OBJECTIVE Our study aimed to assess the impact of genetic modifiers on the significant variation in phenotype that is observed in individuals with SHOX deficiency, which is the most prevalent monogenic cause of short stature. DESIGN AND METHODS We performed a genetic analysis in 98 individuals from 48 families with SHOX deficiency with a target panel designed to capture the entire SHOX genomic region and 114 other genes that modulate growth and/or SHOX action. We prioritized rare potentially deleterious variants. RESULTS We did not identify potential deleterious variants in the promoter or intronic regions of the SHOX genomic locus. In contrast, we found eight heterozygous variants in 11 individuals from nine families in genes with a potential role as genetic modifiers. In addition to a previously described likely pathogenic (LP) variant in CYP26C1 observed in two families, we identified LP variants in PTHLH and ACAN, and variants of uncertain significance in NPR2, RUNX2, and TP53 in more affected individuals from families with SHOX deficiency. Families with a SHOX alteration restricted to the regulatory region had a higher prevalence of a second likely pathogenic variant (27%) than families with an alteration compromising the SHOX coding region (2.9%, P = .04). CONCLUSION In conclusion, variants in genes related to the growth plate have a potential role as genetic modifiers of the phenotype in individuals with SHOX deficiency. In individuals with SHOX alterations restricted to the regulatory region, a second alteration could be critical to determine the penetrance and expression of the phenotype.

中文翻译：

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SHOX 缺陷患者的第二个基因改变的鉴定：表型变异的潜在解释。

目的 我们的研究旨在评估遗传修饰剂对 SHOX 缺陷个体中观察到的表型显着变异的影响，SHOX 缺陷是导致身材矮小的最常见的单基因原因。设计和方法 我们对来自 48 个 SHOX 缺陷家族的 98 名个体进行了遗传分析，目标组旨在捕获整个 SHOX 基因组区域和 114 个调节生长和/或 SHOX 作用的其他基因。我们优先考虑罕见的潜在有害变体。结果我们没有在 SHOX 基因组基因座的启动子或内含子区域中发现潜在的有害变异。相比之下，我们在来自 9 个家族的 11 名个体中发现了 8 个杂合变异，其基因具有潜在的遗传修饰作用。除了先前描述的在两个家族中观察到的 CYP26C1 中可能的致病性 (LP) 变异之外，我们还鉴定了 PTHLH 和 ACAN 中的 LP 变异，以及来自 SHOX 缺陷家族的更多受影响个体中 NPR2、RUNX2 和 TP53 中意义不确定的变异。具有仅限于调节区域的 SHOX 改变的家庭比具有损害 SHOX 编码区的改变的家庭（2.9%，P = .04）具有更高的第二种可能致病性变异（27%）的患病率。结论 总之，与生长板相关的基因变异具有作为 SHOX 缺陷个体表型遗传修饰剂的潜在作用。在 SHOX 改变仅限于调节区域的个体中，第二次改变对于确定表型的外显率和表达可能至关重要。