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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.

SUBMITTER: Bowles B

PROVIDER: S-EPMC8361973 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Compound heterozygous WNT10A missense variations exacerbated the tooth agenesis caused by hypohidrotic ectodermal dysplasia.

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Confirmation of a Phenotypic Entity for <i>TSPEAR</i> Variants in Egyptian Ectodermal Dysplasia Patients and Role of Ethnicity.

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| S-EPMC4167166 | biostudies-literature

Novel EDA or EDAR Mutations Identified in Patients with X-Linked Hypohidrotic Ectodermal Dysplasia or Non-Syndromic Tooth Agenesis.

Project description:Abstract: Both X-linked hypohidrotic ectodermal dysplasia (XLHED) and non-syndromic tooth agenesis (NSTA) result in symptoms of congenital tooth loss. This study investigated genetic causes in two families with XLHED and four families with NSTA. We screened for mutations of WNT10A, EDA, EDAR, EDARADD, PAX9, MSX1, AXIN2, LRP6, and WNT10B through Sanger sequencing. Whole exome sequencing was performed for the proband of NSTA Family 4. Novel mutation c.1051G>T (p.Val351Phe) and the known mutation c.467G>A (p.Arg156His) of Ectodysplasin A (EDA) were identified in families with XLHED. Novel EDA receptor (EDAR) mutation c.73C>T (p.Arg25*), known EDA mutation c.491A>C (p.Glu164Ala), and known Wnt family member 10A (WNT10A) mutations c.511C>T (p.Arg171Cys) and c.742C>T (p.Arg248*) were identified in families with NSTA. The novel EDA and EDAR mutations were predicted as being pathogenic through bioinformatics analyses and structural modeling. Two variants of WNT10A, c.374G>A (p.Arg125Lys) and c.125A>G (p.Asn42Ser), were found in patients with NSTA. The two WNT10A variants were predicted to affect the splicing of message RNA, but minigene experiments showed normal splicing of mutated minigenes. This study uncovered the genetic foundations with respect to six families with XLHED or NSTA. We identified six mutations, of which two were novel mutations of EDA and EDAR. This is the first report of a nonsense EDAR mutation leading to NSTA.

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Clinical, genetic, epidemiologic, evolutionary, and functional delineation of <i>TSPEAR</i>-related autosomal recessive ectodermal dysplasia 14.

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FGFR1 variants contributed to families with tooth agenesis.

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| S-EPMC6728545 | biostudies-literature

Rare and Common Variants Conferring Risk of Tooth Agenesis.

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| S-EPMC5958369 | biostudies-literature

WNT10A variants isolated from Japanese patients with congenital tooth agenesis.

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