University of Oulu

Costantini, A., Skarp, S., Kämpe, A., Mäkitie, R. E., Pettersson, M., Männikkö, M., … Mäkitie, O. (2018). Rare Copy Number Variants in Array-Based Comparative Genomic Hybridization in Early-Onset Skeletal Fragility. Frontiers in Endocrinology, 9.

Rare copy number variants in array-based comparative genomic hybridization in early-onset skeletal fragility

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Author: Costantini, Alice1; Skarp, Sini2,3; Kämpe, Anders1;
Organizations: 1Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
2Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland
3Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
4Folkhälsan Institute of Genetics, University of Helsinki, Helsinki, Finland
5Science for Life Laboratory, Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
6Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
7Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.1 MB)
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Language: English
Published: Frontiers Media, 2018
Publish Date: 2019-09-17


Early-onset osteoporosis is characterized by low bone mineral density (BMD) and fractures since childhood or young adulthood. Several monogenic forms have been identified but the contributing genes remain inadequately characterized. In search for novel variants and novel candidate loci, we screened a cohort of 70 young subjects with mild to severe skeletal fragility for rare copy-number variants (CNVs). Our study cohort included 15 subjects with primary osteoporosis before age 30 years and 55 subjects with a pathological fracture history and low or normal BMD before age 16 years. A custom-made high-resolution comparative genomic hybridization array with enriched probe density in >1,150 genes important for bone metabolism and ciliary function was used to search for CNVs. We identified altogether 14 rare CNVs. Seven intronic aberrations were classified as likely benign. Five CNVs of unknown clinical significance affected coding regions of genes not previously associated with skeletal fragility (ETV1-DGKB, AGBL2, ATM, RPS6KL1-PGF, and SCN4A). Finally, two CNVs were pathogenic and likely pathogenic, respectively: a 4 kb deletion involving exons 1–4 of COL1A2 (NM_000089.3) and a 12.5 kb duplication of exon 3 in PLS3 (NM_005032.6). Although both genes have been linked to monogenic forms of osteoporosis, COL1A2 deletions are rare and PLS3 duplications have not been described previously. Both CNVs were identified in subjects with significant osteoporosis and segregated with osteoporosis within the families. Our study expands the number of pathogenic CNVs in monogenic skeletal fragility and shows the validity of targeted CNV screening to potentially pinpoint novel candidate loci in early-onset osteoporosis.

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Series: Frontiers in endocrinology
ISSN: 1664-2392
ISSN-E: 1664-2392
ISSN-L: 1664-2392
Volume: 9
Article number: 380
DOI: 10.3389/fendo.2018.00380
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
Funding: This study has been supported by the Swedish Research Council (2013-2603), the Academy of Finland (277843), the Sigrid Jusélius Foundation, the Folkhälsan Research Foundation, the Novo Nordisk Foundation (21322), the Stockholm County Council. Furthermore, we would like to thank all the participants and their families to have made this study possible.
Copyright information: © 2018 Costantini, Skarp, Kämpe, Mäkitie, Pettersson, Männikkö, Jiao, Taylan, Lindstrand and Mäkitie. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.