Objective

Next generation sequencing (NGS) has expanded the diagnostic paradigm turning the focus to the growth plate. The aim of the study was to determine the prevalence of variants in genes implicated in skeletal dysplasias in probands with short stature and mild skeletal anomalies.

Design

Clinical and radiological data were collected from 108 probands with short stature and mild skeletal anomalies.

Methods

A customized skeletal dysplasia NGS panel was performed. Variants were classified using ACMG recommendations and Sherloc. Anthropometric measurements and skeletal anomalies were subsequently compared in those with or without an identified genetic defect.

Results

Heterozygous variants were identified in 21/108 probands (19.4%). Variants were most frequently identified in ACAN (n = 10) and IHH (n = 7) whilst one variant was detected in COL2A1, CREBBP, EXT1, and PTPN11. Statistically significant differences (P < 0.05) were observed for sitting height/height (SH/H) ratio, SH/H ratio standard deviation score (SDS), and the SH/H ratio SDS >1 in those with an identified variant compared to those without.

Conclusions

A molecular defect was elucidated in a fifth of patients. Thus, the prevalence of mild forms of skeletal dysplasias is relatively high in individuals with short stature and mild skeletal anomalies, with variants in ACAN and IHH accounting for 81% of the cases. An elevated SH/H ratio appears to be associated with a greater probability in detecting a variant, but no other clinical or radiological feature has been found determinant to finding a genetic cause. Currently, we cannot perform extensive molecular studies in all short stature individuals so detailed clinical and radiological phenotyping may orientate which are the candidate patients to obtain worthwhile results. In addition, detailed phenotyping of probands and family members will often aid variant classification.

中文翻译：

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在身材矮小和轻微骨骼异常的个体中，骨骼发育不良相关基因的变异率很高

客观的

下一代测序 (NGS) 扩展了诊断范式，将重点转向生长板。该研究的目的是确定在身材矮小和轻度骨骼异常的先证者中与骨骼发育不良有关的基因变异的流行率。

设计

从 108 名身材矮小和轻度骨骼异常的先证者中收集临床和放射学数据。

方法

进行了定制的骨骼发育不良 NGS 面板。使用 ACMG 建议和 Sherloc 对变体进行分类。随后在有或没有确定的遗传缺陷的人中比较了人体测量和骨骼异常。

结果

在 21/108 先证者 (19.4%) 中发现了杂合变异。在ACAN ( n  = 10) 和IHH ( n  = 7) 中最常发现变异，而在COL2A1、CREBBP、EXT1和PTPN11中检测到一个变异。 与已识别变异的患者相比，在坐高/身高 (SH/H) 比、SH/H 比标准差评分 (SDS) 和 SH/H 比 SDS >1 方面观察到统计学显着差异 ( P < 0.05)那些没有。

结论

五分之一的患者发现了分子缺陷。因此，在身材矮小和轻度骨骼异常的个体中，轻度骨骼发育不良的患病率相对较高，其中ACAN和IHH的变异占病例的 81%。升高的 SH/H 比似乎与检测变异的可能性更大有关，但没有发现其他临床或放射学特征决定发现遗传原因。目前，我们无法对所有身材矮小的个体进行广泛的分子研究，因此详细的临床和放射学表型可以确定哪些是候选患者以获得有价值的结果。此外，先证者和家庭成员的详细表型分析通常有助于变异分类。