In clinical exome and genome sequencing, there is potential for the recognition and reporting of incidental or secondary findings unrelated to the indication for ordering the sequencing but of medical value for patient care. The American College of Medical Genetics and Genomics (ACMG) recently published a policy statement on clinical sequencing, which emphasized the importance of disclosing the possibility of such results in pretest patient discussions, clinical testing, and reporting of results. The ACMG appointed a Working Group on Incidental Findings in Clinical Exome and Genome Sequencing to make recommendations about responsible management of incidental findings when patients undergo exome or genome sequencing. This Working Group conducted a year-long consensus process, including review by outside experts, and produced recommendations that have been approved by the ACMG Board. Specific and detailed recommendations, and the background and rationale for these recommendations, are described herein. We recommend that laboratories performing clinical sequencing seek and report mutations of the specified classes or types in the genes listed here. This evaluation and reporting should be performed for all clinical germline (constitutional) exome and genome sequencing, including the ‘normal’ of tumor-normal subtractive analyses in all subjects, irrespective of age, but excluding fetal samples. We recognize that there are insufficient data on clinical utility to fully support these recommendations and we encourage the creation of an ongoing process for updating these recommendations at least annually as further data are collected.

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On the basis of the information presented in this review, we propose a comprehensive approach to the diagnosis and treatment of individuals with neurofibromatosis 1 and neurofibromatosis 2.

Neurofibromatosis type 1 is a complex autosomal dominant disorder caused by germline mutations in the NF1 tumour suppressor gene. Nearly all individuals with neurofibromatosis type 1 develop pigmentary lesions (café-au-lait macules, skinfold freckling and Lisch nodules) and dermal neurofibromas. Some individuals develop skeletal abnormalities (scoliosis, tibial pseudarthrosis and orbital dysplasia), brain tumours (optic pathway gliomas and glioblastoma), peripheral nerve tumours (spinal neurofibromas, plexiform neurofibromas and malignant peripheral nerve sheath tumours), learning disabilities, attention deficits, and social and behavioural problems, which can negatively affect quality of life. With the identification of NF1 and the generation of accurate preclinical mouse strains that model some of these clinical features, therapies that target the underlying molecular and cellular pathophysiology for neurofibromatosis type 1 are becoming available. Although no single treatment exists, current clinical management strategies include early detection of disease phenotypes (risk assessment) and biologically targeted therapies. Similarly, new medical and behavioural interventions are emerging to improve the quality of life of patients. Although considerable progress has been made in understanding this condition, numerous challenges remain; a collaborative and interdisciplinary approach is required to manage individuals with neurofibromatosis type1 and to develop effective treatments.

Neurofibromatosis type 1 (NF1) is an autosomal dominant condition with a worldwide incidence of approximately 1 per 2500 to 3000 individuals. Caused by a germ-line-inactivating mutation in the NF1 gene on chromosome 17, the disease is associated with increased morbidity and mortality. In the past several years, significant progress has been made in standardizing management of the major clinical features of neurofibromatosis type 1. Moreover, improved understanding of how the neurofibromatosis type 1 protein, neurofibromin, regulates cell growth recently provided insight into the pathogenesis of the disease and has led to the development of new therapies. In this review, we describe the clinical manifestations, recent molecular and genetic findings, and current and developing therapies for managing clinical problems associated with neurofibromatosis type 1.