Skeletal Abnormalities, Pediatric-onset Severe Osteoporosis, and Multiple Fragility Fractures in a Patient with a Novel Variant

Overview

Journal Bone Rep

Date 2024 Jul 2

PMID 38952406

Authors

Olga Lesnyak

Francesca Marini

Polina Sokolnikova

Margarita Sorokina

Kseniya Sukhareva

Irina Artamonova

Vladimir Kenis

Olga Tkach

Anna Kostareva

Maria Luisa Brandi

Affiliations

Soon will be listed here.

Abstract

We report a case of a patient with a germline heterozygous truncating variant of gene (c.2172del, p.Tyr724Ter) causing neurodevelopmental disorder with spastic diplegia and visual defects syndrome (NEDSDV) associated with a new clinical feature - severe pediatric-onset osteoporosis and multiple fractures. A functional effect of the identified variant was demonstrated using adipose-tissue derived primary mesenchymal stem cells, where we detected the alteration of mRNA and β-catenin protein levels using real-time PCR and Western blot analysis.

References

Damerla R, Cui C, Gabriel G, Liu X, Craige B, Gibbs B . Novel Jbts17 mutant mouse model of Joubert syndrome with cilia transition zone defects and cerebellar and other ciliopathy related anomalies. Hum Mol Genet. 2015; 24(14):3994-4005. PMC: 4476446. DOI: 10.1093/hmg/ddv137. View

Vidal C, Galea R, Brincat M, Anastasi A . Linkage to chromosome 11p12 in two Maltese families with a highly penetrant form of osteoporosis. Eur J Hum Genet. 2007; 15(7):800-9. DOI: 10.1038/sj.ejhg.5201814. View

Mirosevic S, Khandelwal S, Susjan P, Zakelj N, Gosar D, Forstneric V . Correlation between Phenotype and Genotype in CTNNB1 Syndrome: A Systematic Review of the Literature. Int J Mol Sci. 2022; 23(20). PMC: 9604177. DOI: 10.3390/ijms232012564. View

Kuechler A, Willemsen M, Albrecht B, Bacino C, Bartholomew D, van Bokhoven H . De novo mutations in beta-catenin (CTNNB1) appear to be a frequent cause of intellectual disability: expanding the mutational and clinical spectrum. Hum Genet. 2014; 134(1):97-109. DOI: 10.1007/s00439-014-1498-1. View

Hasan L, Aljabban J, Rohr M, Mukhtar M, Adapa N, Salim R . Metaanalysis Reveals Genetic Correlates of Osteoporosis Pathogenesis. J Rheumatol. 2020; 48(6):940-945. PMC: 10298833. DOI: 10.3899/jrheum.200951. View

Verhoeven W, Egger J, Jongbloed R, van Putten M, de Bruin-van Zandwijk M, Zwemer A . A de novo Novel Splice Variant in an Adult Female with Severe Intellectual Disability. Int Med Case Rep J. 2020; 13:487-492. PMC: 7548236. DOI: 10.2147/IMCRJ.S270487. View

Koboldt D . Best practices for variant calling in clinical sequencing. Genome Med. 2020; 12(1):91. PMC: 7586657. DOI: 10.1186/s13073-020-00791-w. View

Unger S, Ferreira C, Mortier G, Ali H, Bertola D, Calder A . Nosology of genetic skeletal disorders: 2023 revision. Am J Med Genet A. 2023; 191(5):1164-1209. PMC: 10081954. DOI: 10.1002/ajmg.a.63132. View

Stuss M, Migdalska-Sek M, Brzezianska-Lasota E, Michalska-Kasiczak M, Bazela P, Sewerynek E . Assessment of Wnt pathway selected gene expression levels in peripheral blood mononuclear cells (PBMCs) of postmenopausal patients with low bone mass. Bosn J Basic Med Sci. 2020; 21(4):461-470. PMC: 8292866. DOI: 10.17305/bjbms.2020.5179. View

10.

Makovey J, Nguyen T, Naganathan V, Wark J, Sambrook P . Genetic effects on bone loss in peri- and postmenopausal women: a longitudinal twin study. J Bone Miner Res. 2007; 22(11):1773-80. DOI: 10.1359/jbmr.070708. View

11.

Peng H, Jenkins Z, White R, Connors S, Hunter M, Ronan A . An Activating Variant in CTNNB1 is Associated with a Sclerosing Bone Dysplasia and Adrenocortical Neoplasia. J Clin Endocrinol Metab. 2020; 105(3). DOI: 10.1210/clinem/dgaa034. View

12.

Malashicheva A, Bogdanova M, Zabirnyk A, Smolina N, Ignatieva E, Freilikhman O . Various lamin A/C mutations alter expression profile of mesenchymal stem cells in mutation specific manner. Mol Genet Metab. 2015; 115(2-3):118-27. DOI: 10.1016/j.ymgme.2015.04.006. View

13.

Kayumi S, Perez-Jurado L, Palomares M, Rangu S, Sheppard S, Chung W . Genomic and phenotypic characterization of 404 individuals with neurodevelopmental disorders caused by CTNNB1 variants. Genet Med. 2022; 24(11):2351-2366. PMC: 9939054. DOI: 10.1016/j.gim.2022.08.006. View

14.

Kim B, Ahn S, Kim H, Ikegawa S, Yang T, Guo Y . Replication of Caucasian Loci Associated with Osteoporosis-related Traits in East Asians. J Bone Metab. 2016; 23(4):233-242. PMC: 5153380. DOI: 10.11005/jbm.2016.23.4.233. View

15.

Choi H, Kim S, Kwon B, Kang H, Lim H, Kim J . Comparison of the Coincidence of Osteoporosis, Fracture, Arthritis Histories, and DEXA T-Score between Monozygotic and Dizygotic Twins: A Cross-Sectional Study Using KoGES HTS Data. Nutrients. 2022; 14(18). PMC: 9506177. DOI: 10.3390/nu14183836. View

16.

Wang C, Hu Y, Su S, Zhong D . LncRNA DANCR and miR-320a suppressed osteogenic differentiation in osteoporosis by directly inhibiting the Wnt/β-catenin signaling pathway. Exp Mol Med. 2020; 52(8):1310-1325. PMC: 8080634. DOI: 10.1038/s12276-020-0475-0. View

17.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J . Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015; 17(5):405-24. PMC: 4544753. DOI: 10.1038/gim.2015.30. View

18.

Toti P, Sbordone C, Martuscelli R, Califano L, Ramaglia L, Sbordone L . Gene clustering analysis in human osteoporosis disease and modifications of the jawbone. Arch Oral Biol. 2013; 58(8):912-29. DOI: 10.1016/j.archoralbio.2013.02.013. View

19.

Styrkarsdottir U, Cazier J, Kong A, Rolfsson O, Larsen H, Bjarnadottir E . Linkage of osteoporosis to chromosome 20p12 and association to BMP2. PLoS Biol. 2003; 1(3):E69. PMC: 270020. DOI: 10.1371/journal.pbio.0000069. View

20.

Kharbanda M, Pilz D, Tomkins S, Chandler K, Saggar A, Fryer A . Clinical features associated with CTNNB1 de novo loss of function mutations in ten individuals. Eur J Med Genet. 2016; 60(2):130-135. PMC: 6070129. DOI: 10.1016/j.ejmg.2016.11.008. View