Figure 1.. Biallelic variants in EXOSC5 cause dysmorphology and abnormal brain findings. (a) Family pedigree, genetic variants, and segregation analysis of biallelic EXOSC5 variants. (b) Pictures of proband P1 showing 1. strabismus, 2. mild retrognathia and microcephaly, 3. absence of scoliosis, 4 and 5. grossly normal appearance of hands with tapering of the fingers, 6 and 7. normal feet. (c) Pictures of P2 showing several dysmorphic features including 1 and 2. microcephaly, sloping forehead, proportionally large ears, high nasal bridge, prominent nose with deviated septum, large mouth with thick lips, large tongue, misalignment of teeth, prognathism, 3. scoliosis, 4 and 5. severe multidigit camptodactyly of bilateral hands with knuckle pads on proximal and distal interphalangeal joints, 6 and 7. outward deviated toes with nodules of metatarsophalangeal joints. (d) and (e) Brain MRI of proband P1 at age 2 and 4 years, respectively, showing microcephaly, cerebellar atrophy, and hypomyelination. 1. Sagittal T1, 2. Coronal T2, 3. Axial T2, and 4. Axial T2/FLAIR. (f) Brain MRI of P2 at age 10 years, showing microcephaly, cerebellar atrophy, and white matter signal abnormalities. 1. sagittal T1, 2. coronal T2, 3. axial T2, and 4. axial T2/FLAIR. (g) Brain MRI of P2 at age 20 years, showing microcephaly, progressive cerebellar and cerebral atrophy, thinning of the corpus callosum, and white

Figure 2.. Cardiac conduction and rhythm abnormalities in patients with biallelic EXOSC5 variants. (a) Electrocardiogram (ECG) of proband P1 showing junctional bradycardia with intermittent sinus capture beats, first degree AV block, and nonspecific intraventricular conduction delay. (b) Holter monitor/Event recorder findings of P1 showing 1. Sinus rhythm with Mobitz Type I Wenckebach, 2. High grade AV block, 3 and 4. Junctional rhythm and ventricular tachycardia. (c) ECG of P2 showing sinus rhythm with first and second degree (Mobitz type I) AV block, complete right bundle branch block and left axis deviation (trifasicular block). (d) Holter monitor findings of P2 showing 1. 2:1 AV block, 2. 1st degree block, Mobitz Type I AV block, 3. Junctional rhythm with pause, 4. Ventricular tachycardia.

Figure 3.. Amino acid residue conservation and location of EXOSC5 variants. (a) Both EXOSC5 variants present in P1 and P2 are fully conserved across species. Conservation data obtained from Vertebrate Multiz Alignment & Conservation (46 Species) in UCSC Genome Browser (http://genome.ucsc.edu). (b) Structure of EXOSC5 mRNA and location of EXOSC5 variants present in P1 and P2 (red) and previously reported variants (black). The EXOSC5 variant observed in all patients with cardiac conduction abnormalities and/or arrhythmias, p.Thr114Ile, is indicated with a heart symbol.