Prenatal Microarray Incidentally Diagnoses a Novel Inherited NF1 Intragenic Duplication

Neurofibromatosis Type 1 (NF1) is a well-described autosomal dominant genetic condition with variable expressivity. Most commonly caused by intragenic heterozygous loss of function variants or whole gene deletions in the NF1 gene, there are few documented cases of NF1 due to partial gene duplication.

Here we present the case of a proband with an undisclosed clinical diagnosis of NF1 who had been lost to follow-up as a teenager. She subsequently received a molecular diagnosis of NF1 following prenatal chromosome microarray. Amniocentesis was performed due to a high probability for trisomy 21 on first trimester combined screening and incidentally detected a novel 17q11.2 duplication. RNA analysis confirmed the pathogenicity of this partial gene duplication involving the NF1 gene, but not before the proband conceived a second pregnancy which also carried the 17q11.2 duplication. This resulted in a mother and baby with differing clinical features of NF1. The mother presented in childhood with the more common features of café-au-lait macules, bilateral axillary freckling, and later left forearm subcutaneous lipoma, while her son presented in the neonatal period with the less common isolated tibial pseudoarthrosis. Therefore, this demonstrates intrafamilial phenotypic variability.

This case describes a pathogenic 17q11.2 duplication not previously reported in NF1 literature as well as demonstrating the ongoing importance of referral to a clinical genetics service in the event of any unexpected result on prenatal microarray, and the importance of thorough medical and family history elicitation, pre-test counseling, and informed consent.