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Palmer EE, Whitton C, Hashem MO, et al. CHEDDA syndrome is an underrecognized neurodevelopmental disorder with a highly restricted ATN1 mutation spectrum. Clin Genet. 2021;100(4):468-477doi: 10.1111/cge.14022.
Palmer, E. E., Whitton, C., Hashem, M. O., Clark, R. D., Ramanathan, S., Starr, L. J., Velasco, D., De Dios, J. K., Singh, E., Cormier-Daire, V., Chopra, M., Rodan, L. H., Nellaker, C., Lakhani, S., Mallack, E. J., Panzer, K., Sidhu, A., Wentzensen, I. M., Lacombe, D., Michaud, V., & Alkuraya, F. S. (2021). CHEDDA syndrome is an underrecognized neurodevelopmental disorder with a highly restricted ATN1 mutation spectrum. Clinical genetics, 100(4), 468-477. https://doi.org/10.1111/cge.14022
Palmer, Elizabeth E, et al. "CHEDDA syndrome is an underrecognized neurodevelopmental disorder with a highly restricted ATN1 mutation spectrum." Clinical genetics vol. 100,4 (2021): 468-477. doi: https://doi.org/10.1111/cge.14022
Palmer EE, Whitton C, Hashem MO, Clark RD, Ramanathan S, Starr LJ, Velasco D, De Dios JK, Singh E, Cormier-Daire V, Chopra M, Rodan LH, Nellaker C, Lakhani S, Mallack EJ, Panzer K, Sidhu A, Wentzensen IM, Lacombe D, Michaud V, Alkuraya FS. CHEDDA syndrome is an underrecognized neurodevelopmental disorder with a highly restricted ATN1 mutation spectrum. Clin Genet. 2021 Oct;100(4):468-477. doi: 10.1111/cge.14022. Epub 2021 Jul 13. PMID: 34212383.
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Clin Genet. 2021 Oct;100(4):468-477. doi: 10.1111/cge.14022. Epub 2021 Jul 13.

CHEDDA syndrome is an underrecognized neurodevelopmental disorder with a highly restricted ATN1 mutation spectrum.

Clinical genetics

Elizabeth E Palmer, Chloe Whitton, Mais O Hashem, Robin D Clark, Subhadra Ramanathan, Lois J Starr, Danita Velasco, John Karl De Dios, Emily Singh, Valerie Cormier-Daire, Maya Chopra, Lance H Rodan, Christoffer Nellaker, Shenela Lakhani, Eric J Mallack, Karin Panzer, Alpa Sidhu, Ingrid M Wentzensen, Didier Lacombe, Vincent Michaud, Fowzan S Alkuraya

Affiliations

  1. Centre for Clinical Genetics, Sydney Children's Hospital, Randwick, New South Wales, Australia.
  2. School of Women's and Children's Health, University of New South Wales, Randwick, New South Wales, Australia.
  3. Faculty of Medicine, University of New South Wales, Randwick, New South Wales, Australia.
  4. Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
  5. Division of Medical Genetics, Department of Pediatrics, Loma Linda University School of Medicine, Loma Linda, CA, USA.
  6. Division of Medical Genetics, Department of Pediatrics, University of Nebraska Medical Center, Omaha, Nebraska, USA, Omaha, Nebraska, USA.
  7. Division of Medical Genetics, Department of Pediatrics, Dayton Children's Hospital, Dayton, Ohio, USA.
  8. Division of Genetics, Medical College of Wisconsin with Children's Wisconsin, Milwaukee, Wisconsin, USA.
  9. Service de Génétique Clinique, INSERM UMR 1163, Hôpital Necker-Enfants Malades, Institut IMAGINE, Université de Paris, Paris, France.
  10. Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Boston, Massachusetts, USA.
  11. Department of Neurology, Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts, USA.
  12. Nuffield Department of Women's and Reproductive Health, University of Oxford, Women's Centre, John Radcliffe Hospital, Oxford, UK.
  13. Institute of Biomedical Engineering, Department of Engineering Science, University of Oxford, Oxford, UK.
  14. Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK.
  15. Centre for Neurogenetics, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA.
  16. Department of Pediatrics, University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA.
  17. GeneDx, Gaithersburg, Maryland, USA.
  18. Service de Génétique Médicale, Centre de Référence Anomalies du Développement et Syndromes Malformatifs, CHU de Bordeaux, Bordeaux, France.
  19. Maladies Rares, Génétique et Métabolisme (MRGM), U 1211 INSERM/Université de Bordeaux, Bordeaux, France.

PMID: 34212383 DOI: 10.1111/cge.14022

Abstract

We describe the clinical features of nine unrelated individuals with rare de novo missense or in-frame deletions/duplications within the "HX motif" of exon 7 of ATN1. We previously proposed that individuals with such variants should be considered as being affected by the syndromic condition of congenital hypotonia, epilepsy, developmental delay, and digital anomalies (CHEDDA), distinct from dentatorubral-pallidoluysian atrophy (DRPLA) secondary to expansion variants in exon 5 of ATN1. We confirm that the universal phenotypic features of CHEDDA are distinctive facial features and global developmental delay. Infantile hypotonia and minor hand and feet differences are common and can present as arthrogryposis. Common comorbidities include severe feeding difficulties, often requiring gastrostomy support, as well as visual and hearing impairments. Epilepsy and congenital malformations of the brain, heart, and genitourinary systems are frequent but not universal. Our study confirms the clinical entity of CHEDDA secondary to a mutational signature restricted to exon 7 of ATN1. We propose a clinical schedule for assessment upon diagnosis, surveillance, and early intervention including the potential of neuroimaging for prognostication.

© 2021 John Wiley & Sons A/S . Published by John Wiley & Sons Ltd.

Keywords: arthrogryposis; developmental delay; genetics; genomics; intellectual disability; neurodevelopmental disorder; rare diseases

References

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