Compound heterozygosity for two variants in BMP5 in human skeletal dysostosis with atrioventricular septal defect.
BMP5
cardiac malformation
rare disease
skeletal dysostosis
skeletal dysplasia
Journal
Clinical genetics
ISSN: 1399-0004
Titre abrégé: Clin Genet
Pays: Denmark
ID NLM: 0253664
Informations de publication
Date de publication:
06 Sep 2024
06 Sep 2024
Historique:
revised:
23
08
2024
received:
27
06
2024
accepted:
26
08
2024
medline:
6
9
2024
pubmed:
6
9
2024
entrez:
6
9
2024
Statut:
aheadofprint
Résumé
The growth and development of the skeleton is regulated by bone morphogenetic proteins of which several are linked to genetic skeletal disorders. So far, no human skeletal malformations have been associated with variants in BMP5. Here, we report a patient with biallelic loss of function variants in BMP5 and a syndromic phenotype including skeletal dysostosis, dysmorphic features, hypermobility, laryngo-tracheo-bronchomalacia and atrioventricular septal defect. We discuss the phenotype in relation to the known tissue-specific expression of Bmp5 and similar morphological abnormalities previously reported in experimental animal models. Our findings suggest a new association between BMP5 variants and a range of developmental anomalies, involving ears, heart and skeleton, thereby increasing understanding of BMP5's role in human development.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Swedish Research Council
Organisme : Region Stockholm
Organisme : Stiftelsen Promobilia
Organisme : Stiftelsen Frimurare
Organisme : Stiftelsen Sällskapet Barnavård
Organisme : Karolinska Institutet
Informations de copyright
© 2024 The Author(s). Clinical Genetics published by John Wiley & Sons Ltd.
Références
Kawabata M, Imamura T, Miyazono K. Signal transduction by bone morphogenetic proteins. Cytokine Growth Factor Rev. 1998;9(1):49‐61.
Urist MR. Bone: formation by autoinduction. Science. 1965;150(3698):893‐899.
Wang RN, Green J, Wang Z, et al. Bone morphogenetic protein (BMP) signaling in development and human diseases. Genes Dis. 2014;1(1):87‐105.
Wu M, Wu S, Chen W, Li YP. The roles and regulatory mechanisms of TGF‐β and BMP signaling in bone and cartilage development, homeostasis and disease. Cell Res. 2024;34(2):101‐123.
Unger S, Ferreira CR, Mortier GR, et al. Nosology of genetic skeletal disorders: 2023 revision. Am J Med Genet A. 2023;191(5):1164‐1209.
Costantini A, Guasto A, Cormier‐Daire V. TGF‐β and BMP signaling pathways in skeletal dysplasia with short and tall stature. Annu Rev Genomics Hum Genet. 2023;24:225‐253.
OMIM. Online Mendelian Inheritance in Man, O., John Hopkins University. 2024.
Kingsley DM, Bland AE, Grubber JM, et al. The mouse short ear skeletal morphogenesis locus is associated with defects in a bone morphogenetic member of the TGF beta superfamily. Cell. 1992;71(3):399‐410.
Yamagishi T, Nakajima Y, Nishimatsu SI, Nohno T, Ando K, Nakamura H. Expression of bone morphogenetic protein‐5 gene during chick heart development: possible roles in valvuloseptal endocardial cushion formation. Anat Rec. 2001;264(4):313‐316.
Liu W, Wang Q, Guo Y, Lin L, Yang Q, Jiang H. Whole‐genome sequencing identifies two novel rare mutations in BMP5 and BMP2 in monozygotic twins with microtia. J Craniofac Surg. 2022;33(2):e212‐e217.
Martin AR, Williams E, Foulger RE, et al. PanelApp crowdsources expert knowledge to establish consensus diagnostic gene panels. Nat Genet. 2019;51(11):1560‐1565.
Terkelsen T, Mikkelsen NS, Bak EN, et al. CRISPR activation to characterize splice‐altering variants in easily accessible cells. Am J Hum Genet. 2024;111(2):309‐322.
Tinggaard J, Aksglaede L, Sørensen K, et al. The 2014 Danish references from birth to 20 years for height, weight and body mass index. Acta Paediatr. 2014;103(2):214‐224.
Jaganathan K, Kyriazopoulou Panagiotopoulou S, McRae JF, et al. Predicting splicing from primary sequence with deep learning. Cell. 2019;176(3):535‐548.e24.
Zeng T, Li YI. Predicting RNA splicing from DNA sequence using Pangolin. Genome Biol. 2022;23(1):103.
Markwald RR, Mjaatvedt CH, Krug EL, Sinning AR. Inductive interactions in heart development. Role of cardiac adherons in cushion tissue formation. Ann N Y Acad Sci. 1990;588:13‐25.
Wenink AC, Gittenberger‐de Groot AC. The role of atrioventricular endocardial cushions in the septation of the heart. Int J Cardiol. 1985;8(1):25‐44.
Guenther C, Pantalena‐Filho L, Kingsley DM. Shaping skeletal growth by modular regulatory elements in the Bmp5 gene. PLoS Genet. 2008;4(12):e1000308.
King JA, Marker PC, Seung KJ, Kingsley DM. BMP5 and the molecular, skeletal, and soft‐tissue alterations in short ear mice. Dev Biol. 1994;166(1):112‐122.
Kuchinskaya E, Grigelioniene G, Hammarsjö A, et al. Extending the phenotype of BMPER‐related skeletal dysplasias to ischiospinal dysostosis. Orphanet J Rare Dis. 2016;11:1.
Braun F, Gangfuß A, Stöbe P, et al. Expansion of the mutational spectrum of BMPER leading to diaphanospondylodysostosis and description of the associated disease process. Mol Genet Genomic Med. 2021;9(12):e1767.
Snelling SJ, Hulley PA, Loughlin J. BMP5 activates multiple signaling pathways and promotes chondrogenic differentiation in the ATDC5 growth plate model. Growth Factors. 2010;28(4):268‐279.