Expanded phenotypic spectrum of neurodevelopmental and neurodegenerative disorder Bryant-Li-Bhoj syndrome with 38 additional individuals

Dana E Layo-Carris^#¹, Emily E Lubin^#^{1

2}, Annabel K Sangree^#^{1

2}, Kelly J Clark^{1

2}, Emily L Durham¹, Elizabeth M Gonzalez^{1

2}, Sarina Smith¹, Rajesh Angireddy¹, Xiao Min Wang¹, Erin Weiss¹, Annick Toutain^{3

4}, Roberto Mendoza-Londono⁵, Lucie Dupuis⁵, Nadirah Damseh⁵, Danita Velasco⁶, Irene Valenzuela^{7

8}, Marta Codina-Solà^{7

8}, Catherine Ziats⁹, Jaclyn Have⁹, Katie Clarkson¹⁰, Dora Steel¹¹, Manju Kurian¹¹, Katy Barwick¹¹, Diana Carrasco¹², Aditi I Dagli¹³, M J M Nowaczyk¹⁴, Miroslava Hančárová¹⁵, Šárka Bendová¹⁵, Darina Prchalova¹⁵, Zdeněk Sedláček¹⁵, Alica Baxová¹⁶, Catherine Bearce Nowak¹⁷, Jessica Douglas¹⁸, Wendy K Chung^{18

19}, Nicola Longo²⁰, Konrad Platzer²¹, Chiara Klöckner²¹, Luisa Averdunk²², Dagmar Wieczorek²², Ilona Krey²¹, Christiane Zweier^{23

24}, Andre Reis²³, Tugce Balci²⁵, Marleen Simon²⁶, Hester Y Kroes²⁶, Antje Wiesener²⁶, Georgia Vasileiou²⁶, Nikolaos M Marinakis²⁷, Danai Veltra²⁷, Christalena Sofocleous²⁷, Konstantina Kosma²⁷, Joanne Traeger Synodinos²⁷, Konstantinos A Voudris²⁸, Marie-Laure Vuillaume^{3

4

29}, Paul Gueguen^{3

4

29}, Nicolas Derive²⁹, Estelle Colin³⁰, Clarisse Battault³⁰, Billie Au³¹, Martin Delatycki^{32

33}, Mathew Wallis^{34

35}, Lyndon Gallacher^{32

33}, Fatma Majdoub^{36

37

38}, Noor Smal^{36

37}, Sarah Weckhuysen^{36

37

39

40

41}, An-Sofie Schoonjans^{39

42}, R Frank Kooy⁴³, Marije Meuwissen^{42

43}, Benjamin T Cocanougher⁴², Kathryn Taylor⁴⁴, Carolyn E Pizoli⁴⁴, Marie T McDonald⁴⁵, Philip James⁴⁶, Elizabeth R Roeder⁴⁷, Rebecca Littlejohn⁴⁷, Nicholas A Borja⁴⁸, Willa Thorson⁴⁸, Kristine King⁴⁹, Radka Stoeva⁵⁰, Manon Suerink⁵¹, Esther Nibbeling⁵¹, Stephanie Baskin^{47

52}, Gwenaël L E Guyader⁵³, Julie Kaplan⁵⁴, Candace Muss⁵⁴, Deanna Alexis Carere⁵⁵, Elizabeth J K Bhoj^{56

57}, Laura M Bryant^{1

58}

Affiliations

¹ Department of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
² Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
³ Service de Génétique, CHU de Tours, Tours, France.
⁴ UMR1253, iBrain, Inserm, University of Tours, Tours, France.
⁵ Division of Clinical and Metabolic Genetics, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
⁶ Children's Nebraska, University of Nebraska Medical Center, Omaha, NE, USA.
⁷ Department of Clinical and Molecular Genetics and Rare Disease Unit Hospital Vall d'Hebron, Barcelona, Spain.
⁸ Medicine Genetics Group, Vall Hebron Research Institute, Barcelona, Spain.
⁹ Shodair Children's Hospital, Helena, MT, USA.
¹⁰ Greenwood Genetic Center, Greenwood, SC, USA.
¹¹ UCL Great Ormond Street Institute of Child Health, London, UK.
¹² Department of Clinical Genetics, Cook Children's Hospital, Fort Worth, TX, USA.
¹³ Orlando Health, Arnold Palmer Hospital For Children, Orlando, FL, USA.
¹⁴ McMaster University Medical Centre, Hamilton, ON, Canada.
¹⁵ Charles University Second Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.
¹⁶ Charles University First Faculty of Medicine and General University Hospital, Prague, Czech Republic.
¹⁷ Division of Genetics and Metabolism, Massachusetts General Hospital for Children, Boston, MA, USA.
¹⁸ Harvard Medical School, Boston, MA, USA.
¹⁹ Boston Children's Hospital, Boston, MA, USA.
²⁰ University of Utah, Salt Lake City, UT, USA.
²¹ Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
²² Institute of Human Genetics, Heinrich-Heine-University Düsseldorf, Medical Faculty, Düsseldorf, Germany.
²³ Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054, Erlangen, Germany.
²⁴ Department of Human Genetics, Inselspital Bern, University of Bern, Bern, Switzerland.
²⁵ University of Western Ontario, London, ON, Canada.
²⁶ Department of Genetics, University Medical Center, Utrecht, Netherlands.
²⁷ Laboratory of Medical Genetics, St. Sophia's Children's Hospital, National and Kapodistrian University of Athens, Athens, Greece.
²⁸ Second Department of Paediatrics, University of Athens, 'P & A Kyriakou' Children's Hospital, Athens, Greece.
²⁹ Laboratoire de Biologie Médicale Multi-Sites SeqOIA, Paris, France.
³⁰ Service de Génétique Médicale, CHU d'Angers, Angers, France.
³¹ University of Calgary, Calgary, AB, Canada.
³² Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, VIC, Australia.
³³ Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia.
³⁴ Tasmanian Clinical Genetics Service, Tasmanian Health Service, Hobart, TAS, Australia.
³⁵ School of Medicine and Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia.
³⁶ Applied and Translational Neurogenomics Group, VIB Center for Molecular Neurology, Antwerp, Belgium.
³⁷ Applied and Translational Neurogenomics Group, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
³⁸ Medical Genetics Department, University Hedi Chaker Hospital of Sfax, Sfax, Tunisia.
³⁹ Department of Pediatric Neurology, University Hospital Antwerp, Antwerp, Belgium.
⁴⁰ Translational Neurosciences, Faculty of Medicine and Health Science, University of Antwerp, Antwerp, Belgium.
⁴¹ NEURO Research Centre of Excellence, University of Antwerp, Antwerp, Belgium.
⁴² Department of Pediatrics, Duke University Hospital, Durham, NC, USA.
⁴³ Center of Medical Genetics, Antwerp University Hospital/University of Antwerp, Edegem, Belgium.
⁴⁴ Division of Pediatric Neurology, Duke University Hospital, Durham, NC, USA.
⁴⁵ Division of Medical Genetics, Duke University Hospital, Durham, NC, USA.
⁴⁶ DMG Children's Rehabilitative Services, Phoenix, AZ, USA.
⁴⁷ Department of Pediatrics, Baylor College of Medicine, San Antonio, TX, USA.
⁴⁸ John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA.
⁴⁹ Genetics Department, Mary Bridge Children's Hospital, Multicare Health System, Tacoma, WA, USA.
⁵⁰ Medical genetics department, Centre Hospitalier, Le Mans, France.
⁵¹ Department of Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands.
⁵² Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
⁵³ Service de Génétique médicale, Centre Labellisé Anomalies du Développement-Ouest Site, Poitiers, France.
⁵⁴ Nemours Children's Health, Wilmington, DE, USA.
⁵⁵ GeneDx, Gaithersburg, MD, USA.
⁵⁶ Department of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA. bhoje@chop.edu.
⁵⁷ Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. bhoje@chop.edu.
⁵⁸ Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA.

^# Contributed equally.

PMID: 38678163
PMCID: PMC11291762
DOI: 10.1038/s41431-024-01610-1

Expanded phenotypic spectrum of neurodevelopmental and neurodegenerative disorder Bryant-Li-Bhoj syndrome with 38 additional individuals

Dana E Layo-Carris et al. Eur J Hum Genet. 2024 Aug.

. 2024 Aug;32(8):928-937.

doi: 10.1038/s41431-024-01610-1. Epub 2024 Apr 27.

Authors

Affiliations

¹ Department of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
² Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
³ Service de Génétique, CHU de Tours, Tours, France.
⁴ UMR1253, iBrain, Inserm, University of Tours, Tours, France.
⁵ Division of Clinical and Metabolic Genetics, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
⁶ Children's Nebraska, University of Nebraska Medical Center, Omaha, NE, USA.
⁷ Department of Clinical and Molecular Genetics and Rare Disease Unit Hospital Vall d'Hebron, Barcelona, Spain.
⁸ Medicine Genetics Group, Vall Hebron Research Institute, Barcelona, Spain.
⁹ Shodair Children's Hospital, Helena, MT, USA.
¹⁰ Greenwood Genetic Center, Greenwood, SC, USA.
¹¹ UCL Great Ormond Street Institute of Child Health, London, UK.
¹² Department of Clinical Genetics, Cook Children's Hospital, Fort Worth, TX, USA.
¹³ Orlando Health, Arnold Palmer Hospital For Children, Orlando, FL, USA.
¹⁴ McMaster University Medical Centre, Hamilton, ON, Canada.
¹⁵ Charles University Second Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.
¹⁶ Charles University First Faculty of Medicine and General University Hospital, Prague, Czech Republic.
¹⁷ Division of Genetics and Metabolism, Massachusetts General Hospital for Children, Boston, MA, USA.
¹⁸ Harvard Medical School, Boston, MA, USA.
¹⁹ Boston Children's Hospital, Boston, MA, USA.
²⁰ University of Utah, Salt Lake City, UT, USA.
²¹ Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
²² Institute of Human Genetics, Heinrich-Heine-University Düsseldorf, Medical Faculty, Düsseldorf, Germany.
²³ Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054, Erlangen, Germany.
²⁴ Department of Human Genetics, Inselspital Bern, University of Bern, Bern, Switzerland.
²⁵ University of Western Ontario, London, ON, Canada.
²⁶ Department of Genetics, University Medical Center, Utrecht, Netherlands.
²⁷ Laboratory of Medical Genetics, St. Sophia's Children's Hospital, National and Kapodistrian University of Athens, Athens, Greece.
²⁸ Second Department of Paediatrics, University of Athens, 'P & A Kyriakou' Children's Hospital, Athens, Greece.
²⁹ Laboratoire de Biologie Médicale Multi-Sites SeqOIA, Paris, France.
³⁰ Service de Génétique Médicale, CHU d'Angers, Angers, France.
³¹ University of Calgary, Calgary, AB, Canada.
³² Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, VIC, Australia.
³³ Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia.
³⁴ Tasmanian Clinical Genetics Service, Tasmanian Health Service, Hobart, TAS, Australia.
³⁵ School of Medicine and Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia.
³⁶ Applied and Translational Neurogenomics Group, VIB Center for Molecular Neurology, Antwerp, Belgium.
³⁷ Applied and Translational Neurogenomics Group, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
³⁸ Medical Genetics Department, University Hedi Chaker Hospital of Sfax, Sfax, Tunisia.
³⁹ Department of Pediatric Neurology, University Hospital Antwerp, Antwerp, Belgium.
⁴⁰ Translational Neurosciences, Faculty of Medicine and Health Science, University of Antwerp, Antwerp, Belgium.
⁴¹ NEURO Research Centre of Excellence, University of Antwerp, Antwerp, Belgium.
⁴² Department of Pediatrics, Duke University Hospital, Durham, NC, USA.
⁴³ Center of Medical Genetics, Antwerp University Hospital/University of Antwerp, Edegem, Belgium.
⁴⁴ Division of Pediatric Neurology, Duke University Hospital, Durham, NC, USA.
⁴⁵ Division of Medical Genetics, Duke University Hospital, Durham, NC, USA.
⁴⁶ DMG Children's Rehabilitative Services, Phoenix, AZ, USA.
⁴⁷ Department of Pediatrics, Baylor College of Medicine, San Antonio, TX, USA.
⁴⁸ John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA.
⁴⁹ Genetics Department, Mary Bridge Children's Hospital, Multicare Health System, Tacoma, WA, USA.
⁵⁰ Medical genetics department, Centre Hospitalier, Le Mans, France.
⁵¹ Department of Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands.
⁵² Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
⁵³ Service de Génétique médicale, Centre Labellisé Anomalies du Développement-Ouest Site, Poitiers, France.
⁵⁴ Nemours Children's Health, Wilmington, DE, USA.
⁵⁵ GeneDx, Gaithersburg, MD, USA.
⁵⁶ Department of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA. bhoje@chop.edu.
⁵⁷ Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. bhoje@chop.edu.
⁵⁸ Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA.

^# Contributed equally.

PMID: 38678163
PMCID: PMC11291762
DOI: 10.1038/s41431-024-01610-1

Erratum in

Correction: Expanded phenotypic spectrum of neurodevelopmental and neurodegenerative disorder Bryant-Li-Bhoj syndrome with 38 additional individuals.
Layo-Carris DE, Lubin EE, Sangree AK, Clark KJ, Durham EL, Gonzalez EM, Smith S, Angireddy R, Wang XM, Weiss E, Toutain A, Mendoza-Londono R, Dupuis L, Damseh N, Velasco D, Valenzuela I, Codina-Solà M, Ziats C, Have J, Clarkson K, Steel D, Kurian M, Barwick K, Carrasco D, Dagli AI, Nowaczyk MJM, Hančárová M, Bendová Š, Prchalova D, Sedláček Z, Baxová A, Nowak CB, Douglas J, Chung WK, Longo N, Platzer K, Klöckner C, Averdunk L, Wieczorek D, Krey I, Zweier C, Reis A, Balci T, Simon M, Kroes HY, Wiesener A, Vasileiou G, Marinakis NM, Veltra D, Sofocleous C, Kosma K, Synodinos JT, Voudris KA, Vuillaume ML, Gueguen P, Derive N, Colin E, Battault C, Au B, Delatycki M, Wallis M, Gallacher L, Majdoub F, Smal N, Weckhuysen S, Schoonjans AS, Kooy RF, Meuwissen M, Cocanougher BT, Taylor K, Pizoli CE, McDonald MT, James P, Roeder ER, Littlejohn R, Borja NA, Thorson W, King K, Stoeva R, Suerink M, Nibbeling E, Baskin S, Guyader GLE, Kaplan J, Muss C, Carere DA, Bhoj EJK, Bryant LM. Layo-Carris DE, et al. Eur J Hum Genet. 2024 Aug;32(8):1032. doi: 10.1038/s41431-024-01659-y. Eur J Hum Genet. 2024. PMID: 39060653 Free PMC article. No abstract available.

Abstract

Bryant-Li-Bhoj syndrome (BLBS), which became OMIM-classified in 2022 (OMIM: 619720, 619721), is caused by germline variants in the two genes that encode histone H3.3 (H3-3A/H3F3A and H3-3B/H3F3B) [1-4]. This syndrome is characterized by developmental delay/intellectual disability, craniofacial anomalies, hyper/hypotonia, and abnormal neuroimaging [1, 5]. BLBS was initially categorized as a progressive neurodegenerative syndrome caused by de novo heterozygous variants in either H3-3A or H3-3B [1-4]. Here, we analyze the data of the 58 previously published individuals along 38 unpublished, unrelated individuals. In this larger cohort of 96 people, we identify causative missense, synonymous, and stop-loss variants. We also expand upon the phenotypic characterization by elaborating on the neurodevelopmental component of BLBS. Notably, phenotypic heterogeneity was present even amongst individuals harboring the same variant. To explore the complex phenotypic variation in this expanded cohort, the relationships between syndromic phenotypes with three variables of interest were interrogated: sex, gene containing the causative variant, and variant location in the H3.3 protein. While specific genotype-phenotype correlations have not been conclusively delineated, the results presented here suggest that the location of the variants within the H3.3 protein and the affected gene (H3-3A or H3-3B) contribute more to the severity of distinct phenotypes than sex. Since these variables do not account for all BLBS phenotypic variability, these findings suggest that additional factors may play a role in modifying the phenotypes of affected individuals. Histones are poised at the interface of genetics and epigenetics, highlighting the potential role for gene-environment interactions and the importance of future research.

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Conflict of interest statement

The authors declare no competing interests.

Figures

**Fig. 1. BLBS genotype and phenotype overview.**
A 2D diagram of the genes that encode the histone H3.3 protein – *H3-3A* (top - ENST00000366815) and *H3-3B* (bottom – ENST00000254810). Green brackets and thicker boxes represent the coding sequence. Arrows represent the transcription start sites. B 2D diagram of histone H3.3 protein (green), including the location of the four alpha helices. Lollipops show the *H3-3A* derived (top) and the *H3-3B* derived (bottom) heterozygous germline variants. Length of lollipop corresponds to number of individuals who harbor a variant at that residue (e.g. *H3-3A* p.T45I represents four individuals with BLBS and H3-3A p.V46M represents one individual with BLBS). C 3D in silico structural model of the H3.3-containing nucleosome (PDB: 5X7X) with the two copies of H3.3 in green; other histones in gray; and DNA in black. The location of heterozygous germline variants in the crystallized histone core are highlighted in purple. D Circular boxplot visualizing BLBS phenotypes. Cyan = growth (height, weight and head circumference); blue = craniofacial anomalies; pink = abnormal neuroimaging findings and seizures; red = developmental milestones; yellow = tone anomalies and oculomotor features; green = review of systems.

**Fig. 2. Interrogating the relationship between BLBS phenotypes and sex, gene, and variant location in H3.3.**
Phenotypic categories (rows) analyzed across all 96 individuals with BLBS include growth; craniofacial features; neuroimaging findings and seizures; attainment of developmental milestones; tone anomalies; and general review of systems. Phenotypic analyses were performed by stratifying the cohort of individuals (columns) based on their sex (reported as male or female) (column 1); on the localization of their causative variant to either *H3-3A* or *H3-3B* (column 2); or on the location of their causative variant to the histone tail or histone core (column 3). Each graph is representative of the percentages of individuals with BLBS for which this category was reported. The colored cells highlight stratifications emphasized in the text. The color-coding is based on the phenotypic overview in Fig. 1D, where cyan = growth (height, weight and head circumference); blue = dysmorphic craniofacial features; pink = neuroimaging findings and seizures; red = developmental milestones; yellow = tone anomalies and oculomotor features; green = review of systems.

**Fig. 3. BLBS-associated phenotypic heterogeneity amongst individuals with similar genotypes.**
A–C Representation of the phenotypic variation across individuals who (A) share the same missense variant in the same residue of the same gene, (B) the same missense variant in the same residue of different genes, or (C) different missense variants affecting the same residue of different genes. The color-coding in the key corresponds to the phenotypic overview in Fig. 1D and Fig. 2. A Representation of the phenotypic variation across the four individuals who share the *H3-3A* p.T45I variant. B Representation of phenotypic variation across the eight individuals who share the H3.3 p.Q125R variant. Five individuals harbor a nucleotide substitution in *H3-3A* while three individuals harbor a nucleotide substitution in *H3-3B*. C Representation of phenotypic variation across the eight individuals who harbor variants affecting the H3.3 p.P121 residue. Four individuals harbor a nucleotide substitution in *H3-3A* (leading to either p.P121L or p.P121R missense variants) while four individuals harbor a nucleotide substitution in *H3-3B* (leading to either p.P121L or p.P121R missense variants). D Phenotypic variation across individuals with BLBS-causing germline variants throughout the disordered histone tail region and histone core (top) compared to hotspot high grade glioma-causing somatic mutations (bottom). Black = amino acids with associated germline variants; magenta = amino acids with associated germline and somatic variants; blue = amino acids with associated somatic variants.

See this image and copyright information in PMC

References

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Expanded phenotypic spectrum of neurodevelopmental and neurodegenerative disorder Bryant-Li-Bhoj syndrome with 38 additional individuals

Affiliations

Expanded phenotypic spectrum of neurodevelopmental and neurodegenerative disorder Bryant-Li-Bhoj syndrome with 38 additional individuals

Authors

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Erratum in

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Conflict of interest statement

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