Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India.
Division of Genetics, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India.
Eur J Med Genet. 2021 Jul;64(7):104235. doi: 10.1016/j.ejmg.2021.104235. Epub 2021 May 1.
Pycnodysostosis is an autosomal recessive skeletal dysplasia with easily recognizable clinical features and marked molecular heterogeneity. In this study, we explored the clinical and molecular spectrum of 25 Indian patients with pycnodysostosis from 20 families.
Clinical information was collected on a predesigned clinical proforma. Sanger method was employed to sequence all the exons and exon/intron boundaries of the CTSK gene. Novel variants were systematically assessed by prediction softwares and protein modelling. The pathogenicity of variant was established based on ACMG-AMP criteria. An attempt was also made to establish a genotype-phenotype correlation and devise a diagnostic scoring system based on clinical and radiological findings.
Consanguinity and positive family history were present in 65% (13/20) and 45% (9/20) of the families respectively. Short stature and fractures were the predominant presenting complaints and was evident in 96% (24/25) and 32% (8/25) of affected individuals respectively. Gestalt facial phenotype and acro-osteolysis were present in 76% (19/25) and 82.6% (19/23) of the individuals respectively. Hepatosplenomegaly was present in 15% (3/20) of the individuals with one of them having severe anaemia. Causative sequence variations were identified in all of them. A total of 19 variants were identified from 20 families amongst which 10 were novel. Homozygous variants were identified in 90% (18/20) families. Amongst the novel variants, there was a considerable proportion (40%) of frameshift variants (4/10). No significant genotype-phenotype correlation was noted. Scoring based on clinical and radiological findings led to the proposal that a minimum of 2 scores in each category is required in addition to high bone density to diagnose pycnodysostosis with certainty.
This study delineated the genotypic and phenotypic characterisation of Indian patients with pycnodysostosis with identification of 10 novel variants. We also attempted to develop a clinically useful diagnostic scoring system which requires further validation.
成骨不全症是一种常染色体隐性骨骼发育不良，具有易于识别的临床特征和明显的分子异质性。在这项研究中，我们从 20 个家庭中探索了 25 例印度成骨不全症患者的临床和分子谱。
采用预设计的临床方案收集临床信息。采用 Sanger 法对 CTSK 基因的所有外显子和外显子/内含子边界进行测序。通过预测软件和蛋白质建模系统地评估新的变异体。根据 ACMG-AMP 标准，确定变异体的致病性。还试图建立一种基于临床和影像学发现的基因型-表型相关性，并制定一种诊断评分系统。
65%（13/20）的家庭存在近亲结婚，45%（9/20）的家庭有阳性家族史。身材矮小和骨折是主要的首发症状，分别在 96%（24/25）和 32%（8/25）的患者中出现。76%（19/25）和 82.6%（19/23）的患者存在Gestalt 面部表型和肢端骨溶解。15%（3/20）的患者存在肝脾肿大，其中 1 例伴有严重贫血。所有患者均发现了致病序列变异。在 20 个家庭中，共从 20 个家庭中发现了 19 个变异，其中 10 个是新的。90%（18/20）的家庭存在纯合变异。在新发现的变异中，有相当比例（40%）的移码变异（4/10）。没有明显的基因型-表型相关性。基于临床和影像学表现的评分导致提出，除了高骨密度外，还需要在每个类别中至少有 2 个分数才能确定诊断为成骨不全症。
本研究描绘了印度成骨不全症患者的基因型和表型特征，确定了 10 个新的变异。我们还试图开发一种具有临床应用价值的诊断评分系统，该系统需要进一步验证。
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