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A missense variant in EXOSC8 causes exon skipping and

expands the phenotypic spectrum of pontocerebellar
hypoplasia type 1C
✉ ✉
Maha S. Zaki1 , Sherif F. Abdel-Ghafar2 and Mohamed S. Abdel-Hamid2

© The Author(s) 2023

Pontocerebellar hypoplasia (PCH) is a rare heterogeneous neurodegenerative disorder affecting the pons and cerebellum and is
currently classified into 17 types (PCH1-PCH17). PCH1 is distinguishable from other types by the association of spinal motor neuron
dysfunction. Based on the underlying genetic etiology, PCH1 is further classified into 6 different subtypes (PCH1 A-F). Of them, PCH
type 1C is caused by pathogenic variants in EXOSC8 gene and so far, only four families have been described in the literature. In this
study, we report a new patient with PCH1 who proved by whole-exome sequencing to harbor a novel homozygous missense
variant in the splice region of EXOSC8 gene (c.238 G > A; p.Val80Ile). Studying mRNA of the patient confirmed that this variant
results in skipping of exon 5 of the gene and early protein truncation. Our patient presented with the main clinical findings of PCH
1234567890();,:

type 1C including psychomotor retardation, spasticity, spinal muscle atrophy, and respiratory problems. However, unlike most of
the reported cases, he did not develop hearing or visual impairment and displayed a longer survival. In addition, our patient had
dysmorphic facies, nystagmus, congenital esotropia and contractures which were infrequently described in patients with EXOSC8.
Diaphragmatic hernia, dilated lateral ventricles, hypoplastic temporal lobes, and thinning of the brain stem were additional new
findings noted in our patient. This study presents the fifth family with this extremely rare type of PCH and expands the associated
clinical and brain imaging findings.

Journal of Human Genetics (2024) 69:79–84; https://doi.org/10.1038/s10038-023-01207-4

INTRODUCTION [10, 11]. Furthermore, dominant variants in DIS3 have been linked
The RNA exosome is an evolutionarily conserved, multi-subunits to multiple myeloma [12].
ribonuclease complex that is critical for processing and/or To date, only four families with PCH type 1C have been
degrading a variety of RNA molecules [1]. Eukaryotic RNA described in the literature [7, 13]. Herein, we describe an
exosome consists of a two layered ring like structure made from additional family with PCH type 1C harboring a novel missense
nine conserved core subunits, through which RNAs could pass. variant in EXOSC8 gene. In addition, we present a review of all
The upper ring (also known as cap of the exosome) is composed reported cases to refine the clinical and brain imaging findings of
of EXOSC1-3 while the lower ring (the barrel of the exosome) is the disorder.
made by EXOSC4-9. The human exosome had two additional
catalytic subunits “EXOSC10 and DIS3” [2, 3]. The RNA exosome
functions in both the nucleus and the cytoplasm [4, 5]. Inside the PATIENTS AND METHODS
nucleus, the exosome processes and degrades multiple RNA Patient
precursors such as un-spliced pre-messenger RNAs and cryptic The Neurogenetics/Neuropediatrics Clinic at the National Research Centre
transcripts while in the cytoplasm, it targets RNAs with AU-rich (NRC), Cairo received a referral for diagnosis and counseling of a 3 years
elements (AREs) or RNAs that escaped nucleus degradation [3]. old boy from Algeria. Thorough medical history, pedigree construction,
Recently, pathogenic variants in six exosome subunits genes and full general and neurological assessments were conducted. Investiga-
have been associated with different tissue specific disorders [3]. tions including karyotyping, metabolic work up, ophthalmological evalua-
Biallelic variants in EXOSC3, EXOSC8, EXOSC9, and EXOSC1 have tion, neurophysiological studies (EEG, electromyography and nerve
conduction velocity, visual evoked potential, electroretinogram, auditory
been reported in different subtypes of pontocerebellar hypoplasia brain stem evoked potential), and neuroimaging were performed.
type 1 (PCH1), which is usually associated with spinal motor The Medical Research Ethics of the NRC in accordance with “World
neurons dysfunction [6–9]. On the other hand, EXOSC2 variants Medical Association Declaration of Helsinki” in 1995 (as revised in Seoul
cause a recessive neurological disease with short stature, hearing 2008) approved the research study (Approval: 20105) and written informed
loss, retinitis pigmentosa, and distinctive facies (MIM #617763) consent was obtained from the parents.

1
Clinical Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt. 2Medical Molecular Genetics Department, Human
Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt. ✉email: dr_mahazaki@yahoo.com; mohamadnrc@hotmail.com

Received: 10 July 2023 Revised: 29 August 2023 Accepted: 6 November 2023

Published online: 29 November 2023
 M.S. Zaki et al.
80
Molecular analysis (Qiagen, Hilden, Germany). Five µg of total RNA were reverse transcribed
Whole exome sequencing (WES) and bioinformatic analysis. Genomic DNA into cDNA using COSMO cDNA Synthesis Kit (Willowfort, Birmingham,
from the patient and his parents was extracted from peripheral blood United Kingdom). The synthesized cDNA was then used as a template for
samples using Qiagen Blood DNA Kit (Qiagen, Hilden, Germany) and partial amplification of the EXOSC8 gene (from exons 3 to 7) using one pair
quantified by a Nanodrop 2000 system (Thermal Fisher Scientific, Inc., of primers: 5′-CCACAACTGTCAACATCGGT-3′ and 5′-CAGACAAGCTTTCCTG-
Waltham, Massachusetts, USA). WES was performed using SureSelect GAGA-3′ under the following conditions: 96 °C for 2 min, a total of 35 cycles
Human All Exome 50 Mb Kit (Agilent, Santa Clara, CA, USA) and analyzed of 94 °C for 30 s, annealing at 62.5 °C for 30 s, 72 °C for 30 s, and a final
on Illumina NovaSeq 6000 (Illumina, San Diego, CA, USA). The obtained extension of 72 °C for 5 min. PCR products were separated by 1% agarose
sequences were aligned to UCSC human genome GRCh37/hg19 and gel electrophoresis and then purified and sequenced as described above.
variants were verified through the GATK pipeline. Identified variants were
checked against public genetic databases like Genome Aggregation
Database (gnomAD, https://gnomad.broadinstitute.org/), 1000 Genomes RESULTS
(www.1000genomes.org), and dbSNP (http://www.ncbi.nlm.nih.gov/SNP/). Clinical evaluation
Pathogenicity of detected variants were predicted using various bioinfor-
matics tools as SIFT (https://provean.jcvi.org/protein), PolyPhen-2 (https:// Our patient is a 3 years and 4 months old boy born to a healthy
genetics.bwh.harvard.edu/pph2/) and MutationTaster (https:// first cousin couples from Algeria (Fig. 1A). He is the first child in the
www.mutationtaster.org/). Analysis of the raw data, variant annotation family and had a healthy younger brother. No similar family
and prioritization were performed using the BaseSpace Variant Interpreter history was recorded. The pregnancy history was uneventful and
Server. Variants were prioritized based on the mode of inheritance, relation delivery was by Cesarean section at the 39th week of gestation.
the patient’s phenotype, minor allele frequency and in silico predicted Lethargy and abnormal breathing were noted few minutes after
pathogenicity. birth and he was admitted to NICU directly for 2 weeks.
Anthropometric measurements at birth were verified as weight
Segregation analysis. Segregation analysis of the identified variant in the 3 kg (−1SD), height 49 cm (−0.5 SD), and head circumference
parents and the healthy sib was conducted by PCR amplification of exon 5 34.3 cm (−0.9 SD). During infancy and early childhood, recurrent
of the EXOSC8 using specific primer designed by Primer3 software followed
by purification with Exo-SAP PCR Clean-up kit (Fermentas, Germany) and vomiting and dyspnea were prominent manifestations owed to
sequencing using the BigDye Terminator v3.1 Cycle Sequencing Kit the presence of diaphragmatic hernia that was operated at the
(Applied Biosystems, Foster City, CA, USA) on the ABI Prism 3500 Genetic age of 16 months. Our proband did not achieve any develop-
Analyzer (Applied Biosystems) according to manufacturer’s instructions. mental milestones except for fairly recognizing his parents and
vocalized. He could not use the hands or respond to his name.
Functional study of the c.238 G > A (p.Val80Ile) variant. To study the effect Epilepsy was not noted by parents. On examination, the patient
of the missense variant c.238 G > A (p.Val80Ile) on splicing, total RNA was had quadriparesis and failed to support the head. His weight was
isolated from patient’s cultured primary fibroblasts using QIAamp RNA kit 9 kg (−3.75 SD), height 87 cm (−2SD) and head circumference

Fig. 1 A Pedigree of the studied family. B, C Face and profile of our patient showing dolichocephaly, long face, sparse arched eye brows,
hypertelorism, broad nasal root, downslanting palpebral fissures, esotropia, hypoplastic alae nasii, smooth long philtrum, prominent upper lip,
receded mandible, pointed chin and low-set large ears. D–H Brain MRI, Axial T2W (D, F, G), Coronal T2W (E), and Sagittal T1W (H) showing
severe hypoplasia of cerebellum (D, E; arrow head), hypoplastic temporal lobe (F; long arrow), mild cortical atrophy (G; short black arrow),
dilated asymmetric lateral ventricles (G), hypoplastic vermis (H; white short arrow), mild brain stem hypoplasia (H, notched arrow) and thin
corpus callosum (H)

Journal of Human Genetics (2024) 69:79 – 84

 M.S. Zaki et al.
81

Fig. 2 A Portions of the gDNA sequencing electropherograms showing the EXOSC8 variant identified in our patient. The arrow indicates the
site of variant. B A 1% agarose gel showing partial amplification of the cDNA of the EXOSC8 (from exons 3 to 7) in our patient and a normal
control subject. C Part of the sequencing electropherograms of the cDNA fragment showing exon 5 skipping. D Schematic diagram of the
EXOSC8 gene showing all reported variants and their location

48.7 cm (−0.9 SD). Craniofacial features showed dolichocephaly, Agarose gel electrophoresis showed that the patient had a shorter
long face, sparse arched eyebrows, hypertelorism, broad nasal band in comparison to the normal control (Fig. 2B) and then
root, downslanting palpebral fissures, esotropia, hypoplastic alae sequence analysis confirmed that this variant induced exon 5
nasii, smooth long philtrum, prominent upper lip, receded skipping and ultimately production of an early stop codon at exon
mandible, pointed chin, microstomia, low-set large protruded 7 (p.Val80Phefs*39) (Fig. 2C).
ears and asymmetric larger right side (Fig. 1B). General examina-
tion was normal except for arthrogryposis, clenched hands and
long toes. DISCUSSION
Neurological evaluation showed severe axial hypotonia, limbs PCH represents a group of clinically and genetically heteroge-
hypertonia and brisk reflexes, and positive Babinski sign. neous neurodegenerative disorders with prenatal onset [14]. PCH1
Investigations revealed normal karyotyping, metabolic screening, is characterized by cerebellar hypoplasia along with degeneration
acylcarnitine profile, organic acids in urine, echocardiography, of the bulbar and spinal motor neurons, which is identical to
abdominal sonar, auditory brain stem evoked potential, electro- spinal muscular atrophy (SMA). Initial reports of PCH1 described it
encephalogram and fundus examination. EMG and NCV identified as a fatal disorder in neonates, with symptoms such as
anterior horn cells dysfunction. Brain MRI revealed mild cortical polyhydramnios, congenital contractures, respiratory failure, and
atrophic changes, asymmetric dilatation of lateral ventricles more severe muscle weakness [15, 16]. However, subsequent studies
in the left side, thin corpus callosum, hypoplastic temporal lobes, illustrated that the ventral pons could be spared, and patients
severe hypoplasia of cerebellum (more involvement of the might survive till puberty, with broadening of the clinical and
hemispheres) and mild brain stem hypoplasia (Fig. 1D–H). neuroradiological spectrum of PCH1 [17, 18].
At present, PCH1 is further classified into six subtypes (PCH1A-F)
Molecular findings based on the underlying causative genes. Of them, four are
WES analysis identified a new homozygous missense variant associated with variants in exosome genes: PCH1B is caused by
(c.238 G > A, p.Val80Ile) in the EXOSC8 (NM_181503.2), which is EXOSC3 [6], PCH1C by EXOSC8 [7], PCH1D by EXOSC9 [8], and
associated with PCH type 1C as the likely cause of the patient’s PCH1F by EXOSC1 [9]. On the other hand, PCH1A and PCH1E are
phenotype. The identified variant affects a highly conserved caused by variants in VRK1 and SLC25A46 genes, respectively
amino acid residue and is located in the last nucleotide of exon 5 [19, 20].
of the gene. Segregation analysis confirmed the presence of the PCH type 1C is an ultra-rare subtype of PCH, with only four
variant in the homozygous state in the patient while both parents reported families [7, 13]. The initial report by Boczonadi and co-
and the healthy sibling were found to be heterozygous (Fig. 2A). authors [7] described three unrelated consanguineous families,
The c.238 G > A variant is not found in public genetic databases or two of them were of Hungarian Romanian origin who shared the
our in-house database of over 1500 exomes and is predicted to be same missense variant (c.815 G > C, p.Ser272Thr). The third family
disease-causing by different bioinformatic tools. In addition, was of Palestinian descent and had a different missense variant
Alamut, SpliceAi, dbscSNV and MaxEntScan software predicted (c.5 C > T, p.Ala2Val). Subsequently, in 2021 Rodríguez-García and
that this variant might influence splicing. coauthors [13] reported a Spanish family with three heterozygous
EXOSC8 variants including the same missense variant found in the
Effect of EXOSC8 variant on patient’s RNA Hungarian Romanian families (Table 1).
As the identified missense variant is located in the splice region, Family 1 of Boczonadi et al. [7] comprised 7 patients, who all
we tested its effect on splicing. We partially amplified the EXOSC8 died with respiratory failure before reaching their second year.
gene in cDNA of the patient and a normal control individual. Similarly, one of the two sibs of Family 2, with the same variant,

Journal of Human Genetics (2024) 69:79 – 84

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Table 1. Clinical, neurological and brain imaging findings of patients with pathogenic EXOSC8 variants
Bocozonadi et al. (2014) Rodríguez-García This study
et al.. (2021)
Family 1 (18 patients) Family 2 Family 3 Family 4 Family 5

Patient 1 Patient 2 Patient Patient 4 Patient 5 Patient 6 Patient 7 Patient 1 Patient 2 Patient 1 Patient 2
3
Sex M F M M F M M F M M M M M
Consanguinity + - + - +
Onset/death 2 m/ 11 m 2 m/ 9 m 4 m/ 1 m/ 14 m 1.5 m/ 18 m 12d/ 8 m 2 m/ 19 m 1.5 m/ 13 m 2 m/ alive 6 m/ 28 m 4 m/ alive 5 m/alive 16 y Since early life/
13 m 9m 5y alive 3 y
Facial + - + + - - - - - - - - +
dysmorphism
Ophthalmological Vision loss Vision loss Vision Vision loss Vision loss Vision loss Vision loss Vision loss Vision loss - - Congenital Congenital
abnormalities loss esotropia, esotropia,
Nystagmus (5 m) nystagmus
Ophthalmoparesis,
Optic disk drusen.
Hearing loss + + + + + + + + + - - - -
Motor dysfunction + + + + + + + + + + + + +
Respiratory + + + + + + + + + + + + Recurrent chest
problems infection, after
birth abnormal
breathing.
tachypnea
Neurological signs
Muscle + + + + + - - + + + + + +
weakness
Spasticity Spastic Spastic + Spastic Spastic Spastic Spastic Spastic Spastic - - Lower limbs Spastic
M.S. Zaki et al.

tetraparesis tetraparesis tetraparesis tetraparesis tetraparesis tetraparesis tetraparesis tetraparesis spasticity tetraparesis
Hypotonia - - + + + - - - - - - - Severe axial
hypotonia
and limbs
hypertonia
Contractions - - - + + - - - - + - - +
MRI findings N/A 2.5 m 5m 11 m 2m N/A 6m N/A 5m 2y 2y
Cortical atrophy + - + - + - - - - +
Cerebellar - - + - - - + + + +
atrophy
Vermis + + - - - - + + + +
hypoplasia
Thin corpus + - + + - + - - - -
callosum
Others - - - Immature - Immature Mega Mega - Dilated third
myelination myelination cisterna cisterna ventricles, mild
magna magna thinning of
brain stem,
hypoplastic
temporal lobes
Other Inguinal Tremor Inguinal Brachycephaly, Tremor Tremor TremorFeeding Inguinal Feeding Feeding Feeding Dysmetria Diaphragmatic
abnormalities hernia hernia Tremor difficulties herniaFeeding difficulties difficulties difficulties Dysdiadochokinesia hernia operated
Scoliosis difficulties at 14 months,
long toes.
Ethnicity Hungarian Romanian Hungarian Romanian Palestinian Spanish Algerian
Variant c.815 G > C c.815 G > C c.5 C > T c.390+1delG/ c.238 G > A
c.618 C > T/
c.815 G > C.
Effect on protein p.Ser272Thr p.Ser272Thr p.Ala2Val p.Ser116Lysfs*27/ p.Val80Ile
p.Pro210Ser/
p.Ser272Thr.

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died at the age of 13 months while the other sib was alive at the In conclusion, we described a new family with PCH type 1C and
time of publishing their study (9 months). The two sibs of Family 3 identified a novel EXOSC8 missense variant that resulted in exon
harboring the c.5 C > T (p.Ala2Val) variant showed a longer survival skipping. Although majority of the clinical findings of our patient
as one died at the age of 28 months while the other was alive (5 were similar to the previously reported patients, new and unusual
years). This led Boczonadi and co-authors [7] to consider PCH type findings such as dysmorphic facies, nystagmus, congenital
1C as a lethal type of PCH. Diversely, Rodríguez-García et al. [13] esotropia, contractures and diaphragmatic hernia were observed.
reported a 16-year-old boy with compound heterozygous variants In addition, brain MRI showed dilated ventricles, hypoplastic
in EXOSC8 and a slowly progressive milder phenotype. Our patient temporal lobes, and thinning of the brain stem, which were not
was 3 years and 4 months old at his last examination that pointed detected before in patients with EXOSC8 variants. Therefore, we
to better longevity in comparison to most of the reported cases. believe that our study refines and expands the phenotypic and
Almost all described patients with EXOSC8 variants including mutational spectrum of PCH type 1C.
ours (n = 13) exhibited psychomotor retardation, spasticity, SMA,
and respiratory problems. The respiratory issues are likely caused
by deficiencies in the respiratory chain complexes resulting in DATA AVAILABILITY
symptoms such as recurrent chest infections, tachypnea, abnor- The data supporting the findings of this study are available with the corresponding
mal breathing patterns which could eventually lead to respiratory author upon request.
failure [7, 13]. Spasticity was noted in 11/13 patients and was
affecting both upper and lower limbs except for one patient who
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ADDITIONAL INFORMATION
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1750-1172-9-23. Correspondence and requests for materials should be addressed to Maha S. Zaki or
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This work was funded by a research grant from the Science and Technology
Development Fund (STDF), Academy of Science Research and Technology, Egypt
(Grant number: 33650). Open access funding provided by The Science, Technology & © The Author(s) 2023

Journal of Human Genetics (2024) 69:79 – 84