Cardio‐facio‐cutaneous syndrome (CFC) is one of the RASopathies and is caused by germline mutations that activate the Ras/mitogen‐activated protein kinase (MAPK) pathway. CFC is due to heterozygous germline mutations in protein kinases BRAF, MEK1, or MEK2 and rarely in KRAS, a small GTPase. CFC is a multiple congenital anomaly disorder in which individuals may have craniofacial dysmorphia, heart issues, skin and hair anomalies, and delayed development. Pathogenic variants for CFC syndrome are usually considered de novo because vertical transmission has only been reported with MEK2 and KRAS. The index case was a 3‐year‐old male with features consistent with the clinical diagnosis of CFC. Sequencing revealed a previously reported heterozygous likely pathogenic variant BRAF p.G464R. Upon detailed family history, the index case's pregnant mother was noted to have similar features to her son. Targeted familial testing of the BRAF pathogenic variant was performed on the mother, confirming her diagnosis. Prenatal genetic testing for the fetus was declined, but postnatal molecular testing of the index case's sister was positive for the familial BRAF p.G464R variant. Functional analysis of the variant demonstrated increased kinase activity. We report the first identified vertically transmitted functional BRAF pathogenic variant. Our findings emphasize the importance of obtaining a comprehensive evaluation of family members and that activating pathogenic variants within the canonical MAPK cascade mediated by BRAF are compatible with human reproduction.

中文翻译：

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家族性心脏面部皮肤综合征：BRAF p.G464R病原体变异的垂直传播和文献综述

心脏-皮肤-皮肤综合征（CFC）是RASopathies之一，由激活Ras /促分裂原活化蛋白激酶（MAPK）途径的种系突变引起。CFC归因于蛋白激酶BRAF，MEK1或MEK2中的杂合种系突变，而很少见于KRAS（一种小GTP酶）中。CFC是一种多发性先天性异常疾病，其中个体可能患有颅面畸形，心脏问题，皮肤和头发异常以及发育迟缓。通常仅从头考虑CFC综合征的致病变异，因为只有MEK2和KRAS报道了垂直传播。索引病例为3岁男性，其特征与CFC的临床诊断相符。测序揭示了先前报道的可能是杂合的致病性变体BRAF p.G464R。根据详细的家族史，索引病例 她的怀孕母亲与儿子具有相似的特征。对母亲进行了BRAF致病性变异的定向家族测试，证实了她的诊断。胎儿的产前基因检测被拒绝，但该索引病例的姐姐的产后分子检测对家族性BRAF p.G464R变体呈阳性。该变体的功能分析表明激酶活性增加。我们报告第一个确定的垂直传播功能BRAF致病变异。我们的发现强调获得家庭成员全面评估的重要性，并且由BRAF介导的经典MAPK级联内激活致病变体与人类繁殖兼容。对母亲进行了BRAF致病性变异的定向家族测试，证实了她的诊断。胎儿的产前基因检测被拒绝，但该索引病例的姐姐的产后分子检测对家族性BRAF p.G464R变体呈阳性。该变体的功能分析表明激酶活性增加。我们报告第一个确定的垂直传播功能BRAF致病变异。我们的发现强调获得家庭成员全面评估的重要性，并且由BRAF介导的经典MAPK级联内激活致病变体与人类繁殖兼容。对母亲进行了BRAF致病性变异的定向家族测试，证实了她的诊断。胎儿的产前基因检测被拒绝，但该索引病例的姐姐的产后分子检测对家族性BRAF p.G464R变体呈阳性。该变体的功能分析表明激酶活性增加。我们报告第一个确定的垂直传播功能BRAF致病变异。我们的发现强调获得家庭成员全面评估的重要性，并且由BRAF介导的经典MAPK级联内激活致病变体与人类繁殖兼容。G464R变体。该变体的功能分析表明激酶活性增加。我们报告第一个确定的垂直传播功能BRAF致病变异。我们的发现强调获得家庭成员全面评估的重要性，并且由BRAF介导的经典MAPK级联内激活致病变体与人类繁殖兼容。G464R变体。该变体的功能分析表明激酶活性增加。我们报告第一个确定的垂直传播功能BRAF致病变异。我们的发现强调获得家庭成员全面评估的重要性，并且由BRAF介导的经典MAPK级联内激活致病变体与人类繁殖兼容。