Rare Copy Number Variants in Array-Based Comparative Genomic Hybridization in Early-Onset Skeletal Fragility.
Rare Copy Number Variants in Array-Based Comparative Genomic Hybridization in Early-Onset Skeletal Fragility.
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DOI：
10.3389/fendo.2018.00380
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发表时间：
2018
影响因子：
5.2
通讯作者：
Mäkitie O
中科院分区：
文献类型：
--
作者：
Costantini A;Skarp S;Kämpe A;Mäkitie RE;Pettersson M;Männikkö M;Jiao H;Taylan F;Lindstrand A;Mäkitie O
早发性骨质疏松症的特点是低骨矿物质密度（BMD）和骨折，因为儿童或青年成年。几个单基因型已被确定，但贡献的基因仍然不充分的特点。为了寻找新的变异和新的候选基因座，我们筛选了一组70名轻度至重度骨骼脆性的年轻受试者，以寻找罕见的拷贝数变异（CNVs）。我们的研究队列包括15名30岁以前患有原发性骨质疏松症的受试者和55名16岁以前有病理性骨折史且BMD低或正常的受试者。使用定制的高分辨率比较基因组杂交阵列来搜索CNV，所述阵列在对骨代谢和纤毛功能重要的> 1，150个基因中具有富集的探针密度。我们共鉴定了14种罕见的CNV。7个内含子畸变被归类为可能良性。5个临床意义未知的CNV影响了先前与骨骼脆性无关的基因的编码区（ETV 1-DGKB、AGBL 2、ATM、RPS 6 KL 1-PGF和SCN 4A）。最后，两个CNV分别是致病性的和可能致病的：涉及COL 1A 2的外显子1-4的4kb缺失（NM_000089.3）和PLS 3中外显子3的12.5kb重复（NM_005032.6）。虽然这两个基因都与单基因形式的骨质疏松症有关，但COL 1A 2缺失是罕见的，PLS 3重复以前也没有描述过。两种CNV均在患有显著骨质疏松症的受试者中鉴定，并在家族内与骨质疏松症隔离。我们的研究扩大了单基因骨骼脆性中致病性CNV的数量，并显示了靶向CNV筛查的有效性，以潜在地确定早发性骨质疏松症的新候选位点。
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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影响因子：
12.3
作者：
McLaren W;Gil L;Hunt SE;Riat HS;Ritchie GR;Thormann A;Flicek P;Cunningham F
通讯作者：
Cunningham F
影响因子：
2.5
作者：
Docherty, S. J.;Davis, O. S. P.;Plomin, R.
通讯作者：
Plomin, R.
影响因子：
6.2
作者：
Fahiminiya, Somayyeh;Majewski, Jacek;Rauch, Frank
通讯作者：
Rauch, Frank
影响因子：
6.2
作者：
Mayranpaa, Mervi K.;Makitie, Outi;Kallio, Pentti E.
通讯作者：
Kallio, Pentti E.
影响因子：
8.8
作者：
Kim JG;Sun BH;Dietrich MO;Koch M;Yao GQ;Diano S;Insogna K;Horvath TL
通讯作者：
Horvath TL