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

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.

Confirmation of a Phenotypic Entity for TSPEAR Variants in Egyptian Ectodermal Dysplasia Patients and Role of Ethnicity

“…Phenotypes associated with biallelic TSPEAR variants can be categorized into: (1) ED with or without TA (57.9%); (2) TA without other ectodermal features (e.g., isolated TA or TA with other non-ED-related features) (21.1%); (3) SNHL without ED features (18.4%); and (4) SNHL with ED, which was reported in only one patient (2.6%). Only four previously reported patients had ED without TA; however, they had conical-shaped teeth, which does not fulfill the criteria of TA; still, it suggests the involvement of teeth [ 24 ]. Clinical presentation of dysmorphic facial features showed statistically high significant dependence ( p = 0.0001) on ethnic origin.…”

“…We compared clinical phenotypes and dysmorphic facial features of our studied cohort of patients to previously published cases that were similarly identified to harbor biallelic TSPEAR disease causing variants [ 24 , 25 , 27 , 28 , 29 , 55 , 56 ]. Patients were grouped according to their reported ethnicities into: North African, Middle Eastern, European and others.…”

“…Unlike ED causative genes that have been well phenotypically and molecularly characterized, mutations of TSPEAR (OMIM#612920, located in chromosome 21q22.3), the gene encoding Thrombospondin-type laminin G domain and Epilepsy-Associated Repeats (EARs) protein, have been recently reported to cause different autosomal recessive ED phenotypes and NSTA [ 24 ]. The 669-amino-acid-long Tspear protein is predicted to harbor two protein-interacting functional domains: the N-terminal thrombospondin-like laminin G domain and the C-terminal-seven EARs domain [ 25 , 26 ].…”

“…However, subsequent reports identified the same TSPEAR (c.1726_1728delGTCinsTT; p.(Val576Leufs*38)) variant in three patients: two ED patients and one NSTA patient all presented with normal hearing [ 27 , 28 , 29 ]. Among a total of 22 previously reported unrelated families with probands harboring biallelic TSPEAR disease-causing variants, the majority of TSPEAR associated phenotypes fall within ED or TA spectra [ 24 , 29 ].…”

Ectodermal Dysplasia: A Case Report

“…The pathogenesis of ectodermal dysplasia and the molecular basis of many of these disorders are still unknown [ 3 ]. Recent reports have shown that loss-of-function variants within the thrombospondin-type laminin G domain and epilepsy-associated repeats (TSPEAR) gene have recently been related to ectodermal dysplasia [ 4 ]. TSPEAR mutations or down-regulation resulted in altered expression of genes known to be regulated by the NOTCH signaling pathway and to be involved in murine hair and tooth development.…”