Genotype-phenotype specificity in Menke-Hennekam syndrome caused by missense variants in exon 30 or 31 of CREBBP
Genotype-phenotype specificity in Menke-Hennekam syndrome caused by missense variants in exon 30 or 31 of CREBBP
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DOI：
10.1002/ajmg.a.61131
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发表时间：
2019-06-01
影响因子：
2
通讯作者：
Clayton-Smith, Jill
中科院分区：
文献类型：
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作者：
Banka, Siddharth;Sayer, Rebecca;Clayton-Smith, Jill
CREBBP功能丧失变异体导致Rubinstein-Taybi综合征（RTS）。有两个独立的报告，在缺乏与RTS相关的特征性面部和肢体畸形的个体中，CREBBP外显子30或31中存在错义变异。这种疾病的常见特征包括各种智力残疾、身材矮小、自闭症行为、小头畸形、喂养问题、癫痫、复发性上呼吸道感染和轻度听力障碍。我们报告了三个新的外显子31 CREBBP错义变异的患者。第一个个体具有c.5357G>A p.（Arg 1786 His）变体，其影响与先前描述的患者之一相同的密码子。这两例患者均可被临床医生识别为轻度RTS。我们的第二个病人有c.5602C>T p。（Arg 1868 Trp）变异已在其他五个人谁都共享一个惊人的相似表型描述。第三个人有一个新的c.5354G>A p。（Cys 1785 Try）变体。我们的报告扩大了临床范围，包括脑室扩大，胼胝体缺失，葡萄肿，耳蜗畸形和外胚层。这些额外的病例也有助于建立这种疾病的基因型-表型相关性。在前两份报告的第一位和最后一位作者之后，我们建议将这种疾病称为“Menke-Hennekam综合征”，以将其建立为不同于RTS的临床实体，并为父母和专业人员提供一个满意的名称，从而促进适当的临床管理和研究。
CREBBP loss-of function variants cause Rubinstein-Taybi syndrome (RTS). There have been two separate reports of patients with missense variants in exon 30 or 31 of CREBBP in individuals lacking the characteristic facial and limb dysmorphism associated with RTS. Frequent features in this condition include variable intellectual disability, short stature, autistic behavior, microcephaly, feeding problems, epilepsy, recurrent upper airway infections, and mild hearing impairment. We report three further patients with de novo exon 31 CREBBP missense variants. The first individual has a c.5357G>A p. (Arg1786His) variant affecting the same codon as one of the previously described patients. Both these patients could be recognized by clinicians as mild RTS. Our second patient has a c.5602C>T p.(Arg1868Trp) variant that has been described in five other individuals who all share a strikingly similar phenotype. The third individual has a novel c.5354G>A p.(Cys1785Try) variant. Our reports expand the clinical spectrum to include ventriculomegaly, absent corpus callosum, staphyloma, cochlear malformations, and exomphalos. These additional cases also help to establish genotype-phenotype correlations in this disorder. After the first and last authors of the previous two reports, we propose to call this disorder "Menke-Hennekam syndrome" to establish it as a clinical entity distinct from RTS and to provide a satisfactory name for adoption by parents and professionals, thus facilitating appropriate clinical management and research.