Clinical and Genetic Characterization of Hereditary Sensory and Autonomic Neuropathy Type <scp>IV</scp> in a Consanguineous Population: Identification of Novel <scp> <i>NTRK1</i> </scp> Variants and Expansion of Phenotypic Spectrum

Hereditary sensory and autonomic neuropathy type IV (HSAN4) is a rare neurological disorder characterized by anhidrosis and congenital insensitivity to pain caused by biallelic pathogenic variants in NTRK1. The condition develops because of dorsal root and autonomic ganglion neurodegeneration, which ultimately results in reduced sensation and autonomic neurological dysfunction. We ascertained several neuropathic patients and performed genetic testing using gene panels and exome sequencing (ES). Genetic variants were confirmed by Sanger sequencing. Thirteen families, each with a single affected individual, participated in this study. Genetic testing revealed that all patients carried disease-causing variants in NTRK1. We identified seven different variants within our cohort, including two novel variants (c.1922T>C:p.Leu641Pro and c.1071_1072insTGCC:p.Asn358Cysfs*45). While some variants suggest a possible founder effect, the identification of new variants reflects the genetic diversity within the Saudi population. In addition to the cardinal clinical feature of HSAN4, patients exhibited various other symptoms like motor difficulties, microcephaly, recurrent hip dislocation, dystrophic nails, hypotrichosis, and various dysmorphic features. This study provides clinical information on a large number of patients, updates the prevalence and epidemiologic data in our population, and further expands the understanding of the disease's genetic and clinical spectrum within a highly consanguineous population.