Molecular and Clinical Landscape of Osteogenesis Imperfecta: Unraveling Autosomal Recessive Forms, Therapeutic Outcomes, and Bone Mineral Density in Carriers.

IF 2.3 3区 医学 Q2 GENETICS & HEREDITY
Haseena Sait, Naik Adarsha, Amita Moirangthem, Deepti Saxena, Lokesh Sharma, Preeti Dabadgao, Avantika Gupta, Shubha R Phadke
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引用次数: 0

Abstract

Osteogenesis imperfecta (OI) is a heritable disorder characterized by bone fragility and marked genetic and phenotypic heterogeneity. This study explores the molecular and clinical spectrum of OI, with a focus on autosomal recessive (AR) forms, therapeutic outcomes, and bone mineral density (BMD) in carriers of AR OI-associated gene variants from the Indian population. A total of 78 clinically suspected OI patients were analyzed, yielding a high diagnostic rate of 92.3%. Exome sequencing was performed in all cases, with whole-genome sequencing in selected exome-negative cases. Autosomal dominant (AD) and AR OI accounted for 66% and 34% of cases, respectively. P3H1 (n = 11) was the most frequently implicated AR gene causing OI, followed by SERPINF1 (n = 5) and WNT1 (n = 4), with 79% of AR variants being novel. Phenotypic evaluation (n = 67) revealed fractures, short stature (87%), and bony deformities (84%) as predominant features. A rare homozygous COL1A1 variant was identified in one patient, while another patient harbored additional variants in AD OI genes, suggesting a potential digenic or modifier effect. Phenotypic severity followed the order from most to least severe: AR genes > COL1A2 (substitution and non-substitution) > COL1A1 (substitution > non-substitution). A self-designed, preliminary clinical severity scoring system ranked CRTAP followed by P3H1, as the AR genes associated with the most severe phenotypes. Therapeutic assessment showed a significant reduction in fracture incidence following zoledronate therapy only in the COL1A1 group, with no notable improvements in the COL1A2 or AR groups. Additionally, BMD evaluation in carrier parents of AR gene causing OI indicated a higher predisposition to low BMD among WNT1 gene carriers. However, these findings are preliminary and limited by small sample size. This study provides an extensive genotypic and phenotypic characterization of OI in the Indian population, with a focus on AR OI. It documents differential therapeutic responses among genetic subgroups and provides preliminary observations on BMD in carrier parents of AR OI-an aspect that has been less explored previously and suggest the need for tailored management strategies. The findings in this study also raise the possibility of genetic modifiers contributing to phenotypic variability, warranting further investigation.

成骨不全的分子和临床特征:揭示常染色体隐性形式、治疗结果和携带者的骨矿物质密度。
成骨不全症(OI)是一种以骨脆性和显著的遗传和表型异质性为特征的遗传性疾病。本研究探讨了OI的分子和临床谱,重点研究了印度人群中AR OI相关基因变异携带者的常染色体隐性(AR)形式、治疗结果和骨矿物质密度(BMD)。我们共分析了78例临床疑似成骨不全患者,诊断率高达92.3%。对所有病例进行外显子组测序,对选择的外显子组阴性病例进行全基因组测序。常染色体显性遗传(AD)和AR型OI分别占66%和34%。P3H1 (n = 11)是导致成骨不全最常见的AR基因,其次是serinf1 (n = 5)和WNT1 (n = 4),其中79%的AR变异是新的。表型评估(n = 67)显示骨折、身材矮小(87%)和骨畸形(84%)是主要特征。在一名患者中发现了罕见的纯合子COL1A1变异,而另一名患者在AD OI基因中发现了额外的变异,这表明潜在的遗传或修饰作用。表型严重程度从最严重到最不严重依次为:AR基因> COL1A2(替代和非替代)> COL1A1(替代>非替代)。一个自行设计的初步临床严重程度评分系统将CRTAP排在P3H1之后,作为与最严重表型相关的AR基因。治疗评估显示,COL1A1组在唑来膦酸钠治疗后骨折发生率显著降低,COL1A2或AR组无显著改善。此外,对导致成骨不全的AR基因携带者父母的骨密度评估表明,WNT1基因携带者更容易出现低骨密度。然而,这些发现是初步的,受限于小样本量。本研究提供了印度人群中成骨不全的广泛基因型和表型特征,重点是AR成骨不全。该研究记录了不同基因亚群的不同治疗反应,并提供了对AR oi携带者父母骨密度的初步观察——这是一个以前很少探索的方面,表明需要量身定制的管理策略。本研究的发现还提出了遗传修饰因子对表型变异的影响的可能性,值得进一步研究。
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来源期刊
Clinical Genetics
Clinical Genetics 医学-遗传学
CiteScore
6.50
自引率
0.00%
发文量
175
审稿时长
3-8 weeks
期刊介绍: Clinical Genetics links research to the clinic, translating advances in our understanding of the molecular basis of genetic disease for the practising clinical geneticist. The journal publishes high quality research papers, short reports, reviews and mini-reviews that connect medical genetics research with clinical practice. Topics of particular interest are: • Linking genetic variations to disease • Genome rearrangements and disease • Epigenetics and disease • The translation of genotype to phenotype • Genetics of complex disease • Management/intervention of genetic diseases • Novel therapies for genetic diseases • Developmental biology, as it relates to clinical genetics • Social science research on the psychological and behavioural aspects of living with or being at risk of genetic disease
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