Clinical, neuroimaging, and molecular spectrum of TECPR2‐associated hereditary sensory and autonomic neuropathy with intellectual disability

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dc.contributor.authorNeuser, Sonja
dc.contributor.authorBrechmann, Barbara
dc.contributor.authorHeimer, Gali
dc.contributor.authorBrösse, Ines
dc.contributor.authorSchubert, Susanna
dc.contributor.authorO'Grady, Lauren
dc.contributor.authorZech, Michael
dc.contributor.authorSrivastava, Siddharth
dc.contributor.authorSweetser, David A.
dc.contributor.authorDincer, Yasemin
dc.contributor.authorMall, Volker
dc.contributor.authorWinkelmann, Juliane
dc.contributor.authorBehrends, Christian
dc.contributor.authorDarras, Basil T.
dc.contributor.authorGraham, Robert J.
dc.contributor.authorJayakar, Parul
dc.contributor.authorByrne, Barry
dc.contributor.authorBar‐Aluma, Bat El
dc.contributor.authorHaberman, Yael
dc.contributor.authorSzeinberg, Amir
dc.contributor.authorAldhalaan, Hesham M.
dc.contributor.authorHashem, Mais
dc.contributor.authorTenaiji, Amal Al
dc.contributor.authorIsmayl, Omar
dc.contributor.authorAl Nuaimi, Asma E.
dc.contributor.authorMaher, Karima
dc.contributor.authorIbrahim, Shahnaz
dc.contributor.authorKhan, Fatima
dc.contributor.authorHoulden, Henry
dc.contributor.authorRamakumaran, Vijayalakshmi S.
dc.contributor.authorPagnamenta, Alistair T.
dc.contributor.authorPosey, Jennifer E.
dc.contributor.authorLupski, James R.
dc.contributor.authorTan, Wen‐Hann
dc.contributor.authorElGhazali, Gehad
dc.contributor.authorHerman, Isabella
dc.contributor.authorMuñoz, Tatiana
dc.contributor.authorRepetto, Gabriela
dc.contributor.authorSeitz, Angelika
dc.contributor.authorKrumbiegel, Mandy
dc.contributor.authorPoli, Cecilia
dc.contributor.authorKini, Usha
dc.contributor.authorEfthymiou, Stephanie
dc.contributor.authorMeiler, Jens
dc.contributor.authorMaroofian, Reza
dc.contributor.authorAlkuraya, Fowzan S.
dc.contributor.authorJamra, Rami Abou
dc.contributor.authorPopp, Bernt
dc.contributor.authorBen‐Zeev, Bruria
dc.contributor.authorEbrahimi‐Fakhari, Darius
dc.date.accessioned2021-12-28T17:06:09Z
dc.date.available2021-12-28T17:06:09Z
dc.date.issued2021
dc.description.abstractBi‐allelic TECPR2 variants have been associated with a complex syndrome with features of both a neurodevelopmental and neurodegenerative disorder. Here, we provide a comprehensive clinical description and variant interpretation framework for this genetic locus. Through international collaboration, we identified 17 individuals from 15 families with bi‐allelic TECPR2‐variants. We systemically reviewed clinical and molecular data from this cohort and 11 cases previously reported. Phenotypes were standardized using Human Phenotype Ontology terms. A cross‐ sectional analysis revealed global developmental delay/intellectual disability, muscular hypotonia, ataxia, hyporeflexia, respiratory infections, and central/nocturnal hypopnea as core manifestations. A review of brain magnetic resonance imaging scans demonstrated a thin corpus callosum in 52%. We evaluated 17 distinct variants. Missense variants in TECPR2 are predominantly located in the N‐ and C‐terminal regions containing β‐propeller repeats. Despite constituting nearly half of disease‐associated TECPR2 variants, classifying missense variants as (likely) pathogenic according to ACMG criteria remains challenging. We estimate a pathogenic variant carrier frequency of 1/1221 in the general and 1/155 in the Jewish Ashkenazi populations. Based on clinical, neuroimaging, and genetic data, we provide recommendations for variant reporting, clinical assessment, and surveillance/ treatment of individuals with TECPR2‐associated disorder. This sets the stage for future prospective natural history studies.es
dc.identifier.citationNeuser S, Brechmann B, Heimer G, Brösse I, Schubert S, O'Grady L, Zech M, Srivastava S, Sweetser DA, Dincer Y, Mall V, Winkelmann J, Behrends C, Darras BT, Graham RJ, Jayakar P, Byrne B, Bar-Aluma BE, Haberman Y, Szeinberg A, Aldhalaan HM, Hashem M, Al Tenaiji A, Ismayl O, Al Nuaimi AE, Maher K, Ibrahim S, Khan F, Houlden H, Ramakumaran VS, Pagnamenta AT, Posey JE, Lupski JR, Tan WH, ElGhazali G, Herman I, Muñoz T, Repetto GM, Seitz A, Krumbiegel M, Poli MC, Kini U, Efthymiou S, Meiler J, Maroofian R, Alkuraya FS, Abou Jamra R, Popp B, Ben-Zeev B, Ebrahimi-Fakhari D. Clinical, neuroimaging, and molecular spectrum of TECPR2-associated hereditary sensory and autonomic neuropathy with intellectual disability. Hum Mutat. 2021 Jun;42(6):762-776. doi: 10.1002/humu.24206.es
dc.identifier.urihttps://doi.org/10.1002/humu.24206es
dc.identifier.urihttp://hdl.handle.net/11447/5301
dc.language.isoenes
dc.subjectHuman Phenotype Ontologyes
dc.subjectNeurodevelopmental disorderes
dc.subjectSensory autonomic neuropathyes
dc.subjectSpastic paraplegiaes
dc.subjectTECPR2es
dc.titleClinical, neuroimaging, and molecular spectrum of TECPR2‐associated hereditary sensory and autonomic neuropathy with intellectual disabilityes
dc.typeArticlees
dcterms.sourceHuman mutationes

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