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Congenital heart defects (CHD) occur in 40% of patients with trisomy 21, while the other 60% have a structurally normal heart. This suggests that the increased dosage of genes on chromosome 21 is a risk factor for abnormal heart development. Interaction of genes on chromosome 21 or their gene products with certain alleles of genes on other chromosomes could contribute to CHD. Here, we identified a pair of monozygotic twins with trisomy 21 but discordant for a ventricular septal defect and epilepsy. Twin-zygosity was confirmed by microsatellite genotyping. We hypothesized that some genetic differences from post-twinning mutations caused the discordant phenotypes. Thus, next generation sequencing (NGS) technologies were applied to sequence both whole genome and exome of their leukocytes. The post-analyses of the sequencing data revealed 21 putative discordant exonic variants between the twins from either genome or exome data. However, of the 15 variants chosen for validation with conventional Sanger sequencing, these candidate variants showed no differences in both twins. The fact that no discordant DNA variants were found suggests that sequence differences of DNA from leukocytes of monozygotic twins might be extremely rare. It also emphasizes the limitation of the current NGS technology in identifying causative genes for discordant phenotypes in monozygotic twins.

Epilepsy is a common neurological disorder and identification of its causes is important for a better understanding of its pathogenesis. We previously studied a Thai family with a type of epilepsy, benign adult familial myoclonic epilepsy type 4 (BAFME4), and localized its gene to chromosome 3q26.32-q28. Here, we used single-molecule real-time sequencing and found expansions of TTTTA and insertions of TTTCA repeats in intron 1 of YEATS2 in one affected member of the family. Of all the available members in the family-comprising 13 affected and eight unaffected-repeat-primed PCR and long-range PCR revealed the co-segregation of the TTTCA repeat insertions with the TTTTA repeat expansions and the disease status. For 1116 Thai control subjects, none were found to harbour the TTTCA repeats while four had the TTTTA repeat expansions. Therefore, our findings suggest that BAFME4 is caused by the insertions of the intronic TTTCA repeats in YEATS2. Interestingly, all four types of BAFMEs for which underlying genes have been found (BAFMEs 1, 4, 6 and 7) are caused by the same molecular pathology, suggesting that the insertions of non-coding TTTCA repeats are involved in their pathogenesis. [ABSTRACT FROM AUTHOR]

• Pathogenic variants in ATP1A3 are known to be associated with three distinct neurological syndromes including AHC, RDP and CAPOS. • This study suggests the broader diversity of ATP1A3 -related disorders. • Atypical features were observed in two patients expanding the phenotypic spectrum of ATP1A3 -related disorders. • Three novel causative variants were identified expanding the genotypic spectrum of ATP1A3. Mutations in the ATP1A3 gene are known to be the cause of three distinct neurological syndromes including alternating hemiplegia of childhood (AHC), rapid-onset dystonia parkinsonism (RDP) and cerebellar ataxia, arefexia, pes cavus, optic atrophy and sensorineural hearing impairment (CAPOS). Recent studies have suggested the broader diversity of ATP1A3- related disorders. This study aimed to investigate the clinical spectrum in patients carrying causative mutations within the ATP1A3 gene. The medical histories of nine unrelated patients with diverse phenotypes harboring variants in ATP1A3 were retrospectively analyzed after they were referred to a tertiary epilepsy center in one of the two different health care systems (Germany or Thailand). Clinical features, neurophysiological data, imaging results, genetic characteristics and treatments were reviewed. Three patients harbor novel mutations in the ATP1A3 gene. Atypical clinical features and imaging findings were observed in two cases, one with hemiplegia-hemiconvulsion-epilepsy syndrome, and the other with neurodegeneration with brain iron accumulation. All nine patients presented with intellectual impairment. Alternating hemiplegia of childhood (AHC) was the most common phenotype (67%). Flunarizine and topiramate led to symptom reduction in 83% and 25% of AHC cases administered, respectively. The present case series expands the clinical and genetic spectrum of ATP1A3 -related disorders. [ABSTRACT FROM AUTHOR]