Clinical diagnosis of neurofibromatosis type I in multiple family members due to cosegregation of a unique balanced translocation with disruption of the NF1 locus: Testing considerations for accurate diagnosis.

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder that causes a predisposition to develop tumors along the peripheral nervous system. The NF1 gene, located at 17q11.2, has the highest mutation rate among known human genes and about half of NF1 patients have de novo pathogenic variants. We present a case of clinical NF1 diagnoses in multiple family members with phenotypes ranging from mild to severe. Chromosome analysis of the 3-year-old female proband with NF1 resulted in an abnormal karyotype that was inherited from her mother: 46,XX,t(4;17)(q21.3;q11.2) mat. However, no NF1 genetic variants were identified by either NGS analysis of NF1 DNA coding regions, deletion-duplication studies, or by cytogenomic microarray copy number analysis. Follow-up chromosome studies of the proband's two male siblings demonstrated cosegregation of the same balanced translocation and a clinical diagnosis of NF1. Based on the cosegregation of the translocation with the NF1 clinical presentation in this family, we hypothesized that the NF1 gene may have been disrupted by this unique rearrangement. Subsequent fluorescence in situ hybridization (FISH) analysis of the metaphase cells of an affected sibling revealed a disruption of the NF1 gene confirming the underlying basis of the clinical NF1 presentation in this family. The utilization of traditional cytogenetic as well as evolving molecular methods was not only pivotal in the diagnosis of NF1 and management for this family, but is also pertinent to other patients with a family history of NF1.