Identification of disease‐causing variants in the EXOSC gene family underlying autosomal recessive intellectual disability in Iranian families

Abstract

Neurodevelopmental delay and intellectual disability (ID) can arise from numerous genetic defects. To date, variants in the EXOSC gene family have been associated with such disorders. Using next‐generation sequencing (NGS), known and novel variants in this gene family causing autosomal recessive ID (ARID) have been identified in five Iranian families. By collecting clinical information on these families and comparing their phenotypes with previously reported patients, we further describe the clinical variability of ARID resulting from alterations in the EXOSC gene family, and emphasize the role of RNA processing dysregulation in ARID.

Risk of sudden cardiac death in EXOSC5‐related disease

“…This individual is a compound heterozygote with a 1023 bp deletion involving exons 5–6 of EXOSC5 in addition to c.341C > T; p.Thr114Ile. EXOSC5 was independently reported as a candidate disease gene in a consanguineous Iranian family with three affected siblings homozygous for c.341C > T; p.Thre114Ile with developmental delay and adolescent onset right bundle branch block and bradycardia requiring pacemakers (Beheshtian et al, 2019). Therefore, six of the 10 individuals with EXOSC5 ‐related disease reported to date have some form of cardiac conduction abnormalities that have been clinically recognized (Suppl.…”

“…Two variants in EXOSC5 were identified in the proband. The first variant [Chr19:41897789: G > A (hg19); NM_020158.4; c.341C > T, p.Thr114Ile] is a known pathogenic variant (Beheshtian et al, 2019;Slavotinek et al, 2020). It is ultra-rare (defined as a MAF < 1/10,000; 17 heterozygotes in gnomAD v2.1.1) and well-conserved (Figure 3a) (Hansen et al, 2019).…”

“…More recently, EXOSC5 was identified as a cause of developmental delay, cerebellar abnormalities, short stature, and hypotonia (MIM *606492, Slavotinek et al, 2020). A unique feature of EXOSC5 ‐related disease is the occurrence of bradycardia or complete heart block requiring a pacemaker in four of the eight previously reported affected individuals (Beheshtian et al, 2019; Slavotinek et al, 2020). Conduction abnormalities and arrhythmias were not previously reported in EXOSC ‐related disease; it is unclear if these are a common trait that should be proactively screened and followed in affected individuals.…”

“…More recently, EXOSC5 was identified as a cause of developmental delay, cerebellar abnormalities, short stature, and hypotonia (MIM *606492, Slavotinek et al, 2020). A unique feature of EXOSC5related disease is the occurrence of bradycardia or complete heart block requiring a pacemaker in four of the eight previously reported affected individuals (Beheshtian et al, 2019;Slavotinek et al, 2020).…”

Integrated Bioinformatic Investigation of EXOSCs in Hepatocellular Carcinoma Followed by the Preliminary Validation of EXOSC5 in Cell Proliferation

“…Ample information accumulated on RNA degradation has been studied intensely [ 8 ]. It is noteworthy that the exosome complex (EXOSC) plays a central role in the degradation process of multiple RNAs both in the nucleus and cytoplasm [ 9 ]. In humans, the EXOSC is composed of ten evolutionarily conserved subunits, including the barrel-shaped core (EXOSC4-9 subunits) and three-subunit cap (EXOSC1-3) covering its surface, while EXOSC10 is bound to the catalytically inactive core and cap subunits of the EXOSC [ 10 ].…”