{"doi":"10.1002/humu.24206","title":"Clinical, neuroimaging, and molecular spectrum of <i>TECPR2</i> ‐associated hereditary sensory and autonomic neuropathy with intellectual disability","abstract":"Bi-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.","journal":"Human Mutation","year":2021,"id":167842,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":31,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9222,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":584740,"name":"Barbara Brechmann","orcid":"0000-0003-1228-4349","position":1,"is_corresponding":false},{"id":325750,"name":"Gali Heimer","orcid":"0000-0001-6218-3170","position":2,"is_corresponding":false},{"id":559827,"name":"Ines Brösse","orcid":null,"position":3,"is_corresponding":false},{"id":584741,"name":"Susanna Schubert","orcid":"0000-0003-2299-1311","position":4,"is_corresponding":false},{"id":584742,"name":"Lauren O’Grady","orcid":"0000-0001-6721-4191","position":5,"is_corresponding":false},{"id":567695,"name":"Michael Zech","orcid":"0000-0001-8112-9153","position":6,"is_corresponding":false},{"id":371860,"name":"Siddharth Srivastava","orcid":"0000-0001-7008-1879","position":7,"is_corresponding":false},{"id":463229,"name":"David A. 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