Molecular characteristics

NIFA-related disorder is caused by variants in the NIFA gene, consistent with an autosomal dominant inheritance pattern. Most reported disease-causing variants are intragenic or whole gene deletion. Loss-of-function (frameshift, nonsense or indels) variants are most frequently single nucleotide variants; however, some missense variants have also been reported in patients with a clear NIFA-related disorder phenotype. NFI proteins play an important role in the development of the central nervous system (CNS), including axon guidance with outgrowth and in glial or neuronal cell differentiation and migration.

De novo and inherited variants have been identified. Approximately 20%-25% of reported individuals inherited a NFIA-related disorder alteration from an affected parent. Because the clinical features can be very subtle, it’s possible that an affected parent only comes to the attention when the (more severely affected) child has been diagnosed with this disorder.

Prenatal testing may be considered for pregnancies at increased risk, in families in which the pathogenic variant has been identified. Pre-implantation genetic diagnosis may be offered to such families.