Genetics in medicine : official journal of the American College of Medical Genetics · 2019
SMAD6 is frequently mutated in nonsyndromic radioulnar synostosis.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Yang Yongjia, Zheng Yu, Li Wangming, Li Liping, Tu Ming, Zhao Liu, Mei Haibo, Zhu Guanghui, Zhu Yimin
Аннотация
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.
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.