Citations 2
TSPEAR variants are primarily associated with ectodermal dysplasia and tooth agenesis but not hearing loss: A novel cohort study
Bowles, Bradley , Ferrer, Alejandro , Nishimura, Carla, Rey, Tristan, Leheup, Bruno, Sullivan, Jennifer A. , Schoch, Kelly, Stong, Nicholas , Agolini, Emanuele , Cocciadiferro, Dario , Williams, Abigail , Cummings, Alex, Genovese, Silvia , Roadhouse, Chelsea, Network, Undiagnosed Diseases, Wentzensen, Ingrid M. , Li, Chumei , Babovic‐Vuksanovic, Dusica , Lanpher, Brendan C. , Dentici, Maria Lisa , Hamm, J. Austin, Shashi, Vandana , Gérard, Bénédicte , Bloch‐Zupan, Agnès , Smith, Richard J. , Klee, Eric W. , Oglesbee, Devin , McCauley, Jacob L. , Nelson, Stanley F. , Azamian, Mahshid S. , Martínez-Agosto, Julián A. , Chang, Ta Chen , Blue, Elizabeth , Woods, Jeremy D. , Baldridge, Dustin , Pinto E Vairo, Filippo, Sullivan, Jennifer , Agolini, Emanuele , Loddo, Sara , Genovese, Silvia , Li, Chumei , Babovic-Vuksanovic, Dusica, Dentici, Maria Lisa , Ankala, Arun , Radio, Francesca Clementina , Bloch-Zupan, Agnes , Oglesbee, Devin , Baldridge, Dustin , Stong, Nicholas , Ferrer, Alejandro , McCauley, Jacob L , Vairo, Filippo Pinto e , McWalter, Kirsty , Network, Undiagnosed Diseases, Dallapiccola, Bruno , Radio, Francesca Clementina
American Journal of Medical Genetics Part A | May 27, 2021 | Volume: 185 | Issue: 8 | Pages: 2417-2433
AbstractBiallelic 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.
Incorporation of Second-Tier Biomarker Testing Improves the Specificity of Newborn Screening for Mucopolysaccharidosis Type I
Peck, Dawn , Lacey, Jean M., White, Amy , Pino, Gisele , Studinski, April, Fisher, Rachel , Ahmad, Ayesha , Viall, Sarah , Shallow, Natalie, Siemon, Amy, Hamm, J. Austin, Murray, Brianna K., Jones, Kelly L. , Gavrilov, Dimitar , Oglesbee, Devin , Raymond, Kimiyo , Matern, Dietrich , Rinaldo, Piero, Tortorelli, Silvia , Price, Theodore J. , Peck, Dawn S, White, Amy L , Studinski, April L, Jones, Kelly L , Oglesbee, Devin , Price, Theodore J , Spencer, Linda J. , Murray, Brianna K.
International Journal of Neonatal Screening | February 7, 2020 | Volume: 6 | Issue: 1 | Pages: 10
Enzyme-based newborn screening for Mucopolysaccharidosis type I (MPS I) has a high false-positive rate due to the prevalence of pseudodeficiency alleles, often resulting in unnecessary and costly follow up. The glycosaminoglycans (GAGs), dermatan sulfate (DS) and heparan sulfate (HS) are both substrates for α-l-iduronidase (IDUA). These GAGs are elevated in patients with MPS I and have been shown to be promising biomarkers for both primary and second-tier testing. Since February 2016, we have measured DS and HS in 1213 specimens submitted on infants at risk for MPS I based on newborn screening. Molecular correlation was available for 157 of the tested cases. Samples from infants with MPS I confirmed by IDUA molecular analysis all had significantly elevated levels of DS and HS compared to those with confirmed pseudodeficiency and/or heterozygosity. Analysis of our testing population and correlation with molecular results identified few discrepant outcomes and uncovered no evidence of false-negative cases. We have demonstrated that blood spot GAGs analysis accurately discriminates between patients with confirmed MPS I and false-positive cases due to pseudodeficiency or heterozygosity and increases the specificity of newborn screening for MPS I.