Expanding Phenotype of Poirier–Bienvenu Syndrome: New Evidence from an Italian Multicentrical Cohort of Patients

Orsini, Alessandro; Santangelo, A.; Bravin, Francesca; Bonuccelli, Alice; Peroni, Diego; Battini, Roberta; Foiadelli, Thomas; Bertini, Veronica; Valetto, Angelo; Iacomino, Michele; Nigro, Vincenzo; Torella, Annalaura; Scala, Marcello; Capra, Valeria; Vari, Maria Stella; Fetta, Anna; Pisa, Veronica Di; Montanari, Francesca; Epifanio, Roberta; Bonanni, Paolo; Giorda, Roberto; Operto, Francesca Felicia; Pastorino, Grazia Maria Giovanna; Sarıgeçili, Esra; Serdaroğlu, Esra; Okuyaz, Çetin; Bozdogan, Sevgan; Musante, Luciana; Faletra, Flavio; Zanus, Caterina; Ferretti, Alessandro; Vigevano, Federico; Striano, Pasquale; Cordelli, Duccio Maria

doi:10.3390/genes13020276

Cited by 14 publications

(18 citation statements)

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“…POBINDS is a very rare autosomal dominant genetic disorder (1). Poirier et al in 2017 provided the first report of mutations in the CSNK2B gene in two unrelated patients with neurodevelopmental abnormality and epilepsy; since then, a total of 57 patients with pathogenic mutations in this gene have been described (1,2,(14)(15)(16)(17)(18)(19)(20). The most frequent manifestations of these subjects with mutations in the CSNK2B gene are epilepsy, developmental delays, and intellectual disabilities (Tables 1, 3).…”

Section: Discussionmentioning

confidence: 99%

“…CSNK2B deficiency alters neuron development and synaptic transmission, resulting in severe neurodevelopmental deficiencies (12,13). Recently, 57 unrelated patients with Poirier-Bienvenu neurodevelopmental syndrome and de novo mutations in the CSNK2B gene have been described (1,2,(14)(15)(16)(17)(18)(19)(20). The phenotypes of these patients were heterogeneous and included treatable or untreatable seizures, mild-to-profound intellectual disabilities/or learning disabilities, language delays, and other symptoms (1,2,(14)(15)(16)(17)(18)(19)(20).…”

Section: Introductionmentioning

confidence: 99%

“…Recently, 57 unrelated patients with Poirier-Bienvenu neurodevelopmental syndrome and de novo mutations in the CSNK2B gene have been described (1,2,(14)(15)(16)(17)(18)(19)(20). The phenotypes of these patients were heterogeneous and included treatable or untreatable seizures, mild-to-profound intellectual disabilities/or learning disabilities, language delays, and other symptoms (1,2,(14)(15)(16)(17)(18)(19)(20). The severity of the phenotypes caused by mutations in the CSNK2B gene and the treatment of patients with Poirier-Bienvenu neurodevelopmental syndrome remain to be fully explored.…”

Section: Introductionmentioning

confidence: 99%

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De Novo CSNK2B Mutations in Five Cases of Poirier–Bienvenu Neurodevelopmental Syndrome

et al. 2022

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The Poirier–Bienvenu neurodevelopmental syndrome is an autosomal dominant disorder characterized by intellectual disability and epilepsy. The disease is caused by mutations in the CSNK2B gene, which encodes the beta subunit of casein kinase II, and it has important roles in neuron development and synaptic transmission. In this study, five Chinese patients were diagnosed with Poirier–Bienvenu neurodevelopmental syndrome caused by CSNK2B mutations by whole exome sequencing. We detected four different de novo variants of the CSNK2B gene in these five unrelated Chinese patients: two novel mutations, namely, c.100delT (p.Phe34fs*16) and c.158_159insA (p.Asp55fs*4), and two recurrent mutations, namely, c.1A>G (p.Met1?) and c.332 G >C (p.R111P). All five patients showed mild-to-profound intellectual disabilities/or learning disabilities and developmental delays, with or without seizures. Although intellectual disability/developmental delay and epilepsy are the most common manifestations of CSNK2B deficiency, the clinical phenotypes of probands are highly variable, and there is no significant correlation between genotype and phenotype. An abnormal stature may be another common manifestation of CSNK2B deficiency. Here, we report the effects of growth hormone (GH) therapy on the patients' linear height. In conclusion, Poirier–Bienvenu neurodevelopmental syndrome is a highly heterogeneous disease caused by mutations in the CSNK2B gene. The phenotype was highly variable, and no significant correlation of genotype and phenotype was found. Patients with short-stature and CSNK2B deficiency may benefit from GH therapy. The identification and characterization of these novel variants will expand the genotypic and phenotypic spectrum of Poirier–Bienvenu neurodevelopmental syndrome.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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De Novo CSNK2B Mutations in Five Cases of Poirier–Bienvenu Neurodevelopmental Syndrome

et al. 2022

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“…During the finalization of the study and manuscript preparation, patients 1, 8, 9, and 10 were eventually presented in a frame of more extensive gene-specific cohort description. These results allowed us to confirm a specific electroclinical syndrome ( SLC13A5 ), to add new elements to known DEEs or NDDs ( SPATA5 , CSNK2B ), and to substantiate a candidate gene as a disease gene ( SPEN ) [ 39 , 40 , 41 , 42 ].…”

Section: Resultsmentioning

confidence: 99%

The Genetic Diagnosis of Ultrarare DEEs: An Ongoing Challenge

Musante

Costa

Zanus

et al. 2022

Genes

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Epileptic encephalopathies (EEs) and developmental and epileptic encephalopathies (DEEs) are a group of severe early-onset neurodevelopmental disorders (NDDs). In recent years, next-generation equencing (NGS) technologies enabled the discovery of numerous genes involved in these conditions. However, more than 50% of patients remained undiagnosed. A major obstacle lies in the high degree of genetic heterogeneity and the wide phenotypic variability that has characterized these disorders. Interpreting a large amount of NGS data is also a crucial challenge. This study describes a dynamic diagnostic procedure used to investigate 17 patients with DEE or EE with previous negative or inconclusive genetic testing by whole-exome sequencing (WES), leading to a definite diagnosis in about 59% of participants. Biallelic mutations caused most of the diagnosed cases (50%), and a pathogenic somatic mutation resulted in 10% of the subjects. The high diagnostic yield reached highlights the relevance of the scientific approach, the importance of the reverse phenotyping strategy, and the involvement of a dedicated multidisciplinary team. The study emphasizes the role of recessive and somatic variants, new genetic mechanisms, and the complexity of genotype–phenotype associations. In older patients, WES results could end invasive diagnostic procedures and allow a more accurate transition. Finally, an early pursued diagnosis is essential for comprehensive care of patients, precision approach, knowledge of prognosis, patient and family planning, and quality of life.

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“…Conversely, variants in CSNK2B have recently been associated with the Poirier-Bienvenu neurodevelopmental syndrome (MIM: #618732), a neurological disorder characterised by early-onset and possibly refractory seizure, intellectual disability of various degree, and ASD. The c.384_394delAGGTGAAGCCA, p.(Pro128fs) frameshift variant was identified in the proband at the heterozygous state and has recently been reported as pathogenic in a small cohort of Poirier-Bienvenu patients [ 28 ]. Familial segregation analysis confirmed that both variants originated de novo in the proband.…”

Section: Resultsmentioning

confidence: 99%

Challenging Occam’s Razor: Dual Molecular Diagnoses Explain Entangled Clinical Pictures

Spedicati

Morgan

Pianigiani

et al. 2022

Genes

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Dual molecular diagnoses are defined as the presence of pathogenic variants at two distinct and independently segregating loci that cause two different Mendelian conditions. In this study, we report the identification of double genetic disorders in a series of patients with complex clinical features. In the last 24 months, 342 syndromic patients have been recruited and clinically characterised. Whole Exome Sequencing analysis has been performed on the proband and on both parents and identified seven patients affected by a dual molecular diagnosis. Upon a detailed evaluation of both their clinical and molecular features, subjects are able to be divided into two groups: (A) five patients who present distinct phenotypes, due to each of the two different underlying genetic diseases; (B) two patients with overlapping clinical features that may be underpinned by both the identified genetic variations. Notably, only in one case a multilocus genomic variation was already suspected during the clinical evaluation. Overall, our findings highlight how dual molecular diagnoses represent a challenging model of complex inheritance that should always be considered whenever a patient shows atypical clinical features. Indeed, an accurate genetic characterisation is of the utmost importance to provide patients with a personalised and safe clinical management.

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Expanding Phenotype of Poirier–Bienvenu Syndrome: New Evidence from an Italian Multicentrical Cohort of Patients

Cited by 14 publications

References 17 publications

De Novo CSNK2B Mutations in Five Cases of Poirier–Bienvenu Neurodevelopmental Syndrome

De Novo CSNK2B Mutations in Five Cases of Poirier–Bienvenu Neurodevelopmental Syndrome

The Genetic Diagnosis of Ultrarare DEEs: An Ongoing Challenge

Challenging Occam’s Razor: Dual Molecular Diagnoses Explain Entangled Clinical Pictures

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