The hereditary spastic paraplegias (HSPs), a group of neurodegenerative movement disorders, are among the genetically most heterogeneous clinical conditions. Still, the more than 50 forms known so far apparently explain less than 80% of cases. The present study identified two large HSP families, which seemed to show an autosomal recessive and an X-linked inheritance pattern. A set of genetic analyses including exome sequencing revealed plausible mutations only when assuming incomplete/sex-dependent penetrance of adjacent alterations in the autosomal dominant HSP gene ATL1 (c.1243C>T and c.1244G>A, respectively). By screening of additional HSP patients for the presence of these alterations, we identified three more cases and obtained additional evidence for reduced penetrance. Bisulfate sequencing and haplotype analysis indicated that c.1243C and c.1244G constitute a mutational hotspot. Our findings suggest that misinterpretation of inheritance patterns and, consequently, misselection of candidate genes to be screened in gene-focused approaches contribute to the apparently missing heritability in HSP and, potentially, in other genetically heterogeneous disorders.
Clinical and genetic characteristics of 9 patients with Nonaka myopathy (GNE-myopathy) from Russia are presented. As a result of exom sequen cing, 11 different mutations were revealed in the GNE gene, 8 of which were described earlier, and 3-Сys203Ser, Met263CysfsTer and deletion of the whole gene-were detected for the first time. The peculiarities of clinical manifestation of Russian patients with GNEmyopathy are described.
Описано большое количество моногенных заболеваний, в клинической картине которых наблюдаются судороги. Среди них особое место занимают ранние эпилептические энцефалопатии (РЭЭ)-генетически гетерогенная группа заболеваний, характеризующихся манифестацией судорог до 2-летнего возраста и тяжелым прогрессирующим течением. К настоящему времени идентифицированы 58 генетических вариантов РЭЭ. Цель исследования-анализ частоты встречаемости и клинико-генетических характеристик РЭЭ II типа в выборке больных из популяции России, выявленных в результате секвенирования экзома нового поколения.
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