Summary

We have sought the molecular diagnosis of OI in 38 Brazilian cases through targeted sequencing of 15 candidate genes. While 71% had type 1 collagen-related OI, defects in FKBP10, PLOD2 and SERPINF1, and a potential digenic P3H1/WNT1 interaction were prominent causes of OI in this underrepresented population.

Introduction

Defects in type 1 collagen reportedly account for 85–90% of osteogenesis imperfecta (OI) cases, but most available molecular data has derived from Sanger sequencing-based approaches in developed countries. Massively parallel sequencing (MPS) allows for systematic and comprehensive analysis of OI genes simultaneously. Our objective was to obtain the molecular diagnosis of OI in a single Brazilian tertiary center cohort.

Methods

Forty-nine individuals (84% adults) with a clinical diagnosis of OI, corresponding to 30 sporadic and 8 familial cases, were studied. Sixty-three percent had moderate to severe OI, and consanguinity was common (26%). Coding regions and 25-bp boundaries of 15 OI genes (COL1A1, COL1A2, IFITM5 [plus 5′UTR], SERPINF1, CRTAP, P3H1, PPIB, SERPINH1, FKBP10, PLOD2, BMP1, SP7, TMEM38B, WNT1, CREB3L1) were analyzed by targeted MPS and variants of interest were confirmed by Sanger sequencing or SNP array.

Results

A molecular diagnosis was obtained in 97% of cases. COL1A1/COL1A2 variants were identified in 71%, whereas 26% had variants in other genes, predominantly FKBP10, PLOD2, and SERPINF1. A potential digenic interaction involving P3H1 and WNT1 was identified in one case. Phenotypic variability with collagen defects could not be explained by evident modifying variants. Four consanguineous cases were associated to heterozygous COL1A1/COL1A2 variants, and two nonconsanguineous cases had compound PLOD2 heterozygosity.

Conclusions

Novel disease-causing variants were identified in 29%, and a higher proportion of non-collagen defects was seen. Obtaining a precise diagnosis of OI in underrepresented populations allows expanding our understanding of its molecular landscape, potentially leading to improved personalized care in the future.

中文翻译：

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巴西第三级队列中成骨不全的分子景观

概要

我们已经通过对15个候选基因的靶向测序，对38例巴西病例的OI进行了分子诊断。虽然71％的人患有1型胶原相关的OI，但在该代表性不足的人群中，FKBP10，PLOD2和SERPINF1的缺陷以及潜在的双基因P3H1 / WNT1相互作用是OI的主要诱因。

介绍

据报道，1型胶原蛋白的缺陷占成骨不全症（OI）病例的85–90％，但大多数可用的分子数据均来自发达国家基于Sanger测序的方法。大规模并行测序（MPS）允许同时对OI基因进行系统和全面的分析。我们的目标是在一个巴西的第三级中心队列中获得OI的分子诊断。

方法

研究了49例临床诊断为OI的个体（84％的成年人），对应于30例散发性和8例家族性病例。百分之六十三的人有中度至重度OI，血缘是常见的（26％）。15个OI基因（COL1A1，COL1A2，IFITM5 [加5'UTR]，SERPINF1，CRTAP，P3H1，PPIB，SERPINH1，FKBP10，PLOD2，BMP1，SP7，TMEM38B，WNT1，CREB3L1的编码区和25bp边界）通过靶向的MPS分析），并通过Sanger测序或SNP阵列确认了感兴趣的变体。

结果

97％的病例获得了分子诊断。在71％中发现了COL1A1 / COL1A2变体，而在其他基因中有26％具有变体，主要是FKBP10，PLOD2和SERPINF1。在一个案例中，发现了涉及P3H1和WNT1的潜在双基因相互作用。胶原缺陷的表型变异性不能通过明显的修饰变体来解释。四个近亲病例与杂合的COL1A1 / COL1A2变体相关，两个非近亲病例具有复合的PLOD2杂合性。

结论

在29％的人群中发现了新的致病变体，并且发现了更高比例的非胶原蛋白缺陷。在代表性不足的人群中获得OI的精确诊断，可以扩大我们对OI分子格局的了解，并有可能在将来改善个性化护理。