Osteogenesis imperfecta (OI) is a group of inherited disorders with increased bone fragility and wide genetic heterogeneity. We report the outcome of clinical exome sequencing validated by Sanger sequencing in clinically diagnosed 54 OI patients in Indian population. In 52 patients, we report 20 new variants involving both dominant and recessive OI‐specific genes and correlate these with phenotypes. COL1A1 and COL1A2 gene variants were identified in 44.23%, of which 28.84% were glycine substitution abnormalities. Two novel compound heterozygous variants in the FKBP10 gene were seen in two unrelated probands. A novel heterogeneous duplication of chromosomal region chr17: 48268168–48278884 from exons 1–33 of the COL1A1 gene was found in one proband. In five probands, there were additional variants in association with OI. These were ANO5 in association with CRTAP in two probands of the same family causing gnathodiaphyseal dysplasia, COL5A2 with LEPRE1 causing Ehlers Danlos syndrome, COL11A1 in addition to COL1A1 causing Stickler syndrome, and a previously unreported combination of SLC34A1 gene variant with FKBP10 leading to Fanconi renal tubular syndrome type II. Our findings demonstrate the efficacy of clinical exome sequencing in screening OI patients, classifying its subtypes, and identifying associated disorders in consanguineous populations.

中文翻译：

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成骨不全症：来自 54 名印度患者的临床外显子组研究的新遗传变异和临床观察

成骨不全症（OI）是一组具有骨脆性增加和广泛遗传异质性的遗传性疾病。我们报告了通过 Sanger 测序在印度人群中临床诊断的 54 名 OI 患者中验证的临床外显子组测序结果。在 52 名患者中，我们报告了 20 种新变异，涉及显性和隐性 OI 特异性基因，并将这些与表型相关联。COL1A1 和 COL1A2 基因变异在 44.23% 中被鉴定，其中 28.84% 是甘氨酸取代异常。在两个不相关的先证者中发现了 FKBP10 基因中的两个新的复合杂合变体。在一名先证者中发现了来自 COL1A1 基因外显子 1-33 的染色体区域 chr17 的新型异质重复：48268168-48278884。在五个先证者中，还有与 OI 相关的其他变异。这些是 ANO5 与 CRTAP 相关的同一家族的两个先证者导致颌骨发育不良，COL5A2 与 LEPRE1 导致 Ehlers Danlos 综合征，COL11A1 和 COL1A1 导致 Stickler 综合征，以及先前未报道的 SLC34A1 基因变异与 FKBP10 的组合导致 Fanconi II型肾小管综合征。我们的研究结果证明了临床外显子组测序在筛查 OI 患者、对其亚型进行分类以及在近亲人群中识别相关疾病方面的功效。