De novo variants in H3-3A and H3-3B are associated with neurodevelopmental delay, dysmorphic features, and structural brain abnormalities

Volkan Okur; Zefu Chen; Liesbeth Vossaert; Sandra Peacock; Jill Rosenfeld; Lina Zhao; Haowei Du; Emily Calamaro; Amanda Gerard; Sen Zhao; Jill Kelsay; Ashley Lahr; Chloe Mighton; Hillary M Porter; Amy Siemon; Josh Silver; Shayna Svihovec; Chin-To Fong; Christina L Grant; Jordan Lerner-Ellis; Kandamurugu Manickam; Suneeta Madan-Khetarpal; Shawn E McCandless; Chantal F Morel; G Bradley Schaefer; Elizabeth M Berry-Kravis; Ryan Gates; Natalia Gomez-Ospina; Guixing Qiu; Terry Jianguo Zhang; Zhihong Wu; Linyan Meng; Pengfei Liu; Daryl A Scott; James R Lupski; Christine M Eng; Nan Wu; Bo Yuan

doi:10.1038/s41525-021-00268-8

De novo variants in H3-3A and H3-3B are associated with neurodevelopmental delay, dysmorphic features, and structural brain abnormalities

NPJ Genom Med. 2021 Dec 7;6(1):104. doi: 10.1038/s41525-021-00268-8.

Authors

Volkan Okur^#^{1

2}, Zefu Chen^#^{3

4}, Liesbeth Vossaert^{1

2}, Sandra Peacock^{1

2}, Jill Rosenfeld¹, Lina Zhao^{3

5}, Haowei Du¹, Emily Calamaro⁶, Amanda Gerard^{1

7}, Sen Zhao^{3

5}, Jill Kelsay⁸, Ashley Lahr⁹, Chloe Mighton^{10

11

12

13}, Hillary M Porter¹⁴, Amy Siemon¹⁵, Josh Silver^{16

17}, Shayna Svihovec¹⁸, Chin-To Fong⁶, Christina L Grant¹⁴, Jordan Lerner-Ellis^{12

13

19}, Kandamurugu Manickam¹⁵, Suneeta Madan-Khetarpal⁹, Shawn E McCandless¹⁸, Chantal F Morel^{16

20}, G Bradley Schaefer⁸, Elizabeth M Berry-Kravis²¹, Ryan Gates²², Natalia Gomez-Ospina²², Guixing Qiu³, Terry Jianguo Zhang³, Zhihong Wu^{3

5}, Linyan Meng^{1

2}, Pengfei Liu^{1

2}, Daryl A Scott^{1

7}, James R Lupski^{1

7

23

24}, Christine M Eng², Nan Wu²⁵, Bo Yuan^{26

27

28

29}

Affiliations

¹ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
² Baylor Genetics Laboratories, Houston, TX, 77021, USA.
³ Department of Orthopedic Surgery, Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Key Laboratory of Big Data for Spinal Deformities, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, 100730, Beijing, China.
⁴ Graduate School of Peking Union Medical College, 100005, Beijing, China.
⁵ Medical Research Center, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, 100730, Beijing, China.
⁶ Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, NY, 14642, USA.
⁷ Texas Children's Hospital, Houston, TX, 77030, USA.
⁸ Section of Genetics and Metabolism, University of Arkansas for Medical Sciences, Little Rock, AR, 72701, USA.
⁹ Department of Medical Genetics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, 15224, USA.
¹⁰ Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, M5T 3M6, Canada.
¹¹ Li Ka Shing Knowledge Institute, St. Michael's Hospital, Unity Health Toronto, Toronto, ON, M5B 1A6, Canada.
¹² Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Sinai Health, Toronto, ON, M5G 1X5, Canada.
¹³ Lunenfeld-Tanenbaum Research Institute, Sinai Health, Toronto, ON, M5G 1X5, Canada.
¹⁴ Rare Disease Institute, Children's National Hospital, Washington, DC, 20010, USA.
¹⁵ Nationwide Children's Hospital (NCH) and The Ohio State University College of Medicine Section of Genetic and Genomic Medicine, Columbus, OH, 43205, USA.
¹⁶ The Fred A. Litwin Family Centre in Genetic Medicine, University Health Network and Mount Sinai Hospital, Toronto, ON, M5T 3L9, Canada.
¹⁷ Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada.
¹⁸ Department of Pediatrics, University of Colorado Anschutz Medical Campus, and Children's Hospital Colorado, Aurora, CO, 80045, USA.
¹⁹ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, M5S 1A8, Canada.
²⁰ Department of Medicine, University of Toronto, Toronto, ON, M5S 1A8, Canada.
²¹ Departments of Pediatrics, Neurological Sciences, and Biochemistry, Rush University Medical Center, Chicago, IL, 60612, USA.
²² Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, 94305, USA.
²³ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA.
²⁴ Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA.
²⁵ Department of Orthopedic Surgery, Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Key Laboratory of Big Data for Spinal Deformities, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, 100730, Beijing, China. dr.wunan@pumch.cn.
²⁶ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA. Bo.Yuan@seattlechildrens.org.
²⁷ Baylor Genetics Laboratories, Houston, TX, 77021, USA. Bo.Yuan@seattlechildrens.org.
²⁸ Seattle Children's Hospital, Seattle, WA, 98105, USA. Bo.Yuan@seattlechildrens.org.
²⁹ Department of Laboratory Medicine and Pathology, University of Washington, Seattle, UW, 98105, USA. Bo.Yuan@seattlechildrens.org.

^# Contributed equally.

Abstract

The histone H3 variant H3.3, encoded by two genes H3-3A and H3-3B, can replace canonical isoforms H3.1 and H3.2. H3.3 is important in chromatin compaction, early embryonic development, and lineage commitment. The role of H3.3 in somatic cancers has been studied extensively, but its association with a congenital disorder has emerged just recently. Here we report eleven de novo missense variants and one de novo stop-loss variant in H3-3A (n = 6) and H3-3B (n = 6) from Baylor Genetics exome cohort (n = 11) and Matchmaker Exchange (n = 1), of which detailed phenotyping was conducted for 10 individuals (H3-3A = 4 and H3-3B = 6) that showed major phenotypes including global developmental delay, short stature, failure to thrive, dysmorphic facial features, structural brain abnormalities, hypotonia, and visual impairment. Three variant constructs (p.R129H, p.M121I, and p.I52N) showed significant decrease in protein expression, while one variant (p.R41C) accumulated at greater levels than wild-type control. One H3.3 variant construct (p.R129H) was found to have stronger interaction with the chaperone death domain-associated protein 6.

Abstract

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