Risk of sudden cardiac death in EXOSC5-related disease.

TitleRisk of sudden cardiac death in EXOSC5-related disease.
Publication TypeJournal Article
Year of Publication2021
AuthorsCalame, DG, Herman, I, Fatih, JM, Du, H, Akay, G, Jhangiani, SN, Coban-Akdemir, Z, Milewicz, DM, Gibbs, RA, Posey, JE, Marafi, D, Hunter, JV, Fan, Y, Lupski, JR, Miyake, CY
JournalAm J Med Genet A
Date Published2021 Aug
KeywordsAntigens, Neoplasm, Atrioventricular Block, Child, Death, Sudden, Cardiac, Echocardiography, Electrocardiography, Exosome Multienzyme Ribonuclease Complex, Facies, Female, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Male, Mutation, Pedigree, Phenotype, RNA-Binding Proteins, Sequence Analysis, DNA, Young Adult

The RNA exosome is a multi-subunit complex involved in the processing, degradation, and regulated turnover of RNA. Several subunits are linked to Mendelian disorders, including pontocerebellar hypoplasia (EXOSC3, MIM #614678; EXOSC8, MIM #616081: and EXOSC9, MIM #618065) and short stature, hearing loss, retinitis pigmentosa, and distinctive facies (EXOSC2, MIM #617763). More recently, EXOSC5 (MIM *606492) was found to underlie an autosomal recessive neurodevelopmental disorder characterized by developmental delay, hypotonia, cerebellar abnormalities, and dysmorphic facies. An unusual feature of EXOSC5-related disease is the occurrence of complete heart block requiring a pacemaker in a subset of affected individuals. Here, we provide a detailed clinical and molecular characterization of two siblings with microcephaly, developmental delay, cerebellar volume loss, hypomyelination, with cardiac conduction and rhythm abnormalities including sinus node dysfunction, intraventricular conduction delay, atrioventricular block, and ventricular tachycardia (VT) due to compound heterozygous variants in EXOSC5: (1) NM_020158.4:c.341C > T (p.Thr114Ile; pathogenic, previously reported) and (2) NM_020158.4:c.302C > A (p.Thr101Lys; novel variant). A review of the literature revealed an additional family with biallelic EXOSC5 variants and cardiac conduction abnormalities. These clinical and molecular data provide compelling evidence that cardiac conduction abnormalities and arrhythmias are part of the EXOSC5-related disease spectrum and argue for proactive screening due to potential risk of sudden cardiac death.

Alternate JournalAm J Med Genet A
PubMed ID34089229
PubMed Central IDPMC8382094
Grant ListU54HG003273 / HG / NHGRI NIH HHS / United States
K23HL136932 / HL / NHLBI NIH HHS / United States
T32 GM007526 / GM / NIGMS NIH HHS / United States
R35 NS105078 / NS / NINDS NIH HHS / United States
R35NS105078 / NS / NINDS NIH HHS / United States
K23 HL136932 / HL / NHLBI NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
K08 HG008986 / HG / NHGRI NIH HHS / United States
T32 GM007526-42 / HG / NHGRI NIH HHS / United States

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