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Intellectual disability with speech delay and behavioural abnormalities, as well as hypotonia, seizures, feeding difficulties and craniofacial dysmorphism, are the main symptoms associated with pathogenic variants of the ZMYND11 gene. The range of clinical manifestations of the ZMYND phenotype is constantly being expanded by new cases described in the literature. Here, we present two previously unreported paediatric patients with neurodevelopmental challenges, who were diagnosed with missense variants in the ZMYND11 gene. It should be noted that one of the individuals manifested with hyperinsulinaemic hypoglycaemia (HH), a symptom that was not described before in published works. The reason for the occurrence of HH in our proband is not clear, so we try to explain the origin of this symptom in the context of the ZMYND11 syndrome. Thus, this paper contributes to knowledge on the range of possible manifestations of the ZMYND disease and provides further evidence supporting its association with neurodevelopmental challenges. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Myofibrillar myopathies (MFM) are a subgroup of protein aggregate myopathies (PAM) characterized by a common histological picture of myofibrillar dissolution, Z-disk disintegration, and accumulation of degradation products into inclusions. Mutations in genes encoding components of the Z-disk or Z-disk-associated proteins occur in some patients whereas in most of the cases, the causative gene defect is still unknown. We aimed to search for pathogenic mutations in genes not previously associated with MFM phenotype. Methods: We performed whole-exome sequencing in four patients from three unrelated families who were diagnosed with PAM without aberrations in causative genes for MFM. Results: In the first patient and her affected daughter, we identified a heterozygous p.(Arg89Cys) missense mutation in LMNA gene which has not been linked with PAM pathology before. In the second patient, a heterozygous p.(Asn4807Phe) mutation in RYR1 not previously described in PAM represents a novel, candidate gene with a possible causative role in the disease. Finally, in the third patient and his symptomatic daughter, we found a previously reported heterozygous p.(Cys30071Arg) mutation in TTN gene that was clinically associated with cardiac involvement. Conclusions: Our study identifies a new genetic background in PAM pathology and expands the clinical phenotype of known pathogenic mutations. [ABSTRACT FROM AUTHOR]

Background: Graves' orbitopathy (GO) as well as Graves' disease (GD) hyperthyroidism originate from an autoimmune reaction against the common auto-antigen, thyroid-stimulating hormone receptor (TSHR). GO phenotype is associated with environmental risk factors, mainly nicotinism, as well as genetic risk factors which initiate an immunologic reaction. In some patients GO is observed before diagnosis of GD hyperthyroidism, while it can also be observed far after diagnosis. The intensity of GO symptoms varies greatly in these patients. Thus, the pathogenesis of GD and GO may correlate with different genetic backgrounds, which has been confirmed by studies of correlations between GO and polymorphisms in cytokines involved in orbit inflammation. The aim of our analysis was to assess genetic predisposition to GO in young patients (age of diagnosis ≤30 years of age), for whom environmental effects had less time to influence outcomes than in adults. Methods: 768 GD patients were included in the study. 359 of them had clinically evident orbitopathy (NOSPECS ≥2). Patients were stratified by age at diagnosis. Association analyses were performed for genes with a known influence on development of GD - TSHR, HLA-DRB1, cytotoxic T-lymphocyte antigen 4 (CTLA4) and lymphoid protein tyrosine phosphatase (PTPN22). Results: The rs179247 TSHR polymorphism was associated with GO in young patients only. In young GO-free patients, allele A was statistically more frequent and homozygous carriers had a considerable lower risk of disease incidence than patients with AG or GG genotypes. Those differences were not found in either elderly patients or the group analyzed as a whole. Conclusions: Allele A of the rs179247 polymorphism in the TSHR gene is associated with lower risk of GO in young GD patients. [ABSTRACT FROM AUTHOR]

Type 2 congenital microcephaly (MCPH2) is a brain development disorder characterized by primary microcephaly with or without brain malformations. MCPH2 is caused by mutations in the WDR62 gene. We present three new patients with MCPH2 and compound heterozygous mutations in the WDR62 gene. In all the cases, the parents were healthy and unrelated. All children were clinically diagnosed with congenital microcephaly and retardation of motor and speech development. Sequencing results in the presented patients revealed five new variants in the WDR62 gene (c.4273C>T, c.1711_1712insTA, c.1777_1778delGA, c.1642+2T>G, c.194T>A) and one previously described in the German population (c.2864_2867delACAG). In two of the presented cases, variants in the SMAD4, DKC1, and ATRX genes were also found with unknown effects on the course of the disease. Moreover, in the article we collected and compared the most common clinical symptoms, dysmorphic features, and changes in radiographic examinations of the brain observed in 120 patients with recessive primary microcephaly type 2 caused by mutations in the WDR62 gene. [ABSTRACT FROM AUTHOR]

Purpose To report on a Polish family with unusual corneal changes associated with the arginine‐124 Methods We report on a 2‐generation Polish family in which corneal phenotype was assessed by slit lamp and confocal microscopy in vivo. Genomic DNA was obtained from blood samples and all exons known to contain mutation hot spots within the TGFBI gene, were PCR amplified and sequenced on both strand Results Affected family members complained of ocular discomfort, pain and visual impairment. The symptoms in the proband began in the third decade of life, while in the daughter in the second decade and have progressed slowly. Ophthalmologic examination revealed the presence of linear and branching structures within the anterior stroma, typically observed in lattice corneal dystrophy. Interestingly, these changes were accompanied by the presence of highly reflective deposits characteristic for granular corneal dystrophy. Genetic testing identified a heterozygous missense (CGC to TGC) mutation, which changed arginine in codon 124 to cysteine in the TGFBI gene in both affected family members Conclusion Mutation of arginine 124 to cysteine (R124C) of the TGFBI gene represents one of the most frequent mutations detected in patients with lattice corneal dystrophy. However, to the best of our knowledge, this is the first report on a family carrying the R124C mutation and presenting features of both granular and lattice lesions. The state of compound heterozygosity does not account for the observed mixed phenotype, as no other mutation within the TGFBI gene was found. If corneal buttons are available, histopathological examinations will be carried out to identify the nature of the deposits and better understand the mechanism of the disease [ABSTRACT FROM AUTHOR]