背景:心面皮肤(CFC)综合征是一种RASopathy亚型,具有独特的颅面畸形,先天性心脏病,皮肤病学异常,生长迟缓,智力残疾。本研究描述了中国CFC的表型谱及其与CFC综合征基因变异的关联。
结果:20名中国CFC患者,年龄0.6-9.5岁,纳入本研究,并将其临床表型谱与非中国种族的186例CFC患者进行了比较。所有20例中国CFC患者均携带从头杂合BRAF,MAP2K1和MAP2K2变体。使用生物信息学工具检测到两个新的变体并一致预测为有害的。中国患者CFC的临床特征包括肥厚型心肌病(2/20,10%),肺动脉瓣狭窄(2/20,10%),卷曲或稀疏的头发(7/20,35%),癫痫(1/20,5%),和低张力(10/20,50%);这些特征在中国患者中观察到的频率低于非中国患者(p<0.05)。相比之下,进食困难(19/20,95%)在中国患者中更为常见.与MAP2K1/2变异患者相比,BRAF变异患者的眉毛缺失和严重身材矮小更为常见。面部识别软件用于使用人工智能识别大多数CFC患者。
结论:本研究在我们20名中国CFC患者的队列中发现了新的和常见的变异。我们发现了中国人和非中国人患者之间临床特征的差异,并检测了BRAF和MAP2K1/2变异亚组之间的基因型-表型相关性。这是我们所知的最大的中国CFC患者队列,提供对RASopy亚型的新见解。
Cardio-facio-cutaneous (CFC) syndrome is a
RASopathy subtype that presents with unique craniofacial dysmorphology, congenital heart disease, dermatologic abnormalities, growth retardation, and intellectual disability. This study describes the phenotypic spectrum of CFC in
China and its association with CFC syndrome gene variants.
Twenty Chinese CFC patients, aged 0.6-9.5 years old, were included in this study and their clinical phenotypic spectrum was compared with that of 186 patients with CFC from non-Chinese ethnicities. All 20 Chinese patients with CFC carried de novo heterozygous BRAF, MAP2K1, and MAP2K2 variants. Two novel variants were detected and consistently predicted to be deleterious using bioinformatic tools. The clinical features of CFC in the Chinese patients included hypertrophic cardiomyopathy (2/20, 10%), pulmonary valve stenosis (2/20, 10%), curly or sparse hair (7/20, 35%), epilepsy (1/20, 5%), and hypotonia (10/20, 50%); these features were less frequently observed in Chinese patients than non-Chinese patients (p < 0.05). In contrast, feeding difficulties (19/20, 95%) were more frequently observed in the Chinese patients. Absent eyebrows and severe short stature were more common in patients with BRAF variants than in those with MAP2K1/2 variants. Facial recognition software was used to recognize most CFC patients using artificial intelligence.
This study identified novel and common variants in our cohort of 20 Chinese patients with CFC. We uncovered differences in clinical features between Chinese and non-Chinese patients and detected genotype-phenotype correlations among the BRAF and MAP2K1/2 variant subgroups. This is the largest cohort of Chinese CFC patients to our knowledge, providing new insights into a subtype of
RASopathy.