CAMK2D De Novo Missense Variant in Patient with Syndromic Neurodevelopmental Disorder: A Case Report

Background: Intellectual disability with developmental delay is the most common developmental disorder. However, this diagnosis is rarely associated with congenital cardiomyopathy. In the current report, we present the case of a patient suffering from dilated cardiomyopathy and developmental delay. Methods: Neurological pathology in a newborn was diagnosed immediately after birth, and the acquisition of psychomotor skills lagged behind by 3–4 months during the first year of life. WES analysis of the proband did not reveal a causal variant, so the search was extended to trio. Results: Trio sequencing revealed a de novo missense variant in the CAMK2D gene (p.Arg275His), that is, according to the OMIM database and available literature, not currently associated with any specific inborn disease. The expression of Ca2+/calmodulin-dependent protein kinase II delta (CaMKIIδ) protein is known to be increased in the heart tissues from patients with dilated cardiomyopathy. The functional effect of the CaMKIIδ Arg275His mutant was recently reported; however, no specific mechanism of its pathogenicity was proposed. A structural analysis and comparison of available three-dimensional structures of CaMKIIδ confirmed the probable pathogenicity of the observed missense variant. Conclusions: We suggest that the CaMKIIδ Arg275His variant is highly likely the cause of dilated cardiomyopathy and neurodevelopmental disorders

De Novo Variant in the <i>KCNJ9</i> Gene as a Possible Cause of Neonatal Seizures

Background: The reduction in next-generation sequencing (NGS) costs allows for using this method for newborn screening for monogenic diseases (MDs). In this report, we describe a clinical case of a newborn participating in the EXAMEN project (ClinicalTrials.gov Identifier: NCT05325749). Methods: The child presented with convulsive syndrome on the third day of life. Generalized convulsive seizures were accompanied by electroencephalographic patterns corresponding to epileptiform activity. Proband WES expanded to trio sequencing was performed. Results: A differential diagnosis was made between symptomatic (dysmetabolic, structural, infectious) neonatal seizures and benign neonatal seizures. There were no data in favor of the dysmetabolic, structural, or infectious nature of seizures. Molecular karyotyping and whole exome sequencing were not informative. Trio WES revealed a de novo variant in the KCNJ9 gene (1:160087612T > C, p.Phe326Ser, NM_004983), for which, according to the OMIM database, no association with the disease has been described to date. Three-dimensional modeling was used to predict the structure of the KCNJ9 protein using the known structure of its homologs. According to the predictions, Phe326Ser change possibly disrupts the hydrophobic contacts with the valine side chain. Destabilization of the neighboring structures may undermine the formation of GIRK2/GIRK3 tetramers necessary for their proper functioning. Conclusions: We believe that the identified variant may be the cause of the disease in this patient but further studies, including the search for other patients with the KCNJ9 variants, are needed

Suspension Cell Culture of <i>Dioscorea deltoidea</i>—A Renewable Source of Biomass and Furostanol Glycosides for Food and Pharmaceutical Industry

Dioscorea deltoidea is a medicinal plant valued for its high content of steroidal glycosides (SG)—bioactive compounds with cardioprotective and immunomodulation actions, also used to treat reproductive system disorders. To overcome the limitations of natural resources of this species, a suspension cell culture of D. deltoidea was developed as a renewable and ecologically sustainable source of raw biomass and SG. Cell culture demonstrated stable and intensive growth in the laboratory (20 L) and industrial (630 L) bioreactors operated under a semi-continuous regime (specific growth rate 0.11–1.12 day−1, growth index 3.5–3.7). Maximum dry weight accumulation (8.5–8.8 g/L) and SG content (47–57 mg/g DW) were recorded during the stationary phase. Bioreactor-produced cell biomass contained inorganic macro (K, Ca, Mg, Na) and micro (Zn, Mn, Fe, B, Al, Cu, Cr, Se, Co, Ni) elements in concentrations within the safe range of dietary recommendations. Acute toxicity test showed no or insignificant changes in organ weight, hematological panel and blood biochemistry of laboratory animals fed with 2000 and 5000 mg/kg dry biomass. The results suggest that cell culture of D. deltoidea grown in bioreactors has great potential to be used as functional foods and a component of specialized dietary supplements in complex therapy of reproductive system disorders and mineral deficiency

Compound phenotype in a girl with r(22), concomitant microdeletion 22q13.32-q13.33 and mosaic monosomy 22

Abstract Background Ring chromosome instability may influence a patient’s phenotype and challenge its interpretation. Results Here, we report a 4-year-old girl with a compound phenotype. Cytogenetic analysis revealed her karyotype to be 46,XX,r(22). aCGH identified a 180 kb 22q13.32 duplication, a de novo 2.024 Mb subtelomeric 22q13.32-q13.33 deletion, which is associated with Phelan-McDermid syndrome, and a maternal single gene 382-kb TUSC7 deletion of uncertain clinical significance located in the region of the 3q13.31 deletion syndrome. All chromosomal aberrations were confirmed by real-time PCR in lymphocytes and detected in skin fibroblasts. The deletions were also found in the buccal epithelium. According to FISH analysis, 8% and 24% of the patient’s lymphocytes and skin fibroblasts, respectively, had monosomy 22. Conclusions We believe that a combination of 22q13.32-q13.33 deletion and monosomy 22 in a portion of cells can better define the clinical phenotype of the patient. Importantly, the in vivo presence of monosomic cells indicates ring chromosome instability, which may favor karyotype correction that is significant for the development of chromosomal therapy protocols