Sequence variants in malignant hyperthermia genes in Iceland: classification and actionable findings in a population database.

Malignant hyperthermia (MH) susceptibility is a rare life-threatening disorder that occurs upon exposure to a triggering agent. MH is commonly due to protein-altering variants in RYR1 and CACNA1S. The American College of Medical Genetics and Genomics recommends that when pathogenic and likely pathogenic variants in RYR1 and CACNA1S are incidentally found, they should be reported to the carriers. The detection of actionable variants allows the avoidance of exposure to triggering agents during anesthesia. First, we report a 10-year-old Icelandic proband with a suspected MH event, harboring a heterozygous missense variant NM_000540.2:c.6710G>A r.(6710g>a) p.(Cys2237Tyr) in the RYR1 gene that is likely pathogenic. The variant is private to four individuals within a three-generation family and absent from 62,240 whole-genome sequenced (WGS) Icelanders. Haplotype sharing and WGS revealed that the variant occurred as a somatic mosaicism also present in germline of the proband's paternal grandmother. Second, using a set of 62,240 Icelanders with WGS, we assessed the carrier frequency of actionable pathogenic and likely pathogenic variants in RYR1 and CACNA1S. We observed 13 actionable variants in RYR1, based on ClinVar classifications, carried by 43 Icelanders, and no actionable variant in CACNA1S. One in 1450 Icelanders carries an actionable variant for MH. Extensive sequencing allows for better classification and precise dating of variants, and WGS of a large fraction of the population has led to incidental findings of actionable MH genotypes.

ARDS from miliary tuberculosis successfully treated with ECMO.

Tuberculosis is a rare cause of acute respiratory distress syndrome (ARDS) and mortality rates are high in tuberculosis patients that need treatment with mechanical ventilation. Experience of the use of extracorporeal membrane oxygenation (ECMO) in such circumstances is scarce. We report the case of an 18 year old man where prolonged therapy (50 days) with extracorporeal membrane oxygenation (ECMO) allowed extensive lung damage from miliary tuberculosis to heal. The case reflects how challenging the diagnosis of tuberculosis may be and how difficult it is to reach adequate blood levels of anti-tuberculosis drugs while on ECMO. It's also an example of how indications for ECMO have been expanding the last years and that long term ECMO therapy is possible without serious complications.