Abstract：
Skeletal deformity is characterized by an abnormal anatomical structure of bone and cartilage. In our previous studies, we have found that a substantial proportion of patients with skeletal deformity could be explained by monogenic disorders. More recently, complex phenotypes caused by more than one genetic defect (i.e., dual molecular diagnosis) have also been reported in skeletal deformities and may complicate the diagnostic odyssey of patients. In this study, we report the molecular and phenotypic characteristics of patients with dual molecular diagnosis and variable skeletal deformities.
From 1108 patients who underwent exome sequencing, we identified eight probands with dual molecular diagnosis and variable skeletal deformities. All eight patients had dual diagnosis consisting of two autosomal dominant diseases. A total of 16 variants in 12 genes were identified, 5 of which were of de novo origin. Patients with dual molecular diagnosis presented blended phenotypes of two genetic diseases. Mendelian disorders occurred more than once include Osteogenesis Imperfecta Type I (COL1A1, MIM:166200), Neurofibromatosis, Type I (NF1, MIM:162200) and Marfan Syndrome (FBN1, MIM:154700).
This study demonstrated the complicated skeletal phenotypes associated with dual molecular diagnosis. Exome sequencing represents a powerful tool to detect such complex conditions.
From 1108 patients who underwent exome sequencing, we identified eight probands with dual molecular diagnosis and variable skeletal deformities. All eight patients had dual diagnosis consisting of two autosomal dominant diseases. A total of 16 variants in 12 genes were identified, 5 of which were of de novo origin. Patients with dual molecular diagnosis presented blended phenotypes of two genetic diseases. Mendelian disorders occurred more than once include Osteogenesis Imperfecta Type I (COL1A1, MIM:166200), Neurofibromatosis, Type I (NF1, MIM:162200) and Marfan Syndrome (FBN1, MIM:154700).
This study demonstrated the complicated skeletal phenotypes associated with dual molecular diagnosis. Exome sequencing represents a powerful tool to detect such complex conditions.
摘要：
骨骼畸形的特征在于骨骼和软骨的异常解剖结构。在我们之前的研究中,我们发现，相当比例的骨骼畸形患者可以通过单基因疾病来解释。最近,由一种以上的遗传缺陷引起的复杂表型(即，双分子诊断）在骨骼畸形中也有报道，可能会使患者的诊断变得复杂。在这项研究中,我们报道了双分子诊断和可变骨骼畸形患者的分子和表型特征。
从1108名接受外显子组测序的患者中，我们确定了8位具有双重分子诊断和可变骨骼畸形的先证者。所有8例患者均具有由两种常染色体显性疾病组成的双重诊断。共鉴定出12个基因中的16个变异体,其中5个是从头起源的。双重分子诊断的患者表现出两种遗传疾病的混合表型。多次发生的孟德尔疾病包括I型成骨不全症（COL1A1，MIM：166200），神经纤维瘤病,I型（NF1，MIM：162200）和马凡氏综合征（FBN1，MIM：154700）。
这项研究证明了复杂的骨骼表型与双分子诊断相关。外显子组测序代表了检测此类复杂条件的强大工具。
从1108名接受外显子组测序的患者中，我们确定了8位具有双重分子诊断和可变骨骼畸形的先证者。所有8例患者均具有由两种常染色体显性疾病组成的双重诊断。共鉴定出12个基因中的16个变异体,其中5个是从头起源的。双重分子诊断的患者表现出两种遗传疾病的混合表型。多次发生的孟德尔疾病包括I型成骨不全症（COL1A1，MIM：166200），神经纤维瘤病,I型（NF1，MIM：162200）和马凡氏综合征（FBN1，MIM：154700）。
这项研究证明了复杂的骨骼表型与双分子诊断相关。外显子组测序代表了检测此类复杂条件的强大工具。
