Molecular and phenotypic spectrum of cardio-facio-cutaneous syndrome in Chinese patients.

BACKGROUND: 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. RESULTS: 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. CONCLUSION: 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.

Whole exome and target sequencing identifies MAP2K5 as novel susceptibility gene for familial non-medullary thyroid carcinoma.

Although the genotype-phenotype for familial medullary thyroid carcinoma (FMTC) is well studied, only few low susceptibility risk loci were identified for familial non-medullary thyroid carcinoma (FNMTC). The aim of this study is to screen and identify high-penetrate genes for FNMTC. A total of 34 families with more than two first-degree relatives diagnosed as papillary thyroid cancer without other familial syndrome were recruited. Whole exome and target gene sequencing were performed for candidate variants. These variants were screened and analyzed with ESP6500, ExAC, 1000 genomes project, and the Cancer Genome Atlas (TCGA) with SIFT score and Polyphen2 prediction. Finally, we identified recurrent genetic mutation of MAP2K5 variants c.G961A and c.T1100C (p. A321T and p.M367 T) as susceptibility loci for FNMTC. The frequencies of MAP2K5 c.G961A and c.T1100C were found, 0.0385 and 0.0259 in FNMTC and 0 and 0.00022523 in healthy Chinese controls (n = 2200, P < 0.001), respectively. Both variants were located in the protein kinase domain. The functional study showed that MAP2K5 A321T or M367 T could consistently phosphorylate downstream protein ERK5 on site Ser731 + Thr733 or Ser496, promoting nuclear translocation and subsequently altering target gene expressions. Our data revealed that MAP2K5 variants A321T or M367 T can activate MAP2K5-ERK5 pathway, alter downstream gene expression, and subsequently induce thyroid epithelial cell malignant transformation. While classic MAP2K1/2(MEK1/2)-ERK1/2 signaling is well known for driving sporadic NMTC, our research indicated that MAP2K5 (MEK5) is a susceptibility gene for FNMTC. These findings highlight the potential application of MAP2K5 for molecular diagnosis as well as early prevention.