NEW PATHOGENIC VARIANTS IN A PATIENT WITH CENTRAL CORE DISEASE AND MALIGNANT HYPERTHERMIA SUSCEPTIBILITY

Abstract

PURPOSE: Central Core Disease and malignant hyperthermia susceptibility results from RYR1 gene mutations. More than 200 different mutations in RYR1 have been reported, and they are also associated with other conditions, such as Malignant Hyperthermia (MH) susceptibility.  Report new pathogenic variants in a patient with Central Core Disease and Malignant Hyperthermia susceptibility. Medical record research of the index case and data obtained from the patient's mother (legal guardian). CASE DESCRIPTION: The index case is a seven years old Caucasian presented marked generalized hypotonia and failed to achieve motor milestone.  Investigation was not a muscle biopsy, but whole exome sequencing identified three variants in RYR1, two inherited in block from the mother, and one from the father: pathogenic c.7373G>A (p.Arg2458His) in exon 46 (associated with MH), likely pathogenic c.7093G>A (p.Gly2365Arg) in exon 44 and c.13746+4C>G in intron 94 (variant of uncertain significance), respectively. CONCLUSION: The described variants of maternal origin corroborated the clinical diagnosis of central core disease of autosomal recessive inheritance and heterozygous manifestation. Patient and his mother are predisposed to malignant hyperthermia episodes. Failure of the genetic test to detect the second mutation, or a synergistic effect of cis mutations on the protein, may explain the genotype-phenotype correlation.