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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., In this article we analysed and summarized the genotype‐phenotype correlation in patients with a ATP1A3 variant in residue 756 from literature and also we described two new patients with a p.Arg756His variant.

Background Phenotypically discordant monozygotic twins (PDMZTs) offer a unique opportunity to study post‐zygotic genetic variation and provide insights into the linkage between genotype and phenotype. We report a comprehensive analysis of a pair of PDMZTs. Methods Dysmorphic features and delayed neuro‐motor development were observed in the proband, whereas her twin sister was phenotypically normal. Four tissues (blood, skin, hair follicles, and buccal mucosa) from both twins were studied using four complementary methods, including whole‐exome sequencing, karyotyping, array CGH, and SNP array. Results In the proband, tetrasomy 18p affecting all studied tissues except for blood was identified. Karyotyping of fibroblasts revealed isochromosome 18p [i(18p)] in all metaphases. The corresponding analysis of the phenotypically normal sister surprisingly revealed low‐level mosaicism (5.4%) for i(18p) in fibroblasts. Conclusion We emphasize that when mosaicism is suspected, multiple tissues should be studied and we highlight the usefulness of non‐invasive sampling of hair follicles and buccal mucosa as a convenient source of non‐mesoderm‐derived DNA, which complements the analysis of mesoderm using blood. Moreover, low‐level mosaic tetrasomy 18p is well tolerated and such low‐level mosaicism, readily detected by karyotyping, can be missed by other methods. Finally, mosaicism for low‐level tetrasomy 18p might be more common in the general population than it is currently recognized, due to detection limitations., Herein, for the first time, we present phenotypically discordant monozygotic twins due to variable degree of mosaicism for tetrasomy 18p. In the proband tetrasomy 18p affecting all studied tissues (skin fibroblasts, hair follicles, and buccal mucosa) except for blood was identified. Karyotyping of proband's fibroblasts revealed isochromosome 18p [i(18p)] in all metaphases. The corresponding analysis of the phenotypically normal sister surprisingly revealed low‐level mosaicism (5.4%) for i(18p) in fibroblasts. We emphasize that when mosaicism is suspected, multiple tissues should be studied and low‐level mosaicism, readily detected by karyotyping, can be missed by other methods.

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., In the paper, we present both, clinical symptoms as well as newly identified SON variants in our two patients with Zhu‐Tokita‐Takenouchi‐Kim syndrome in relation to clinical and molecular alterations in 30 cases described up to now.