Clinical Features of Okur-Chung Neurodevelopmental Syndrome: Case Report and Literature Review

Khamirani, Hossein Jafari; Zoghi, Sina; Motealleh, Ali Reza; Dianatpour, Mehdi; Tabei, Seyed Mohammad Bagher; Mohammadi, Sanaz; Dastgheib, Seyed Alireza

doi:10.1159/000522353

Cited by 8 publications

(6 citation statements)

References 41 publications

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“…We found a novel heterozygous deleterious variant in CSNK2A1 (Arg172Leu) (likely pathogenic) with unknown origin, as the mother's sample was unavailable. A defective CSNK2A1 is known to cause Okur-Chung neurodevelopmental syndrome (OCNDS) with autosomal dominant inheritance (38). Although this variant lies close to a previously reported OCNDS deleterious variant (Ile174Met), our patient does not display any of the syndrome's characteristics, apart from seizures.…”

Section: Identi Cation Of Deleterious In Low Con Dence Genescontrasting

confidence: 47%

The complex etiology of Epilepsy in the Middle East: Genetic analysis and HLA associations

Fadda,

Alsabbagh,

Vasudeva

et al. 2024

Preprint

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Objectives Epilepsy is one of the most common neurological disorders. The cost to the health system and the impact on quality of life for patients with intractable epilepsies and associated comorbidities is significant. Disease etiology and pathogenesis are still not well understood. Genetic variants have been shown to be associated with 70% of epilepsies, and the remaining 30% enigmatic. This knowledge gap necessitates further research. The goal of this study is to partially bridge this gap through the genetic analysis of a cohort of patients with epilepsy from an understudied and highly consanguineous population, primarily of ethnicities from the Middle East and North Africa region. Methods Whole exome sequencing was carried out in 67 patients and their family members at a tertiary center in Qatar. The focus was on identifying deleterious genetic variants associated with epilepsy. Additionally, we performed in silico typing for 13 class I & II HLA genes and performed association analysis with disease status. Results Approximately 30% of cases were resolved through genetic analysis, revealing deleterious variants within 15 genes of established relevance to epilepsy and 5 others with weaker ties to the condition. These variants include single nucleotide variations (SNVs), small insertion/deletions (indels), copy number variations (CNVs) and loss of heterozygosity (LOH). Around 40% of the SNVs and indels are novel. The mode of inheritance is roughly evenly distributed between autosomal dominant and autosomal recessive, with two cases of X-linked recessive and one case of X-linked inheritance. Furthermore, we identified positive associations between epilepsy and alleles DRB1*07:01:01G and DRB4*01:01:01G, while allele DRB3*01:01:02Gexhibited a negative association. Significance Collectively, these findings delineate novel variants and a multifaceted genetic etiology in epilepsy pathogenesis, encompassing both immune and non-immune genes.

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Section: Identi Cation Of Deleterious In Low Con Dence Genescontrasting

confidence: 47%

The complex etiology of Epilepsy in the Middle East: Genetic analysis and HLA associations

Fadda,

Alsabbagh,

Vasudeva

et al. 2024

Preprint

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“…Sixteen articles reporting 47 OCNDS patients with germline CSNK2A1 pathogenic variants were included in the study (Akahira‐Azuma et al., 2018 ; Belnap et al., 2023 ; Chiu et al., 2018 ; Colavito et al., 2018 ; Duan et al., 2019 ; Jafari Khamirani et al., 2022 ; Martinez‐Monseny et al., 2020 ; Murakami et al., 2022 ; Nakashima et al., 2019 ; Okur et al., 2016 ; Owen et al., 2018 ; Trinh et al., 2017 ; Wafik et al., 2023 ; Wu et al., 2020 , 2021 ; Xu et al., 2020 ). Together with the two patients reported in our study, 49 patients were included in the final analysis.…”

Section: Resultsmentioning

confidence: 99%

“…CSNK2A1 predominantly consists of a single extensive functional domain (Figure 1a ). OCNDS typically presents with developmental delays, mild‐to‐moderate intellectual impairment, hypotonia, feeding challenges, distinctive facial features, speech delay, and may include non‐specific clinical characteristics such as behavioral issues, disrupted sleep patterns, microcephaly, seizures, and short stature in some cases (Jafari Khamirani et al., 2022 ; Okur et al., 2016 ). Previously, OCNDS cases were diagnosed as simplex cases due to de novo heterozygous pathogenic variants in CSNK2A1 with unaffected parents (Chiu et al., 2018 ; Okur et al., 2016 ).…”

Section: Introductionmentioning

confidence: 99%

“…However, a clear genotype–phenotype correlation has not been established. Most variants in OCNDS are missense variants primarily clustered within the functional regions of the CSNK2A1 kinase domain, while less commonly, frameshift variants have been reported as well (Jafari Khamirani et al., 2022 ; Okur et al., 2016 ). The molecular mechanisms underlying CSNK2A1 variants remain incompletely elucidated (Wafik et al., 2023 ).…”

Section: Introductionmentioning

confidence: 99%

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Okur‐Chung neurodevelopmental syndrome: Implications for phenotype and genotype expansion

Nan,

Chu,

Zhang

et al. 2024

Molec Gen & Gen Med

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BackgroundOkur‐Chung neurodevelopmental syndrome (OCNDS) is a rare autosomal dominant disorder caused by pathogenic variants in CSNK2A1. It is characterized by intellectual disability, developmental delay, and multisystemic abnormalities.MethodsWe performed the whole‐exome sequencing for a patient in a Chinese family. The co‐segregation study using the Sanger sequencing method was performed among family members. Reverse transcription and quantitative real‐time polymerase chain reaction were carried out using total RNA from blood samples of the proband and wild‐type control subjects. A review of patients with OCNDS harboring CSNK2A1 pathogenic variants was conducted through a comprehensive search of the PubMed database.ResultsWe identified a novel CSNK2A1 frameshift variant p.Tyr323Leufs*16 in a Chinese family. The proband, a 31‐year‐old female, presented with abnormal eating habits, recurrent seizures, language impairment, and intellectual disability. Her mother exhibited postnatal hernias, splenomegaly, and a predisposition to infections, but showed no significant developmental impairments or intellectual disability. Genetic studies revealed the presence of this variant in CSNK2A1 in both the proband and her mother. Transcription analysis revealed this variant may lead to nonsense‐mediated mRNA decay, suggesting haploinsufficiency as a potential disease mechanism. We reviewed 47 previously reported OCNDS cases and discovered that individuals carrying CSNK2A1 null variants may exhibit a diminished frequency of symptoms linked to language deficits, dysmorphic facial features, or intellectual disability, consequently presenting an overall milder phenotype when compared to those with missense variants.ConclusionWe report a novel frameshift variant, p.Tyr323Leufs*16, in an OCNDS family with a generally mild phenotype. This study may broaden the spectrum of clinical presentations associated with OCNDS and contribute novel insights into the genotype–phenotype correlation of this condition.

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“…MRI often reveals cortical neuronal migration defects. Published variants to date include 27 missense, 1 loss of start codon leading to loss of the first 137 amino acids in N terminal, 2 nonsense variants, 1 frameshift variant and 2 splice site variants (Okur et al ., 2016; Trinh et al ., 2017; Akahira-Azuma et al ., 2018; Chiu et al ., 2018; Colavito et al ., 2018; Owen et al ., 2018; Duan et al ., 2019; Nakashima et al ., 2019; Martinez-Monseny et al ., 2020; Wu et al ., 2020, 2021; Xu et al ., 2020a, b; Ranganath et al ., 2021; Jafari Khamirani et al ., 2022; Murakami et al ., 2022; Belnap et al ., 2023; Drenushe et al ., 2024; Wafik et al ., 2023). Clinvar and DECIPHER, however, list 25 and 3 loss of function variants, respectively including nonsense, frameshift and splice site variants.…”

Section: Introductionmentioning

confidence: 99%

Inherited loss of function variant in CSNK2A1: the oldest reported cases of Okur–Chung syndrome in a single family

Goel,

O’Donnell

2024

Clinical Dysmorphology

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Clinical Features of Okur-Chung Neurodevelopmental Syndrome: Case Report and Literature Review

Cited by 8 publications

References 41 publications

The complex etiology of Epilepsy in the Middle East: Genetic analysis and HLA associations

The complex etiology of Epilepsy in the Middle East: Genetic analysis and HLA associations

Okur‐Chung neurodevelopmental syndrome: Implications for phenotype and genotype expansion

Inherited loss of function variant in CSNK2A1: the oldest reported cases of Okur–Chung syndrome in a single family

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