An identical‐by‐descent novel splice‐donor variant in <i>PRUNE1</i> causes a neurodevelopmental syndrome with prominent dystonia in two consanguineous Sudanese families

Koko, Mahmoud; Elsayed, Liena; Hamed, Ahlam A.; Mohammed, Ibrahim; Elseed, Maha A.; Hamad, Muddathir H.; Babai, Arwa; Siddig, Rayan A; Allah, Amal S I Abd; Mohamed, Mayada; EL-Amin, Melka O.; Esteves, Typhaine; Altmüller, Janine; Toliat, Mohammad Reza; Thiele, Holger; Nürnberg, Peter; Salih, Mustafa A.; Ahmed, Ammar; Lerche, Holger; Stevanin, Giovanni

doi:10.1111/ahg.12437

Cited by 5 publications

(4 citation statements)

References 33 publications

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“…The increased homozygosity in our cohort was re ected by the predominance of mono-allelic recessive diseases (73%) and the detection of three established/possible founder variants. Two of these founder variants were in ADAT3 and PRUNE1 genes as we reported previously (19,27). The third possible founder variant, NM_024306.4(FA2H):c.674T > C (p.Leu225Pro), was detected in two unrelated families, F61 and F68, that descended from different tribes in Kordofan province, western Sudan.…”

Section: Discussionsupporting

confidence: 61%

Clinical phenotyping and genetic diagnosis of a large cohort of Sudanese families with hereditary spinocerebellar degeneration

Stevanin

Hamed

Mohamed

et al. 2022

Preprint

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Hereditary spinocerebellar degenerative disorders (SCDs) is an umbrella term that covers a group of monogenic conditions that share common pathogenic mechanisms and include spastic paraplegia, spastic ataxia, cerebellar ataxia, and spinocerebellar ataxia. They are often complicated with axonal neuropathy and/or intellectual impairment. More than 200 genes and loci inherited through all modes of Mendelian inheritance are known. Autosomal recessive inheritance predominates in consanguineous communities; however, autosomal dominant and X-linked inheritance can also occur. Sudan is inhabited by genetically diverse populations, yet it has high consanguinity rates. We used next-generation sequencing, genotyping, bioinformatics analysis, and candidate gene approaches to study 90 patients from 38 unrelated Sudanese families segregating multiple forms of SCDs focusing on known human disease-associated genes. We reached the genetic diagnosis in 63% and up to 73% of the studied families when considering variants of unknown significance. Taking into account a series of Sudanese families that we previously analyzed, the combined success rate in the two series reached 52–59% (31–35/59 families). We also highlighted the genetic and clinical heterogeneity of SCDs in Sudan, as we identified no single major gene in our cohort and the potential for discovering novel SCDs genes in this population.

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Section: Discussionsupporting

confidence: 61%

Clinical phenotyping and genetic diagnosis of a large cohort of Sudanese families with hereditary spinocerebellar degeneration

Stevanin

Hamed

Mohamed

et al. 2022

Preprint

Self Cite

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“…The high level of homozygosity in our cohort was reflected by the predominance of homozygous recessive diseases (75%) and the detection of three established/possible founder variants. Two of these founder variants were in ADAT3 and PRUNE1 genes as we reported previously [19,27]. The third possible founder variant, NM_024306.5:c.674 T > C (p.Leu225Pro), was in FA2H and was detected in two unrelated families, F61 and F68, that descended from different tribes in Kordofan province, western Sudan.…”

Section: Diagnosis Yieldsupporting

confidence: 60%

Clinical phenotyping and genetic diagnosis of a large cohort of Sudanese families with hereditary spinocerebellar degenerations

et al. 2023

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Hereditary spinocerebellar degenerations (SCDs) is an umbrella term that covers a group of monogenic conditions that share common pathogenic mechanisms and include hereditary spastic paraplegia (HSP), cerebellar ataxia, and spinocerebellar ataxia. They are often complicated with axonal neuropathy and/or intellectual impairment and overlap with many neurological conditions, including neurodevelopmental disorders. More than 200 genes and loci inherited through all modes of Mendelian inheritance are known. Autosomal recessive inheritance predominates in consanguineous communities; however, autosomal dominant and X-linked inheritance can also occur. Sudan is inhabited by genetically diverse populations, yet it has high consanguinity rates. We used next-generation sequencing, genotyping, bioinformatics analysis, and candidate gene approaches to study 90 affected patients from 38 unrelated Sudanese families segregating multiple forms of SCDs. The age-at-onset in our cohort ranged from birth to 35 years; however, most patients manifested childhood-onset diseases (the mean and median ages at onset were 7.5 and 3 years, respectively). We reached the genetic diagnosis in 63% and possibly up to 73% of the studied families when considering variants of unknown significance. Combining the present data with our previous analysis of 25 Sudanese HSP families, the success rate reached 52–59% (31–35/59 families). In this article we report candidate variants in genes previously known to be associated with SCDs or other phenotypically related monogenic disorders. We also highlight the genetic and clinical heterogeneity of SCDs in Sudan, as we did not identify a major causative gene in our cohort, and the potential for discovering novel SCD genes in this population.

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“…Mild cortical, subcortical, and cerebellar atrophy, and a thin corpus callosum, were described on brain MRI in these affected patients. Additionally, periventricular subcortical white matter hyperintensities were detected in one individual ( 25 ).…”

Section: Imaging Findingsmentioning

confidence: 99%

Neuroimaging in PRUNE1 syndrome: a mini-review of the literature

Scorrano,

Battaglia,

Spiaggia

et al. 2023

Front. Neurol.

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Prune exopolyphosphatase 1 (PRUNE1) is a short-chain phosphatase that is part of the aspartic acid-histidine-histidine (DHH) family of proteins. PRUNE1 is highly expressed in the central nervous system and is crucially involved in neurodevelopment, cytoskeletal rearrangement, cell migration, and proliferation. Recently, biallelic PRUNE1 variants have been identified in patients with neurodevelopmental disorders, hypotonia, microcephaly, variable cerebral anomalies, and other features. PRUNE1 hypomorphic mutations mainly affect the DHH1 domain, leading to an impactful decrease in enzymatic activity with a loss-of-function mechanism. In this review, we explored both the clinical and radiological spectrum related to PRUNE1 pathogenic variants described to date. Specifically, we focused on neuroradiological findings that, together with clinical phenotypes and genetic data, allow us to best characterize affected children with diagnostic and potential prognostic implications.

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An identical‐by‐descent novel splice‐donor variant in PRUNE1 causes a neurodevelopmental syndrome with prominent dystonia in two consanguineous Sudanese families

Cited by 5 publications

References 33 publications

Clinical phenotyping and genetic diagnosis of a large cohort of Sudanese families with hereditary spinocerebellar degeneration

Clinical phenotyping and genetic diagnosis of a large cohort of Sudanese families with hereditary spinocerebellar degeneration

Clinical phenotyping and genetic diagnosis of a large cohort of Sudanese families with hereditary spinocerebellar degenerations

Neuroimaging in PRUNE1 syndrome: a mini-review of the literature

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