Rare Copy Number Variants in Array-Based Comparative Genomic Hybridization in Early-Onset Skeletal Fragility

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Costantini , A , Skarp , S , Kampe , A , Mäkitie , R E , Pettersson , M , Männikkö , M , Jiao , H , Taylan , F , Lindstrand , A & Mäkitie , O 2018 , ' Rare Copy Number Variants in Array-Based Comparative Genomic Hybridization in Early-Onset Skeletal Fragility ' , Frontiers in Endocrinology , vol. 9 , 380 . https://doi.org/10.3389/fendo.2018.00380

Title: Rare Copy Number Variants in Array-Based Comparative Genomic Hybridization in Early-Onset Skeletal Fragility
Author: Costantini, Alice; Skarp, Sini; Kampe, Anders; Mäkitie, Riikka E.; Pettersson, Maria; Männikkö, Minna; Jiao, Hong; Taylan, Fulya; Lindstrand, Anna; Mäkitie, Outi
Other contributor: University of Helsinki, University of Helsinki
University of Helsinki, Clinicum







Date: 2018-07-10
Language: eng
Number of pages: 10
Belongs to series: Frontiers in Endocrinology
ISSN: 1664-2392
DOI: https://doi.org/10.3389/fendo.2018.00380
URI: http://hdl.handle.net/10138/237282
Abstract: 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.
Subject: osteoporosis
bone fracture
cilia
copy number variant (CNV)
array CGH
EHLERS-DANLOS-SYNDROME
OSTEOGENESIS-IMPERFECTA
BONE MASS
SEQUENCE VARIANTS
MEDICAL GENETICS
AMERICAN-COLLEGE
PRIMARY CILIA
COL1A2 GENE
OSTEOPOROSIS
MUTATIONS
3121 General medicine, internal medicine and other clinical medicine
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