Missense and truncating variants in CHD5 in a dominant neurodevelopmental disorder with intellectual disability, behavioral disturbances, and epilepsy PMID: 33944996

RQC and Longevity Regulation

2026-09-03

Missense and truncating variants in CHD5 in a dominant neurodevelopmental disorder with intellectual disability, behavioral disturbances, and epilepsy

Hum Genet. 2021 Jul;140(7):1109-1120. doi: 10.1007/s00439-021-02283-2.

Ilaria Parenti ^# ¹ , Daphné Lehalle ^# ² , Caroline Nava ³ , Erin Torti ⁴ , Elsa Leitão ¹ , Richard Person ⁴ , Takeshi Mizuguchi ⁵ , Naomichi Matsumoto ⁵ , Mitsuhiro Kato ⁶ , Kazuyuki Nakamura ⁷ , Stella A de Man ⁸ , Heidi Cope ⁹ , Vandana Shashi ⁹ , Undiagnosed Diseases Network , Jennifer Friedman ¹⁰ , Pascal Joset ¹¹ ¹² , Katharina Steindl ¹¹ ¹² , Anita Rauch ¹¹ ¹² , Irena Muffels ¹³ , Peter M van Hasselt ¹³ , Florence Petit ¹⁴ , Thomas Smol ¹⁵ , Gwenaël Le Guyader ¹⁶ ¹⁷ , Frédéric Bilan ¹⁶ ¹⁷ , Arthur Sorlin ¹⁸ ¹⁹ ²⁰ , Antonio Vitobello ¹⁸ ¹⁹ , Christophe Philippe ¹⁸ ¹⁹ , Ingrid M B H van de Laar ²¹ , Marjon A van Slegtenhorst ²¹ , Philippe M Campeau ²² ²³ , Ping Yee Billie Au ²⁴ , Mitsuko Nakashima ²⁵ , Hirotomo Saitsu ²⁵ , Tatsuya Yamamoto ²⁶ , Yumiko Nomura ²⁷ ²⁸ , Raymond J Louie ²⁹ , Michael J Lyons ²⁹ , Amy Dobson ²⁹ , Astrid S Plomp ³⁰ , M Mahdi Motazacker ³¹ , Frank J Kaiser ¹ , Andrew T Timberlake ³² , Sabine A Fuchs ¹³ , Christel Depienne ^# ³³ ³⁴ , Cyril Mignot ^# ³⁵ ³⁶

Affiliations

1. Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
2. Département de Génétique, Centre de Référence Déficiences Intellectuelles de Causes Rares, Groupe Hospitalier Pitié-Salpêtrière and Hôpital Trousseau, APHP, Sorbonne Université, Paris, France.
3. Institut du Cerveau (ICM), UMR S 1127, Inserm U1127, CNRS UMR 7225, Sorbonne Université, 75013, Paris, France.
4. GeneDx, Gaithersburg, MD, USA.
5. Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan.
6. Department of Pediatrics, Showa University School of Medicine, Tokyo, 142-8666, Japan.
7. Department of Pediatrics, Yamagata University Faculty of Medicine, Yamagata, 990-9585, Japan.
8. Department of Pediatrics, Amphia Hospital, Breda, The Netherlands.
9. Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Durham, NC 27710, USA.
10. Departments of Neuroscience and Pediatrics, Division of Neurology, Rady Children's Hospital, UCSD, San Diego and Rady Children's Institute for Genomic Medicine, San Diego, CA, USA.
11. Institute of Medical Genetics, University of Zurich, Schlieren, 8952, Zurich, Switzerland.
12. Rare Disease Initiative Zurich, Clinical Research Priority Program for Rare Diseases University of Zurich, 8032, Zurich, Switzerland.
13. Department of Metabolic Diseases, University Medical Centre Utrecht, Utrecht, The Netherlands.
14. Clinique de Génétique, CHU Lille, 59000, Lille, France.
15. Institut de Génétique Médicale, CHRU Lille, Université de Lille, Lille, France.
16. Service de Génétique Médicale, CHU de Poitiers, Poitiers, France.
17. EA3808 NEUVACOD, University of Poitiers, Poitiers, France.
18. Unité Fonctionnelle d'Innovation Diagnostique des Maladies Rares, FHU-TRANSLAD, France Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD), Centre Hospitalier Universitaire Dijon Bourgogne, CHU Dijon Bourgogne, Dijon, France.
19. INSERM-Université de Bourgogne UMR1231 GAD « Génétique Des Anomalies du Développement », FHU-TRANSLAD, UFR Des Sciences de Santé, Dijon, France.
20. Centre de Référence Maladies Rares «Anomalies du Développement et Syndromes Malformatifs », Centre de Génétique, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France.
21. Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
22. CHU Sainte-Justine Research Center, Montreal, QC, H3T 1C5, Canada.
23. Sainte-Justine Hospital, University of Montreal, Montreal, QC, H3T 1C5, Canada.
24. Department of Medical Genetics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N 4N1, Canada.
25. Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, 431-3192, Japan.
26. Department of Pediatrics, Hirosaki University Graduate School of Medicine and School of Medicine, Hirosaki, 036-8562, Japan.
27. Department of Pediatrics, Hirosaki National Hospital, Hirosaki, 036-8545, Japan.
28. Aomori City Health Center, Aomori, 030-0962, Japan.
29. Greenwood Genetic Center, Greenwood, SC, 29646, USA.
30. Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
31. Laboratory of Genome Diagnostics, Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
32. Hansjörg Wyss Department of Plastic Surgery, NYU Langone Health, New York, NY, USA.
33. Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany. [email protected].
34. Institut du Cerveau (ICM), UMR S 1127, Inserm U1127, CNRS UMR 7225, Sorbonne Université, 75013, Paris, France. [email protected].
35. Département de Génétique, Centre de Référence Déficiences Intellectuelles de Causes Rares, Groupe Hospitalier Pitié-Salpêtrière and Hôpital Trousseau, APHP, Sorbonne Université, Paris, France. [email protected].
36. Institut du Cerveau (ICM), UMR S 1127, Inserm U1127, CNRS UMR 7225, Sorbonne Université, 75013, Paris, France. [email protected].
# Contributed equally.

Abstract

Located in the critical 1p36 microdeletion region, the chromodomain helicase DNA-binding protein 5 (CHD5) gene encodes a subunit of the nucleosome remodeling and deacetylation (NuRD) complex required for neuronal development. Pathogenic variants in six of nine chromodomain (CHD) genes cause autosomal dominant neurodevelopmental disorders, while CHD5-related disorders are still unknown. Thanks to GeneMatcher and international collaborations, we assembled a cohort of 16 unrelated individuals harboring heterozygous CHD5 variants, all identified by exome Sequencing. Twelve patients had de novo CHD5 variants, including ten missense and two splice site variants. Three familial cases had nonsense or missense variants segregating with speech delay, learning disabilities, and/or craniosynostosis. One patient carried a frameshift variant of unknown inheritance due to unavailability of the father. The most common clinical features included language deficits (81%), behavioral symptoms (69%), intellectual disability (64%), Epilepsy (62%), and motor delay (56%). Epilepsy types were variable, with West syndrome observed in three patients, generalized tonic-clonic seizures in two, and other subtypes observed in one individual each. Our findings suggest that, in line with other CHD-related disorders, heterozygous CHD5 variants are associated with a variable neurodevelopmental syndrome that includes intellectual disability with speech delay, Epilepsy, and behavioral problems as main features.