PT - JOURNAL ARTICLE AU - Shalini Roy Choudhury AU - Parthasarathy Satishchandra AU - Sanjib Sinha AU - Anuranjan Anand TI - Gene variants in <em>ZGRF1</em> implicated for a rare sensory reflex epilepsy AID - 10.1101/728188 DP - 2019 Jan 01 TA - bioRxiv PG - 728188 4099 - http://biorxiv.org/content/early/2019/08/07/728188.short 4100 - http://biorxiv.org/content/early/2019/08/07/728188.full AB - Hot water epilepsy (HWE) is a rare sensory reflex epilepsy syndrome where seizures are precipitated by a stimulus of contact with hot water. While there is genetic basis to its etiology, identity of specific genes underlying this relatively uncommon disorder has remained unknown. Here, we present our studies aimed at identifying a causative gene in a four-generation family (Family 227) with several of its members affected with the disorder, from the southern parts of India. We conducted whole exome-based sequencing, and examined the HWE genetic locus previously known to map to 4q24-q28 (HWE2, MIM: 613340) in the family and identified a sequence variant, c.1805C&gt;T (p.Thr602Ile) in ZGRF1 co-segregating with the disorder. Complete transcript structure of ZGRF1 was examined in 288 HWE patients and five missense variants, Arg326Gln, Glu660Gly, Arg1862*, Phe1940Leu and Asp1984Gly, present exclusively or almost exclusively in the patients were found. Functional correlates of the six variants identified were examined in cultured mammalian cells. We observed spindle pole defects during cell division and partially disrupted localization of UPF1, a protein involved in cell cycle regulation, at spindles. Our observations provide insights into the genetic basis of HWE and suggest involvement of unanticipated molecular mechanisms underlying this neurobehavioral phenotype.