Yongjia Yang1, Yu Zheng2, Wangming Li3, Liping Li2, Ming Tu2, Liu Zhao2, Haibo Mei4, Guanghui Zhu4, Yimin Zhu5,6. 1. The Laboratory of Genetics and Metabolism, Hunan Children's Research Institute (HCRI), Hunan Children's Hospital, University of South China, Changsha, China. yongjia727@aliyun.com. 2. The Laboratory of Genetics and Metabolism, Hunan Children's Research Institute (HCRI), Hunan Children's Hospital, University of South China, Changsha, China. 3. Department of Radiology, Hunan Children's Hospital, University of South China, Changsha, China. 4. Department of Orthopedics, Hunan Children's Hospital, University of South China, Changsha, China. 5. The Laboratory of Genetics and Metabolism, Hunan Children's Research Institute (HCRI), Hunan Children's Hospital, University of South China, Changsha, China. xiangeryiym@aliyun.com. 6. Hunan Institute of Emergency Medicine, Hunan People's Hospital, Changsha, China. xiangeryiym@aliyun.com.
Abstract
PURPOSE: Radioulnar synostosis (RUS) can be syndromic or nonsyndromic. The genetic basis for several RUS syndromes have been reported. However, the genetic cause of nonsyndromic RUS (nsRUS) remains unknown. METHODS: We performed Giemsa (GTG) banding, Sanger sequencing, and exome sequencing on patients (n = 140) and families (n = 11) who suffered from RUS. RESULTS: GTG banding identified 10% RUS sporadic cases affected by sex chromosome aneuploidy. Sanger sequencing on candidate genes revealed noggin (NOG) rarely mutated in nsRUS. Exome sequencing identified 16 loss-of-function (LOF) and 6 missense variants (minor allele frequency [MAF] < 0.0001) in 22/117 nsRUS sporadic patients. Genetic association analysis found a significant association between SMAD6-LOF variants and nsRUS risk (odds ratio [OR] = 430, 95% confidence interval [CI]: 238-780, P < 0.000001). SMAD6 mutated in nsRUS was further confirmed by direct Sanger sequencing of SMAD6-coding regions on other unrelated cohorts of nsRUS cases or families. In summary, we detected 27 SMAD6 rare variants in nsRUS, most of which were LOF variants, 4 were de novo, and 3 were transmitted in families with autosomal dominant inheritance. CONCLUSION: As an intracellular bone morphogenetic protein (BMP) antagonist gene, SMAD6 is frequently mutated in nsRUS. NOG, which encodes an extracellular BMP antagonist, is rarely mutated in nsRUS. This work is the first genetic study on nsRUS.
PURPOSE: Radioulnar synostosis (RUS) can be syndromic or nonsyndromic. The genetic basis for several RUS syndromes have been reported. However, the genetic cause of nonsyndromic RUS (nsRUS) remains unknown. METHODS: We performed Giemsa (GTG) banding, Sanger sequencing, and exome sequencing on patients (n = 140) and families (n = 11) who suffered from RUS. RESULTS: GTG banding identified 10% RUS sporadic cases affected by sex chromosome aneuploidy. Sanger sequencing on candidate genes revealed noggin (NOG) rarely mutated in nsRUS. Exome sequencing identified 16 loss-of-function (LOF) and 6 missense variants (minor allele frequency [MAF] < 0.0001) in 22/117 nsRUS sporadic patients. Genetic association analysis found a significant association between SMAD6-LOF variants and nsRUS risk (odds ratio [OR] = 430, 95% confidence interval [CI]: 238-780, P < 0.000001). SMAD6 mutated in nsRUS was further confirmed by direct Sanger sequencing of SMAD6-coding regions on other unrelated cohorts of nsRUS cases or families. In summary, we detected 27 SMAD6 rare variants in nsRUS, most of which were LOF variants, 4 were de novo, and 3 were transmitted in families with autosomal dominant inheritance. CONCLUSION: As an intracellular bone morphogenetic protein (BMP) antagonist gene, SMAD6 is frequently mutated in nsRUS. NOG, which encodes an extracellular BMP antagonist, is rarely mutated in nsRUS. This work is the first genetic study on nsRUS.