Abstract KBG syndrome is a rare genetic disorder caused by heterozygous pathogenic variants in ANKRD11 . Affected individuals have developmental delay, short stature, characteristic facial features, and other dysmorphic findings. To date, a spectrum of unspecific neuroradiological defects has been reported in KBG patients, such as cortical defects, white matter abnormalities, corpus callosum, and cerebellar vermis hypoplasia. Deep clinical and neuroradiological phenotyping and genotype of a patient presenting with mild cognitive and behavioral problems were obtained after written informed consent. We herein describe the first KBG patient presenting with cerebellar heterotopia, a heterogeneous malformation characterized by the presence of clusters of neurons within the white matter of cerebellar hemispheres. This novel association broadens the neuroradiological spectrum of KBG syndrome, and further prompts to investigate the potential functions of ANKRD11 in cerebellar development. 

Cerebellar Heterotopia: Broadening the Neuroradiological Spectrum of KBG Syndrome.

KBG syndrome is characterised by developmental delay, dental (macrodontia of upper central incisors), craniofacial and skeletal anomalies. Since the identification of variants in the gene (ANKRD11) responsible for KBG syndrome, wider phenotypes are emerging. While there is phenotypic variability within many features of KBG syndrome, epilepsy is not usually markedly severe and movement disorders largely undocumented. Here we describe a novel early onset phenotype of dyskinetic epileptic encephalopathy in a male, who presented during infancy with a florid hyperkinetic movement disorder and developmental regression. Initially he had epileptic spasms and tonic seizures, and EEGs revealed a modified hypsarrhythmia. The epilepsy phenotype evolved to Lennox-Gastaut syndrome with seizures resistant to multiple anti-seizure therapies and the movement disorder evolved to choreoathetosis of limbs and head with oro-lingual dyskinesias. Previous extensive neurometabolic and imaging investigations, including panel-based exome sequencing were unremarkable. Later trio exome sequencing identified a de novo pathogenic heterozygous frameshift deletion of ANKRD11 (c.6792delC; p.Ala2265Profs*72). Review of the literature did not identify any individuals with such a hyperkinetic movement disorder presentation in combination with early-onset epileptic encephalopathy. This report expands the phenotype of ANKRD11-related KBG syndrome to include epileptic dyskinetic encephalopathy. 

Epileptic dyskinetic encephalopathy in KBG syndrome: Expansion of the phenotype

Marine phytoplankton has a wide range of distribution forming patterns. This study generally aims to determine the multi-directional distribution and dynamic patterns of phytoplankton 15 km off coast from the docking area of Bahrain Yacht Club in Sitra, Kingdom of Bahrain. Specifically to identify individual species’ population in the sampling stations; identify multi-directional distribution and pattern of marine plankton; find out significant differences in the station-to-station distribution of marine plankton; and relate the effect physicochemical parameter on the population of phytoplankton taxa. Results revealed 21 species of phytoplankton consisting of two phyla, Chrysophyta or diatoms with 13 species and Dinoflagellata or dinoflagellates with 8 species. Plankton population based on microscopy count varies from station-to-station. Thalasionema sp. of the diatom taxon dominates Station 1 (northeast), Station 3 (west) and Station 4 (northwest); Pseudo-Nitzschia australis in Station 2 (southwest) and Asteromphalus sp. in Station 5 (north) and C. furca of the dinoflagellates in Station1 (northeast) and 2 (southwest). Statistical analysis using t-test at p˂.05 depicted significant differences between Station 1 and 5; and Station 1 and 3 among the diatoms taxa while Station 1, 3 and 4 for dinoflagellates. Recorded physicochemical readings are within the acceptable level, therefore exerts insignificant effect on the population of phytoplankton where r = -0.38867. Multi-directional and dynamic patterns are illustrated using radar graph based on species population. The greater number of diatom species indicates good water quality and the physicochemical values which are within the standard level.

/pdf/dynamic-patterns-of-marine-phytoplankton-in-bahrain-sea-4xsz8wr2gq.pdf

Dynamic Patterns of Marine Phytoplankton in Bahrain Sea

KBG syndrome is a rare autosomal dominant condition characterized by multisystem developmental disorder, primarily caused by loss-of-function variants in ankyrin repeat domain-containing protein 11 (ANKRD11). Approximately 80 % of ANKRD11 variants associated with KBG syndrome, are frameshift and nonsense variants. Current insight into the pathogenesis of KBG syndrome resulting from ANKRD11 truncating variants remains limited. Here, we presented two members from a non-consanguineous Chinese pedigree both exhibiting characteristics fitting the KBG syndrome-associated phenotypic spectrum. Whole-exome sequencing identified a novel heterozygous frameshift variant in ANKRD11 (NM_013275.6, c.2280_2281delGT, p.Y761Qfs*20) in the proband. Sanger sequencing confirmed that the variant was inherited from her mother and co-segregated with KBG syndrome phenotype. In vitro functional assays revealed that the frameshift variant escaped nonsense-mediated mRNA decay, and resulting in a truncated protein with significantly increased expression levels compared to full-length ANKRD11. Immunofluorescence results demonstrated that truncated protein was predominantly expressed in the nucleus of HEK293 cells, while wild-type ANKRD11 was equally distributed in both the nucleus and cytoplasm. Moreover, the truncated protein significantly reduced CDKN1A/P21-promoter luciferase activity in comparison to wild-type ANKRD11 protein, as well as a remarkably decrease in the endogenous CDKN1A/P21 mRNA level in HEK293 cells. These findings suggest a loss of transcriptional activation function and potentially a dominant-negative mechanism. Overall, our study expands the mutational spectrum of ANKRD11 gene and provides new insights into the pathogenic mechanism of KBG syndrome caused by ANKRD11 truncating variants. 

Functional investigation of a novel ANKRD11 frameshift variant identified in a Chinese family with KBG syndrome

KBG syndrome (KBGS, OMIM: 148050), a rare genetic disorder, is clinically characterized by megalodontia, short stature, skeletal abnormalities, and nervous system manifestations. In the study, we explore the clinical and genetic characteristics of one neonate suffering KBGS caused by ANKRD11 gene mutation.The proband, a female, was born prematurely at 31 + 2 weeks. There were repeated infections and abdominal distension in the first month after birth, and the platelets could not rise to normal. Head ultrasound showed intracranial brain injury and intracranial hemorrhage.Sequencing revealed that there was a heterozygous mutation in exon 9 of the ANKRD11 gene (NM_013275.5) for the child, c.1896_1897delTA (p.H632Qfs*30), which was a de novo mutation and has not been reported. Combining clinical features and genetic results, the proband was diagnosed as KBGS.The brain sonography on day 4 after birth showed brain injury and intracranial hemorrhage. Therefore, 140 mg of bovine lung surfactant was administered through endotracheal intubation in addition to ventilator-assisted ventilation. Antibiotic treatment was also given till the inflammatory indicators of the infant returned to normal levels. The following-up of 1-year-6-month showed that the language, motion and height of development is slight falling behind the children of the same age.This is the first case of KBGS was diagnosed in the neonatal period, which provides a reference for the child to receive timely and correct treatment. 

Clinical feature and genetic mutation of KBG syndrome diagnosed in neonatal period: A case report

Background KBG syndrome is a highly variable neurodevelopmental disorder and clinical diagnostic criteria have changed as new patients have been reported. Both loss-of-function sequence variants and large deletions (copy number variations, CNVs) involving ANKRD11 cause KBG syndrome, but no genotype–phenotype correlation has been reported. Methods 67 patients with KBG syndrome were assessed using a custom phenotypical questionnaire. Manifestations present in >50% of the patients and a ‘phenotypical score’ were used to perform a genotype–phenotype correlation in 340 patients from our cohort and the literature. Results Neurodevelopmental delay, macrodontia, triangular face, characteristic ears, nose and eyebrows were the most prevalentf (eatures. 82.8% of the patients had at least one of seven main comorbidities: hearing loss and/or otitis media, visual problems, cryptorchidism, cardiopathy, feeding difficulties and/or seizures. Associations found included a higher phenotypical score in patients with sequence variants compared with CNVs and a higher frequency of triangular face (71.1% vs 42.5% in CNVs). Short stature was more frequent in patients with exon 9 variants (62.5% inside vs 27.8% outside exon 9), and the prevalence of intellectual disability/attention deficit hyperactivity disorder/autism spectrum disorder was lower in patients with the c.1903_1907del variant (70.4% vs 89.4% other variants). Presence of macrodontia and comorbidities were associated with larger deletion sizes and hand anomalies with smaller deletions. Conclusion We present a detailed phenotypical description of KBG syndrome in the largest series reported to date of 67 patients, provide evidence of a genotype–phenotype correlation between some KBG features and specific ANKRD11 variants in 340 patients, and propose updated clinical diagnostic criteria based on our findings.

Clinical description, molecular delineation and genotype–phenotype correlation in 340 patients with KBG syndrome: addition of 67 new patients

Determination of the spatial distribution of marine plankton off-coast of Sitra, Kingdom of Bahrain was conducted from August 2014-July 2015 to identify, categorize, and classify taxonomically the phyto-and-zooplankton. Population size was calculated based on abundance, density, and biomass from the collected water samples. Results showed 20 species of phytoplankton and 14 species of zooplankton. The phytoplankton includes 13 species which belong to Phylum Chrysophyta or diatoms, and seven species in Phylum Dinoflagellata or dinoflagellates. The 14 species of zooplankton were categorized to eight phyla—Protozoa, Cnidaria, Platyhelminthes, Rotifer, Annelida, Mollusca, Arthropoda, and Chordata. The identified species of phytoplankton and zooplankton vary in abundance, density, and biomass. Fragillariopsis and Navicula species were identified as the most abundant phytoplankton with higher density and biomass while Ceratium furca and Ceratium fusus of the zooplankton. Statistical analysis using ANOVA (Analysis of Variance) revealed significant differences at p = 0.05 on abundance and density, however, insignificant difference in biomass. Based on dispersion index, the phytoplankton and zooplankton were found to be vertically distributed and aggregated mostly on the upper column where sunlight is abundant. Surface water temperature and salinity significantly affect the spatial distribution and population size of the identified marine plankton.

Spatial Distribution of Marine Planktons off the Coast of Sitra, Kingdom of Bahrain

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Clinical description, molecular delineation and genotype–phenotype correlation in 340 patients with KBG syndrome: addition of 67 new patients

Spatial Distribution of Marine Planktons off the Coast of Sitra, Kingdom of Bahrain