Novel phenotypes of NF1 patients from unrelated Chinese families with tibial pseudarthrosis and anemia

// Santasree Banerjee 1,* , Dongzhu Lei 2,* Shengran Liang 1,* , Li Yang 3,* , Saijun Liu 1 , Zhu Wei 4 and Jian Ping Tang 4,* 1 BGI-Shenzhen, Shenzhen, China 2 Center of Prenatal Diagnosis, ChenZhou No.1 peoples hospital, Hunan, China 3 Biological therapy center, The Third Affiliated Hospital, Sun-Yet-San University, Guangzhou, China 4 Department of dermatology, Hunan Children’s Hospital, Hunan, China * These authors have contributed equally to the manuscript Correspondence to: Jian Ping Tang, email: // Keywords : neurofibromatosis type 1, next generation sequencing, novel mutation, NF1 gene, mutational screening Received : July 10, 2016 Accepted : December 06, 2016 Published : December 14, 2016 Abstract Neurofibromatosis type 1 (NF1) is an autosomal dominant, multi-system, neurocutaneous disorder, manifested with neurofibromas and Cafe´-au-lait spots. Germline mutations in NF1 gene are associated with Neurofibromatosis type 1. NF1 gene encodes neurofibromin, a RAS-specific GTPase activating protein. In our study, we present a clinical molecular study of four Chinese probands with NF1 from four unrelated families, showing extreme phenotypic variation with rare phenotype. In family 1, the proband is a 16 months old girl with multiple café-au-lait spots throughout her whole body. In family 2, the proband is a 6 months old girl with several café-au-lait spots mostly in her trunk and in lower limbs. In family 3, the proband is a 4 months old boy with several café-au-lait spots, tibial pseudarthrosis, and chronic iron deficiency anemia. In family 4, the proband is a 14 years old boy with multiple café-au-lait spots of variable sizes. Targeted exome capture based next generation sequencing and Sanger sequencing identified a novel mutation and three previously reported mutations in these four probands. These four mutations in NF1 gene were causing disease phenotypes in these four probands and was absent in unaffected family members and in healthy controls. According to the variant interpretation guideline of American College of Medical Genetics and Genomics (ACMG), these four mutations, are classified as “likely pathogenic”. Our result expands the mutational spectrum of the NF1 gene associated with neurofibromatosis type1.