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Background: Variants in ATP1A3 cause well-known phenotypes-alternating hemiplegia of childhood (AHC), rapid-onset dystonia-parkinsonism (RDP), cerebellar ataxia, areflexia, pes cavus, optic atrophy, sensorineural hearing loss (CAPOS), and severe early infantile epileptic encephalopathy. Recently, there has been growing evidence for genotype-phenotype correlations in the ATP1A3 variants, and a separate phenotype associated with variants in residue 756-two acronyms are proposed for the moment-FIPWE (fever-induced paroxysmal weakness and encephalopathy) and RECA (relapsing encephalopathy with cerebellar ataxia)., Materials and Methods: Herein, we are describing two new pediatric cases with a p.Arg756His change in the ATP1A3 gene. Both patients have had more than one episode of a neurological decompensation triggered by fever with severe hypotonia and followed by ataxia. Thirty-three cases from literature were analyzed to define and strengthen the genotype-phenotype correlation of variants located in residue 756 (p.Arg756His, p.Arg756Cys, p.Arg756Leu)., Conclusions: Patients with a ATP1A3 variant in residue 756 are characterized by recurrent paroxysmal episodes of neurological decompensations triggered by fever, with severe hypotonia, ataxia, dysarthria, symptoms from the orofacial area (dysphagia, drooling) as well as with altered consciousness. Recovery is slow and usually not full with the persistent symptoms of cerebellar ataxia, dysarthria, dystonic and choreiform movements., (© 2021 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Microdeletions of 7p12.1 encompassing the IKZF1 gene locus are rare, with few cases reported. The common phenotype includes intellectual disability, overgrowth, and facial dysmorphism accompanied, albeit rarely, by congenital anomalies. Haploinsufficiency of IKZF1 predisposes individuals to childhood acute lymphoblastic leukemia (ALL). In this study, we comprehensively analyzed the frequency of 7p12.1 deletions among 4581 Polish individuals who underwent chromosomal microarray testing for unexplained developmental delay, intellectual disability, and/or congenital anomalies. Two unrelated individuals (0.04%) with a de novo interstitial 7p12.1 microdeletion encompassing IKZF1 were identified. One developed ALL. Analysis of the incidence and the phenotype of constitutional 7p12.1 microdeletion, which based on the previously annotated patients data in public databases and literature reports, revealed 21 cases including five patients diagnosed with ALL., (© 2020 Wiley Periodicals LLC.)

Background: The genetic etiology of intellectual and psychomotor disability without a defined spectrum of dysmorphic features is usually monogenic. As no diagnostic criteria for such diseases are established, the clinical diagnosis becomes to be a challenge. The object of our paper is to present two patients with non-specific clinical symptoms for whom whole-exome-sequencing identified the new SON mutations and thus allowed for establishing the diagnosis of Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome. In both patients, the same symptoms including hypotonia, developmental and speech delay, feeding difficulties as well as frequent infections of the respiratory tract and internal ear were observed. However, both cases presented also with exceptional symptoms such as in case 1 ventriculomegaly and asymmetry of ventricles, hypoplastic left heart syndrome (HLHS), intellectual disability, intestinal malrotation, gastroparesis, and duodenal atresia and in the case 2 febrile seizures and reduced IgA levels. We will be presenting the patients and comparing them to 30 previously described cases., Methods: Whole-exome sequencing (WES) was performed on the probands' DNA and paired-end sequenced (2x100 bp) on HiSeq 1500. Variants considered as disease-causing were validated in the proband and studied in all available family members by amplicon deep sequencing performed using Nextera XT Kit and sequenced on HiSeq 1500., Results: We have identified two new variants in SON gene. In case 1 it has been a heterozygous frameshift variant p.(Ala1340GlnfsTer26), while in case 2 it has been a heterozygous frameshift variant, p.(Asp1640GlyfsTer7). Both variants are described for the first time and up to now, are not mentioned in any database., Conclusion: As there are no precise criteria established for the clinical diagnosis of ZTTK, an identification of SON gene mutation by whole-exome-sequencing is the best method that allows for a diagnosis of this syndrome., (© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Epileptic encephalopathies (EE) include a range of severe epilepsies in which intractable seizures or severe sub-clinical epileptiform activity are accompanied by impairment of motor and cognitive functions. Mutations in several genes including ion channels and other genes whose function is not completely understood have been associated to some EE. In this report, we provide a detailed clinical description of a sporadic male patient with early-onset epilepsy and epileptic encephalopathy in whom we performed complete exome sequencing (WES) and identified a GRIN2B mutation. The GRIN2B splicing mutation in intron 10 (c.2011-1G>A) was revealed in a WES study. The result was confirmed by Sanger sequencing. No mutation was found in both parents. Our finding confirms that early-onset EE may be caused not only by gain-of-function variants but also by splice site mutations-in particular those affecting the splice acceptor site of the 10th intron of the GRIN2B gene. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Hirschsprung disease (HSCR) is a congenital, heterogeneous disorder, characterized by the absence of intestinal ganglion cells. Recent advances show that the RET gene is a major locus involved in the pathogenesis of HSCR. The aim of this study was to analyse if the HSCR phenotype in the Polish population is associated with the presence of polymorphisms in exons 2, 3, 7, 11, 13, 14 and 15 of the RET gene. Molecular results were compared with clinical and long-term follow-up data in 70 Polish patients with HSCR (84.3% with a short segment and 15.7% with a long segment of aganglionic gut). Single-nucleotide polymorphisms were analysed by using the minisequencing SNaPshot multiplex method. The 135G>A polymorphism in RET exon 2 was overrepresented in HSCR patients, compared with a healthy control group. Moreover, the 135G>A variant was shown to be associated with the severe HSCR phenotype. Two other polymorphisms, 2071G>A in exon 11 and 2712C>G in exon 15, were underrepresented in the patients. The results confirm that these RET polymorphisms play a role in the aetiology of HSCR.