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. 2021 Aug;185(8):2417-2433.
doi: 10.1002/ajmg.a.62347. Epub 2021 May 27.

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

Bradley Bowles  1 , Alejandro Ferrer  1 , Carla J Nishimura  2 , Filippo Pinto E Vairo  1   3 , Tristan Rey  4   5   6 , Bruno Leheup  7 , Jennifer Sullivan  8 , Kelly Schoch  8 , Nicholas Stong  9   10 , Emanuele Agolini  11 , Dario Cocciadiferro  11 , Abigail Williams  12 , Alex Cummings  12   13 , Sara Loddo  11 , Silvia Genovese  11 , Chelsea Roadhouse  14 , Kirsty McWalter  15 ; Undiagnosed Diseases Network; Ingrid M Wentzensen  15 , Chumei Li  14 , Dusica Babovic-Vuksanovic  1   3 , Brendan C Lanpher  1   3 , Maria Lisa Dentici  16 , Arun Ankala  17   18 , J Austin Hamm  12 , Bruno Dallapiccola  16 , Francesca Clementina Radio  16 , Vandana Shashi  8 , Benedicte Gérard  5 , Agnes Bloch-Zupan  4   19   6 , Richard J Smith  2 , Eric W Klee  1
Affiliations

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

Bradley Bowles et al. Am J Med Genet A. 2021 Aug.

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.

Keywords: TSPEAR; autosomal recessive deafness; ectodermal dysplasia; hearing loss; tooth agenesis.

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Conflict of interest statement

IMW and KMc are employees of GeneDx, Inc.

Figures

FIGURE 1
FIGURE 1
Representative oligodontia phenotypes for TSPEAR cohort subjects. Eighteen of the cohort subjects detailed in this article presented with tooth agenesis, which varied in severity from hypodontia to oligodontia, while a subset of study individuals presented with additional features such as taurodontism and conical teeth. (a) Orthopantomographs for cohort subject 15 show the absence of 19 permanent teeth and cone‐shaped canines that are characteristic of a subset of TSPEAR subjects detailed in this report. (b) The subject presented at 11 years of age and was born to unaffected, nonconsanguineous parents of Peruvian ancestry. Sequencing indicates that the subject is homozygous for c.1505delA (p.Lys502Argfs*67) variants. (c) The identified deletion is located in exon 9 within the epilepsy‐associated repeat (EAR) protein motif. (d) Orthopantomographs for cohort subject 17 show oligodontia with agenesis of 12, 13, 22, 23, 31, 32, 33, 41, 42, 43, as well as taurodontism of 16 and 26. (e) The subject was born to unaffected parents of European ancestry and presented for sequencing at age 9 with oligodontia, eczema, dry skin, and taurodontism. Sequencing identified two missense variants, c.1915G>A (p.Asp639Asn) and c.1331G>A (p.Arg444Gln). (f) These variants fall within exons 8 and 12, both of which form EAR protein motifs. (g) Orthopantomographs for cohort subject 18 show oligontia with agenesis of teeth 12, 13, 14, 17, 18, 22, 23, 24, 27, 28, 31, 32, 33, 34, 38, 41, 42, 43, 44, and 48. (h) The subject was born to unaffected parents of European ancestry and presented for sequencing at age 18 with tooth agenesis and scoliosis. Sequencing indicated the subject is heterozygous for two c.1633C>T and c.1899dup variants. (i) These variants are located within exons 10 and 12 and occur within EAR protein motifs. del, deletion; dup, duplication [Color figure can be viewed at wileyonlinelibrary.com]
FIGURE 2
FIGURE 2
Variant location and gene structure. All variants associated with tooth agenesis or ectodermal dysplasia (with and without tooth agenesis, black) and variants associated with hearing loss (red) were mapped to their location within the NM_144991.2 TSPEAR transcript to provide an indication of exons or protein motifs that may be intolerant to variation. Newly reported variants are shown above the diagram, while previously reported variants are shown below the diagram. Large gene deletions are not shown. The c.1726_1728delGTCinsTT variant (p.Val576Leufs*38) in exon 10 has been separately reported in association with both hearing loss and ectodermal dysplasia. TSPEAR contains a laminin G structural domain and seven epilepsy‐associated repeat (EAR) domains which may mediate protein–protein interactions; both domains are indicated below the gene diagram. EAR, epilepsy‐associated repeat; del, deletion; dup, duplication [Color figure can be viewed at wileyonlinelibrary.com]
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