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Cited by 20dental development and anomaliesHearing, Cochlea, Tinnitus, GeneticsHair Growth and Disorders

TSPEAR variants are primarily associated with ectodermal dysplasia and tooth agenesis but not hearing loss: A novel cohort study

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Bowles, Bradley, Ferrer, Alejandro, Nishimura, Carla J., Pinto e Vairo, Filippo, Rey, Tristan, Leheup, Bruno, Sullivan, Jennifer, Schoch, Kelly +24 more·2021·American Journal of Medical Genetics Part A
DOI 10.1002/ajmg.a.62347PMC PMC8361973
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Abstract

Biallelic loss-of-function variants in the thrombospondin-type laminin G domain and epilepsy-associated repeats (TSPEAR) gene have recently been associated with ectodermal dysplasia and hearing loss. The first reports describing a TSPEAR disease association identified this gene is a cause of nonsyndromic hearing loss, but subsequent reports involving additional affected families have questioned this evidence and suggested a stronger association with ectodermal dysplasia. To clarify genotype-phenotype associations for TSPEAR variants, we characterized 13 individuals with biallelic TSPEAR variants. Individuals underwent either exome sequencing or panel-based genetic testing. Nearly all of these newly reported individuals (11/13) have phenotypes that include tooth agenesis or ectodermal dysplasia, while three newly reported individuals have hearing loss. Of the individuals displaying hearing loss, all have additional variants in other hearing-loss-associated genes, specifically TMPRSS3, GJB2, and GJB6, that present competing candidates for their hearing loss phenotype. When presented alongside previous reports, the overall evidence supports the association of TSPEAR variants with ectodermal dysplasia and tooth agenesis features but creates significant doubt as to whether TSPEAR variants are a monogenic cause of hearing loss. Further functional evidence is needed to evaluate this phenotypic association.

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Authors
Bowles, B., Ferrer, A., Nishimura, C. J., Pinto e Vairo, F., Rey, T., Leheup, B., Sullivan, J., Schoch, K., Stong, N., Agolini, E., Cocciadiferro, D., Williams, A., Cummings, A., Loddo, S., Genovese, S., Roadhouse, C., McWalter, K., Undiagnosed Diseases Network, Wentzensen, I. M., Li, C., Babovic‐Vuksanovic, D., Lanpher, B. C., Dentici, M. L., Ankala, A., Hamm, J. A., Dallapiccola, B., Radio, F. C., Shashi, V., Gérard, B., Bloch‐Zupan, A., Smith, R. J., & Klee, E. W.
Affiliations
  • Mayo Clinic (US)
  • University of Iowa (US)
  • Center for Individualized Medicine, Mayo Clinic Rochester Minnesota USA
  • Centre National de la Recherche Scientifique (FR)
  • Centre Hospitalier Régional et Universitaire de Nancy (FR)
  • Duke University (US)
  • Columbia University Irving Medical Center (US)
  • Bambino Gesù Children's Hospital (IT)
  • East Tennessee Children's Hospital (US)
  • University of Wisconsin–Madison (US)
  • McMaster University (CA)
  • GeneDx Inc. Gaithersburg Maryland USA
  • Emory University (US)
  • EGL Genetics LLC Tucker Georgia USA
  • Laboratoires de Diagnostic génétique, Pôle de Biologie, Hôpitaux Universitaires de Strasbourg Institut de Génétique Médicale d'Alsace Strasbourg France
  • Faculté de Chirurgie Dentaire Université de Strasbourg Strasbourg France
Corresponding author
Klee, Eric W.
ORCID
Venue
American Journal of Medical Genetics Part A
Publisher
Wiley
Published
2021-05-27
Volume
185
Issue
8
Pages
2417-2433
ISSN
  • 1552-4825 (ISSN-L)
  • 1552-4833
DOI
10.1002/ajmg.a.62347
PMC
PMC8361973
OpenAlex
W3165039645
Cited by
20
References
51
Citations by year
2026: 1 · 2025: 7 · 2024: 3 · 2023: 4 · 2022: 3 · 2021: 2
FWCI
0.94
Type
journal article
Language
en
Open access
Licence
Locations
  • American Journal of Medical Genetics Part A (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, cc-by-nc)
Funders
  • National Institute on Deafness and Other Communication Disorders (DC002842, DC012049)
  • National Science Foundation (NSF1744557)
  • NIH Office of the Director (U01HG007672)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › dental development and anomalies
  • Life Sciences › Neuroscience › Sensory Systems › Hearing, Cochlea, Tinnitus, Genetics
  • Health Sciences › Medicine › Urology › Hair Growth and Disorders
Keywords
biallelic loss-of-function variants, ectodermal dysplasia, tooth agenesis, non-syndromic hearing loss, genotype-phenotype correlation, TMPRSS3, GJB2, GJB6
MeSH terms
Alleles, Anodontia, Ectodermal Dysplasia, Female, Humans, Male, Mutation, Pedigree, Phenotype, Proteins, Radiography, Genetic Variation, Cohort Studies, Amino Acid Substitution, Genetic Loci, Genetic Association Studies

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