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

Sonja Neuser¹, Barbara Brechmann^{2

3}, Gali Heimer^{4

5}, Ines Brösse³, Susanna Schubert¹, Lauren O'Grady⁶, Michael Zech^{7

8}, Siddharth Srivastava², David A Sweetser⁶, Yasemin Dincer^{9

10}, Volker Mall^{9

11}, Juliane Winkelmann^{7

8

12

13}, Christian Behrends¹³, Basil T Darras¹⁴, Robert J Graham¹⁵, Parul Jayakar¹⁶, Barry Byrne¹⁷, Bat El Bar-Aluma^{4

5}, Yael Haberman^{4

5

18}, Amir Szeinberg^{4

5}, Hesham M Aldhalaan¹⁹, Mais Hashem¹⁹, Amal Al Tenaiji²⁰, Omar Ismayl²⁰, Asma E Al Nuaimi²⁰, Karima Maher²⁰, Shahnaz Ibrahim²¹, Fatima Khan²¹, Henry Houlden²², Vijayalakshmi S Ramakumaran²³, Alistair T Pagnamenta²⁴, Jennifer E Posey²⁵, James R Lupski^{25

26

27

28}, Wen-Hann Tan²⁹, Gehad ElGhazali²⁰, Isabella Herman^{25

27

30}, Tatiana Muñoz³¹, Gabriela M Repetto³¹, Angelika Seitz³², Mandy Krumbiegel³³, Maria Cecilia Poli^{26

31}, Usha Kini²³, Stephanie Efthymiou²², Jens Meiler^{34

35}, Reza Maroofian²², Fowzan S Alkuraya^{19

36}, Rami Abou Jamra¹, Bernt Popp¹, Bruria Ben-Zeev^{4

5}, Darius Ebrahimi-Fakhari²

Affiliations

¹ Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
² Department of Neurology, The F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
³ Department of Pediatrics, Hospital for Children and Adolescents, Heidelberg University Hospital, Heidelberg, Germany.
⁴ Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel.
⁵ Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
⁶ Department of Pediatrics, Division of Medical Genetics and Metabolism, Massachusetts General Hospital, Boston, Massachusetts, USA.
⁷ Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany.
⁸ Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
⁹ Lehrstuhl für Sozialpädiatrie, Department of Pediatrics, Technische Universität München, Germany.
¹⁰ Zentrum für Humangenetik und Laboratoriumsdiagnostik (MVZ), Martinsried, Germany.
¹¹ kbo-Kinderzentrum München, Munich, Germany.
¹² Lehrstuhl für Neurogenetik, Technische Universität München, Munich, Germany.
¹³ Munich Cluster for Systems Neurology (Synergy), Ludwig-Maximilians-Universität München, Munich, Germany.
¹⁴ Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
¹⁵ Department of Anesthesia, Critical Care and Pain Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
¹⁶ Nicklaus Children's Hospital, Miami, Florida, USA.
¹⁷ Powell Gene Therapy Center, University of Florida, Gainesville, Florida, USA.
¹⁸ Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
¹⁹ Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
²⁰ Sheikh Khalifa Medical City, Abu Dhabi, United Arab Emirates.
²¹ Department of Paediatrics and Child Health, Aga Khan University Hospital, Karachi, Pakistan.
²² Department of Neuromuscular Disorders, Queen Square Institute of Neurology, University College London, London, UK.
²³ Oxford Centre for Genomic Medicine, Oxford, UK.
²⁴ NIHR Biomedical Research Centre, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
²⁵ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
²⁶ Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
²⁷ Texas Children's Hospital, Houston, Texas, USA.
²⁸ Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
²⁹ Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts, USA.
³⁰ Department of Pediatrics, Section of Pediatric Neurology and Developmental Neuroscience, Baylor College of Medicine, Houston, Texas, USA.
³¹ Facultad de Medicina, Clinica Alemana Universidad del Desarrollo, Santiago, Chile.
³² Department of Diagnostic and Interventional Radiology, Heidelberg University Hospital, Heidelberg, Germany.
³³ Institute of Human Genetics, Friedrich-Alexander-Universität (FAU), Erlangen, Germany.
³⁴ Department of Chemistry, Vanderbilt University, Nashville, Tennessee, USA.
³⁵ Institute for Drug Discovery, University of Leipzig Medical Center, Leipzig, Germany.
³⁶ Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.

PMID: 33847017
DOI: 10.1002/humu.24206

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

Sonja Neuser et al. Hum Mutat. 2021 Jun.

. 2021 Jun;42(6):762-776.

doi: 10.1002/humu.24206. Epub 2021 May 11.

Authors

Affiliations

¹ Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
² Department of Neurology, The F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
³ Department of Pediatrics, Hospital for Children and Adolescents, Heidelberg University Hospital, Heidelberg, Germany.
⁴ Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel.
⁵ Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
⁶ Department of Pediatrics, Division of Medical Genetics and Metabolism, Massachusetts General Hospital, Boston, Massachusetts, USA.
⁷ Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany.
⁸ Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
⁹ Lehrstuhl für Sozialpädiatrie, Department of Pediatrics, Technische Universität München, Germany.
¹⁰ Zentrum für Humangenetik und Laboratoriumsdiagnostik (MVZ), Martinsried, Germany.
¹¹ kbo-Kinderzentrum München, Munich, Germany.
¹² Lehrstuhl für Neurogenetik, Technische Universität München, Munich, Germany.
¹³ Munich Cluster for Systems Neurology (Synergy), Ludwig-Maximilians-Universität München, Munich, Germany.
¹⁴ Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
¹⁵ Department of Anesthesia, Critical Care and Pain Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
¹⁶ Nicklaus Children's Hospital, Miami, Florida, USA.
¹⁷ Powell Gene Therapy Center, University of Florida, Gainesville, Florida, USA.
¹⁸ Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
¹⁹ Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
²⁰ Sheikh Khalifa Medical City, Abu Dhabi, United Arab Emirates.
²¹ Department of Paediatrics and Child Health, Aga Khan University Hospital, Karachi, Pakistan.
²² Department of Neuromuscular Disorders, Queen Square Institute of Neurology, University College London, London, UK.
²³ Oxford Centre for Genomic Medicine, Oxford, UK.
²⁴ NIHR Biomedical Research Centre, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
²⁵ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
²⁶ Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
²⁷ Texas Children's Hospital, Houston, Texas, USA.
²⁸ Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
²⁹ Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts, USA.
³⁰ Department of Pediatrics, Section of Pediatric Neurology and Developmental Neuroscience, Baylor College of Medicine, Houston, Texas, USA.
³¹ Facultad de Medicina, Clinica Alemana Universidad del Desarrollo, Santiago, Chile.
³² Department of Diagnostic and Interventional Radiology, Heidelberg University Hospital, Heidelberg, Germany.
³³ Institute of Human Genetics, Friedrich-Alexander-Universität (FAU), Erlangen, Germany.
³⁴ Department of Chemistry, Vanderbilt University, Nashville, Tennessee, USA.
³⁵ Institute for Drug Discovery, University of Leipzig Medical Center, Leipzig, Germany.
³⁶ Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.

PMID: 33847017
DOI: 10.1002/humu.24206

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.

Keywords: Human Phenotype Ontology; TECPR2; neurodevelopmental disorder; sensory autonomic neuropathy; spastic paraplegia.

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References

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

Affiliations

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

Authors

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Abstract

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