory Open Access Journal |
| issn | 2073-4425 |
| language | English |
| last_indexed | 2024-03-10T18:57:11Z |
| publishDate | 2020-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Genes |
| spelling | doaj.art-4535190296da4481867787f794e0f1e42023-11-20T04:41:44ZengMDPI AGGenes2073-44252020-06-0111668710.3390/genes11060687Autosomal Dominantly Inherited GREB1L Variants in Individuals with Profound Sensorineural Hearing ImpairmentIsabelle Schrauwen0Khurram Liaqat1Isabelle Schatteman2Thashi Bharadwaj3Abdul Nasir4Anushree Acharya5Wasim Ahmad6Guy Van Camp7Suzanne M. Leal8Center for Statistical Genetics, Sergievsky Center, Taub Institute for Alzheimer’s Disease and the Aging Brain, and the Department of Neurology, Columbia University Medical Center, New York, NY 10032, USADepartment of Biotechnology, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, PakistanDepartment of ENT, St-Augustinus Hospital Antwerp, 2610 Antwerp, BelgiumCenter for Statistical Genetics, Sergievsky Center, Taub Institute for Alzheimer’s Disease and the Aging Brain, and the Department of Neurology, Columbia University Medical Center, New York, NY 10032, USASynthetic Protein Engineering Lab (SPEL), Department of Molecular Science and Technology, Ajou University, Suwon 443-749, KoreaCenter for Statistical Genetics, Sergievsky Center, Taub Institute for Alzheimer’s Disease and the Aging Brain, and the Department of Neurology, Columbia University Medical Center, New York, NY 10032, USADepartment of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, PakistanCenter of Medical Genetics, University of Antwerp & Antwerp University Hospital, 2650 Antwerp, BelgiumCenter for Statistical Genetics, Sergievsky Center, Taub Institute for Alzheimer’s Disease and the Aging Brain, and the Department of Neurology, Columbia University Medical Center, New York, NY 10032, USACongenital hearing impairment is a sensory disorder that is genetically highly heterogeneous. By performing exome sequencing in two families with congenital nonsyndromic profound sensorineural hearing loss (SNHL), we identified autosomal dominantly inherited missense variants [p.(Asn283Ser); p.(Thr116Ile)] in <i>GREB1L</i>, a neural crest regulatory molecule. The p.(Thr116Ile) variant was also associated with bilateral cochlear aplasia and cochlear nerve aplasia upon temporal bone imaging, an ultra-rare phenotype previously seen in patients with de novo <i>GREB1L</i> variants. An important role of GREB1L in normal ear development has also been demonstrated by <i>greb1l</i><sup>−/−</sup> zebrafish, which show an abnormal sensory epithelia innervation. Last, we performed a review of all disease-associated variation described in <i>GREB1L</i>, as it has also been implicated in renal, bladder and genital malformations. We show that the spectrum of features associated with <i>GREB1L</i> is broad, variable and with a high level of reduced penetrance, which is typically characteristic of neurocristopathies. So far, seven <i>GREB1L</i> variants (14%) have been associated with ear-related abnormalities. In conclusion, these results show that autosomal dominantly inherited variants in <i>GREB1L</i> cause profound SNHL. Furthermore, we provide an overview of the phenotypic spectrum associated with <i>GREB1L</i> variants and strengthen the evidence of the involvement of <i>GREB1L</i> in human hearing.https://www.mdpi.com/2073-4425/11/6/687autosomal dominant inheritanceexome sequencing<i>GREB1L</i>profound nonsyndromic hearing impairmentcochlear aplasiacochlear nerve aplasia |
| spellingShingle | Isabelle Schrauwen Khurram Liaqat Isabelle Schatteman Thashi Bharadwaj Abdul Nasir Anushree Acharya Wasim Ahmad Guy Van Camp Suzanne M. Leal Autosomal Dominantly Inherited GREB1L Variants in Individuals with Profound Sensorineural Hearing Impairment Genes autosomal dominant inheritance exome sequencing <i>GREB1L</i> profound nonsyndromic hearing impairment cochlear aplasia cochlear nerve aplasia |
| title | Autosomal Dominantly Inherited GREB1L Variants in Individuals with Profound Sensorineural Hearing Impairment |
| title_full | Autosomal Dominantly Inherited GREB1L Variants in Individuals with Profound Sensorineural Hearing Impairment |
| title_fullStr | Autosomal Dominantly Inherited GREB1L Variants in Individuals with Profound Sensorineural Hearing Impairment |
| title_full_unstemmed | Autosomal Dominantly Inherited GREB1L Variants in Individuals with Profound Sensorineural Hearing Impairment |
| title_short | Autosomal Dominantly Inherited GREB1L Variants in Individuals with Profound Sensorineural Hearing Impairment |
| title_sort | autosomal dominantly inherited greb1l variants in individuals with profound sensorineural hearing impairment |
| topic | autosomal dominant inheritance exome sequencing <i>GREB1L</i> profound nonsyndromic hearing impairment cochlear aplasia cochlear nerve aplasia |
| url | https://www.mdpi.com/2073-4425/11/6/687 |
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