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Spyridakis, Ana C; Cao, Ying; Litra, Florentina

doi:10.7759/cureus.c100

Cited by 3 publications

(4 citation statements)

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“…PCH1 is characterized by anterior horn degeneration in the spinal cord with muscle weakness and hypotonia (Namavar et al, 2011), and specific MRI findings of cerebellar hypoplasia with variable involvement of cerebellar hemispheres, cerebrum, and pons (Rudnik‐Schöneborn et al, 2003). A wide range of clinical manifestations may affect individuals with PCH1 including developmental delay, psychomotor retardation, joint contractures, primary hypoventilation, feeding difficulties, visual and hearing impairment, seizures, and progressive microcephaly (Namavar et al, 2011; Spyridakis et al, 2022). To date, single amino acid variants in four different subunits of the RNA exosome (EXOSC1, EXOSC3, EXOSC8, and EXOSC9) have been reported to be associated with PCH1 (Van Dijk et al, 2017, 2021), although previously only a single individual with an EXOSC1 variant was known.…”

Section: Discussionmentioning

confidence: 99%

Pontocerebellar hypoplasia associated with p.Arg183Trp homozygous variant in EXOSC1 gene: A case report

Damseh

Obeidat

Ahammed

et al. 2023

American J of Med Genetics Pt A

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Pontocerebellar hypoplasia (PCH) is a heterogeneous group of rare neurodegenerative disorders characterized by a wide phenotypic range including severe motor and cognitive impairments, microcephaly, distinctive facial features, and other features according to the type. Several classes of PCH1 have been linked to mutations in the evolutionarily conserved RNA exosome complex that consists of nine subunits (EXOSC1 to EXOSC9) and facilitates the degradation and processing of cytoplasmic and nuclear RNA from the 3′ end. Only a single individual with an EXOSC1 mutation was reported with clinical features of PCH type 1 (PCH1F). Here, we report a 3‐month‐old female with PCH and additional clinical features not previously reported to be associated with PCH1, including dilated cardiomyopathy. On assessment, failure to thrive, microcephaly, distinctive facial features, and bluish sclera, were noted. Whole‐exome sequencing was performed and revealed a novel homozygous missense variant c.547C > T (p.Arg183Trp) in the EXOSC1 gene. Functional studies in a budding yeast model that expresses the human EXOSC1 variant Arg183Trp show a slow‐growth phenotype, whereas the previously identified PCH1F allele EXOSC1‐Ser35Leu is lethal, indicating impaired exosome function for both of these variants. The protein levels of both EXOSC1 variants are reduced compared with wild‐type when expressed in budding yeast. Herein, we ascertain the second case of PCH associated with a EXOSC1 variant that causes defects in RNA exosome function and provide a model organism system to distinguish between benign and pathogenic variants in EXOSC1.

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Section: Discussionmentioning

confidence: 99%

Pontocerebellar hypoplasia associated with p.Arg183Trp homozygous variant in EXOSC1 gene: A case report

Damseh

Obeidat

Ahammed

et al. 2023

American J of Med Genetics Pt A

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“…A total of 170 articles were included in the final review (alphabetically ordered based on author in Supplementary Table 2). 1,2,7–50,55,56,68–189 A PRISMA flow diagram is presented to track the process and number of studies included and excluded (Figure 1).…”

Section: Resultsmentioning

confidence: 99%

Genetic counselling considerations with genetic/genomic testing in Neonatal and Pediatric Intensive Care Units: A scoping review

Kim,

Pistawka,

Langlois

et al. 2023

Clinical Genetics

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Genetic and genomic technologies can effectively diagnose numerous genetic disorders. Patients benefit when genetic counselling accompanies genetic testing and international guidelines recommend pre‐ and post‐test genetic counselling with genome‐wide sequencing. However, there is a gap in knowledge regarding the unique genetic counselling considerations with different types of genetic testing in the Neonatal Intensive Care Unit (NICU) and the Pediatric Intensive Care Unit (PICU). This scoping review was conducted to identify the gaps in care with respect to genetic counselling for infants/pediatric patients undergoing genetic and genomic testing in NICUs and PICUs and understand areas in need of improvement in order to optimize clinical care for patients, caregivers, and healthcare providers. Five databases (MEDLINE [Ovid], Embase [Ovid], PsycINFO [Ebsco], CENTRAL [Ovid], and CINHAL [Ebsco]) and grey literature were searched. A total of 170 studies were included and used for data extraction and analysis. This scoping review includes descriptive analysis, followed by a narrative account of the extracted data. Results were divided into three groups: pre‐test, post‐test, and comprehensive (both pre‐ and post‐test) genetic counselling considerations based on indication for testing. More studies were conducted in the NICU than the PICU. Comprehensive genetic counselling was discussed in only 31% of all the included studies demonstrating the need for both pre‐test and post‐test genetic counselling for different clinical indications in addition to the need to account for different cultural aspects based on ethnicity and geographic factors.

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“…The hallmark of PCH type 1 is severe muscle weakness and hypotonia. Intellectual disability, as well as cerebellar symptoms such as nystagmus and ataxia, are observed later 11 …”

Section: Introductionmentioning

confidence: 99%

“…Intellectual disability, as well as cerebellar symptoms such as nystagmus and ataxia, are observed later. 11 Pontocerebellar hypoplasia is inherited in an autosomal recessive pattern. Males and females are equally affected, with more than 100 PCH type 1B cases have been reported.…”

Section: Introductionmentioning

confidence: 99%

No, it is not mutually exclusive! A case report of a girl with two genetic diagnoses: Craniofrontonasal dysplasia and pontocerebellar hypoplasia type 1B

Ibrahim

Scriver

Basalom

2023

Clinical Case Reports

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Key Clinical Message Multiple genetic disorders can coexist in one patient. When the phenotype is not fully explained with one diagnosis, it is recommended to perform further genetic investigations in search for coexisting second diagnosis. Abstract Craniofrontonasal dysplasia (CFND) (MIM: 304110) is an X‐linked dominant disorder that shows paradoxically greater severity in heterozygous females than in hemizygous males. It is caused by a pathogenic variant in EFNB1 . Pontocerebellar hypoplasia type 1B (PCH1B) (MIM: 614678) is an extremely rare condition with over 100 individuals reported to date. It is caused by biallelic pathogenic variants in EXOSC3 . This report presents the case of a girl who was diagnosed prenatally with CFND based on the findings on the prenatal imaging and the known diagnosis of CFND in her mother. She has severe global development delay that cannot be explained solely by the CFND diagnosis. Around the age of 2 years, she was diagnosed with PCH1B following whole exome sequencing (WES) testing. The objective of this study is to highlight the importance of pursuing genetic investigation if the available genetic diagnosis cannot fully explain the clinical picture. This is a case report of one patient and review of the literature. Informed consent was obtained from the parents. WES was performed by a private lab using next‐generation sequencing (NGS), DNA was sequenced on the NovaSeq 6000 using 2 × 150 bp paired‐end read. WES identified the following: homozygous pathogenic variant in EXOSC3 : C.395A>C, p.ASp132Ala, maternally inherited, likely pathogenic duplication at Xq13.1 (includes EFNB1 ) and paternally inherited 16p11.2 duplication that is classified as a variant of uncertain significance. Perusing more extensive genetic testing like: WES is indicated if the current genetic diagnosis cannot fully explain the phenotype in a patient.

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Cited by 3 publications

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Pontocerebellar hypoplasia associated with p.Arg183Trp homozygous variant in EXOSC1 gene: A case report

Pontocerebellar hypoplasia associated with p.Arg183Trp homozygous variant in EXOSC1 gene: A case report

Genetic counselling considerations with genetic/genomic testing in Neonatal and Pediatric Intensive Care Units: A scoping review

No, it is not mutually exclusive! A case report of a girl with two genetic diagnoses: Craniofrontonasal dysplasia and pontocerebellar hypoplasia type 1B

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