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TSPEAR variants are primarily associated with ectodermal dysplasia and tooth agenesis but not hearing loss: A novel cohort study
Author(s) -
Bowles Bradley,
Ferrer Alejandro,
Nishimura Carla J.,
Pinto e Vairo Filippo,
Rey Tristan,
Leheup Bruno,
Sullivan Jennifer,
Schoch Kelly,
Stong Nicholas,
Agolini Emanuele,
Cocciadiferro Dario,
Williams Abigail,
Cummings Alex,
Loddo Sara,
Genovese Silvia,
Roadhouse Chelsea,
McWalter Kirsty,
Wentzensen Ingrid M.,
Li Chumei,
BabovicVuksanovic Dusica,
Lanpher Brendan C.,
Dentici Maria Lisa,
Ankala Arun,
Hamm J. Austin,
Dallapiccola Bruno,
Radio Francesca Clementina,
Shashi Vandana,
Gérard Benedicte,
BlochZupan Agnes,
Smith Richard J.,
Klee Eric W.
Publication year - 2021
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.62347
Subject(s) - ectodermal dysplasia , hearing loss , phenotype , loss function , genetics , congenital hearing loss , exome sequencing , sensorineural hearing loss , biology , agenesis , tooth loss , audiology , medicine , gene , dentistry , oral health
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.