Abstract
CNTNAP1 encodes the Contactin-Associated Protein 1 (CNTNAP1), also known as Caspr1, which is a transmembrane protein critical for nervous system function. CNTNAP1 is localized to the paranodal regions of all myelinated axons, flanking either side of the node of Ranvier. It plays a vital role in axonal domain organization and is essential for the propagation of action potentials along nerve fibers. This specialized arrangement of axonal domains, which contain distinct molecular complexes, enables saltatory conduction and significantly increases the speed and efficiency of neuronal communication. To date, there are 47 children with biallelic CNTNAP1 variants who have been reported exhibiting a wide spectrum of phenotypes including congenital hypomyelinating neuropathy, hypotonia, and joint contractures among other clinical features. In this review, we compiled all previously published cases and detailed the specific genetic variants of every known individual, including clinical manifestations. Additionally, we present seven new cases of individuals identified through direct collaborations with clinicians and families, bringing the total to 54 individuals who harbor biallelic variants in CNTNAP1. This review and the additional case studies demonstrate that while children with CNTNAP1 mutations can present with a broad spectrum of symptoms, there is a recurrence of key clinical features across these cases. These key features commonly include respiratory distress, generalized hypotonia, hypomyelination, intellectual disabilities, and reduced life expectancy. These newly described cases provide valuable insights into the phenotypic diversity of CNTNAP1 variants, deepening our understanding of the clinical impact in patients with this rare genetic disorder.