Abstract：
Molecular genetics enables more precise diagnoses of skeletal dysplasia and other skeletal disorders (SDs). We investigated the clinical utility of multigene panel testing for 5011 unrelated individuals with SD in the United States (December 2019-April 2022). Median (range) age was 8 (0-90) years, 70.5% had short stature and/or disproportionate growth, 27.4% had a positive molecular diagnosis (MDx), and 30 individuals received two MDx. Genes most commonly contributing to MDx were FGFR3 (16.9%), ALPL (13.0%), and COL1A1 (10.3%). Most of the 112 genes associated with ≥1 MDx were primarily involved in signal transduction (n = 35), metabolism (n = 23), or extracellular matrix organization (n = 17). There were implications associated with specific care/treatment options for 84.4% (1158/1372) of MDx-positive individuals; >50% were linked to conditions with targeted therapy approved or in clinical development, including osteogenesis imperfecta, achondroplasia, hypophosphatasia, and mucopolysaccharidosis. Forty individuals with initially inconclusive results became MDx-positive following family testing. Follow-up mucopolysaccharidosis enzyme activity testing was positive in 14 individuals (10 of these were not MDx-positive). Our findings showed that inclusion of metabolic genes associated with SD increased the clinical utility of a gene panel and confirmed that integrated use of comprehensive gene panel testing with orthogonal testing reduced the burden of inconclusive results.
摘要：
分子遗传学可以更精确地诊断骨骼发育不良和其他骨骼疾病（SD）。我们调查了美国5011名SD无关个体（2019年12月至2022年4月）的多基因小组检测的临床实用性。中位（范围）年龄为8（0-90）岁，70.5%的人身材矮小和/或不成比例的增长，27.4%的分子诊断(MDx)为阳性,30个人接受了两个MDX。最常见的MDx基因是FGFR3（16.9%），ALPL（13.0%），和COL1A1（10.3%）。与≥1MDx相关的112个基因中，大多数主要参与信号转导（n=35），新陈代谢（n=23），或细胞外基质组织(n=17)。对于84.4%(1158/1372)的MDx阳性个体，存在与特定护理/治疗方案相关的影响；>50%与批准靶向治疗或临床开发的病症相关。包括成骨不全症,软骨发育不全,低磷酸盐增多症,和粘多糖贮积症.经过家庭测试，有40名最初结果不确定的人变为MDx阳性。14个个体的后续粘多糖贮积酶活性测试为阳性（其中10个不是MDx阳性）。我们的发现表明，包含与SD相关的代谢基因增加了基因组的临床效用，并证实了综合使用综合基因组测试与正交测试可以减少不确定结果的负担。
