Leucine-485 deletion variant of BRAF may exhibit the severe end of the clinical spectrum of CFC syndrome

• Published in: Journal of human genetics Vol. 64; no. 5; pp. 499 - 504
• Main Authors: Suzuki-Muromoto, Sato, Miyabayashi, Takuya, Nagai, Koki, Yamamura-Suzuki, Saeko, Anzai, Mai, Takezawa, Yusuke, Sato, Ryo, Okubo, Yukimune, Endo, Wakaba, Inui, Takehiko, Togashi, Noriko, Kikuchi, Atsuo, Niihori, Tetsuya, Aoki, Yoko, Kure, Shigeo, Haginoya, Kazuhiro
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01-05-2019
• Subjects: Age; Amino Acid Sequence; Case reports; Child, Preschool; Convulsions & seizures; Defects; Differential diagnosis; Ectodermal Dysplasia - genetics; Ectodermal Dysplasia - pathology; Electroencephalography; Epilepsy; Facies; Failure to Thrive - genetics; Failure to Thrive - pathology; Genotype & phenotype; Genotypes; Heart Defects, Congenital - genetics; Heart Defects, Congenital - pathology; Humans; Intellectual disabilities; Kinases; Leucine; Magnetic resonance imaging; Male; MAP kinase; Mutation; Myelination; Neuroimaging; NMR; Nuclear magnetic resonance; Ostomy; Phenotypes; Polycystic kidney; Protein kinase; Proto-Oncogene Proteins B-raf - genetics; Seizures; Sequence Deletion; Severity of Illness Index; Startle response
• ISSN: 1434-5161; 1435-232X
• DOI: 10.1038/s10038-019-0579-3

The genotype-phenotype correlation in BRAF variant in cardio-facio-cutaneous (CFC) syndrome is not clearly defined. Here we report a case with a severe clinical phenotype and a novel BRAF variant, p.Leu485del. The present case showed severe intellectual disability, impaired awareness, hyperekplexia, involuntary movements, early onset refractory seizures, and delayed myelination on brain magnetic resonance imaging as well as a polycystic and dysplastic kidney, which are previously unreported anomalies in CFC or RAS/mitogen-activated protein kinase syndromes related to BRAF variant. CFC syndrome, especially caused by BRAF variant, should be included in the differential diagnosis of patients with developmental and epileptic encephalopathies and hyperekplexia. Furthermore, we need to keep in mind that missense variants or the deletion of Leucine-485 may be associated with severe symptoms.