Browsing by Author "Dal, G. M."
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Item Open Access Early postzygotic mutations contribute to de novo variation in a healthy monozygotic twin pair(B M J Group, 2014) Dal, G. M.; Ergüner, B.; Saǧıroǧlu, M. S.; Yüksel, B.; Onat, O. E.; Alkan C.; Özçelik, T.Background: Human de novo single-nucleotide variation (SNV) rate is estimated to range between 0.82-1.70×10-8 mutations per base per generation. However, contribution of early postzygotic mutations to the overall human de novo SNV rate is unknown. Methods: We performed deep whole-genome sequencing (more than 30-fold coverage per individual) of the whole-blood-derived DNA samples of a healthy monozygotic twin pair and their parents. We examined the genotypes of each individual simultaneously for each of the SNVs and discovered de novo SNVs regarding the timing of mutagenesis. Putative de novo SNVs were validated using Sanger-based capillary sequencing. Results: We conservatively characterised 23 de novo SNVs shared by the twin pair, 8 de novo SNVs specific to twin I and 1 de novo SNV specific to twin II. Based on the number of de novo SNVs validated by Sanger sequencing and the number of callable bases of each twin, we calculated the overall de novo SNV rate of 1.31×10-8 and 1.01×10-8 for twin I and twin II, respectively. Of these, rates of the early postzygotic de novo SNVs were estimated to be 0.34×10-8 for twin I and 0.04×10-8 for twin II. Conclusions: Early postzygotic mutations constitute a substantial proportion of de novo mutations in humans. Therefore, genome mosaicism resulting from early mitotic events during embryogenesis is common and could substantially contribute to the development of diseases.Item Open Access Identification of a novel missense mutation in RAD51 in a large family with congenital mirror movements(American Society of Human Genetics, 2012-11) Onat, Onur Emre; Gülsüner, Süleyman; Bilgen, R.; Dal, G. M.; Bilguvar, K.; Boyacı, Hüseyin; Doerschner, Katja; Uysal, H.; Günel, M.; Özçelik, TayfunCongenital mirror movements (CMM) are a rare and heterogeneous group of disorders characterized by involuntary contralateral movements of mainly the upper extremities during intentional movements on the opposite side. Isolated cases are usually familial and suggest autosomal dominant inheritance with incomplete penetrance. In two chromosome 18 linked families, causative mutations were identified in DCC (Science 328:592, 2010; MRMV1; MIM:157600). Here, we describe a three-generation consanguineous Turkish family with six members affected by CMM. Linkage analysis with a dominant model and 90 percent penetrance parameters resulted in peaks on 15q13.3-q21.1, 15q26.2, and 19q12 with maximum multipoint LOD scores of 3.6, 2.6, and 2.6, respectively. However, a region of homozygosity segregating with the phenotype was not observed, and thus excluded the possibility of recessive inheritance of the disease allele in this consanguineous family. Whole-exome sequencing of an affected individual uncovered 7 coding, 33 intronic and 3 intergenic novel variants located within the three linkage intervals, which were filtered against the dbSNP132 dataset. Segregation analysis, population filtering using 1000 genomes and EVS data sets, and conservation considerations using prediction tools revealed a novel missense mutation (c.404C>T [p.T134N], RefSeq accession number NM_002875) in exon 5 of RAD51 (MIM:179617), consistent with the dominant inheritance of the disease allele in the family. The mutation resides in the highly conserved AAA (ATPases associated with diverse cellular activities) domain of the protein, and it was not observed in 436 chromosomes from healthy individuals coming from a geographical matched region. Recently, truncating mutations in RAD51 were identified in two families with CMM (Am J Hum Genet 90:301,2012; MRMV2; MIM:614508). Our findings support the totally unexpected role of RAD51 in neurodevelopment and further suggest that alterations of this gene may lead to neurological phenotypes.