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Different X-linked KDM5C mutations in affected male siblings: is maternal reversion error involved?

Fujita, A. ; Waga, C. ; Hachiya, Y. ; Kurihara, E. ; Kumada, S. ; Takeshita, E. ; Nakagawa, E. ; Inoue, K. ; Miyatake, S. ; Tsurusaki, Y. ; Nakashima, M. ; Saitsu, H. ; Goto, Y.-i. ; Miyake, N. ; Matsumoto, N.

Clinical genetics, 2016-09, Vol.90 (3), p.276-281 [Periódico revisado por pares]

Oxford, UK: Blackwell Publishing Ltd

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  • Título:
    Different X-linked KDM5C mutations in affected male siblings: is maternal reversion error involved?
  • Autor: Fujita, A. ; Waga, C. ; Hachiya, Y. ; Kurihara, E. ; Kumada, S. ; Takeshita, E. ; Nakagawa, E. ; Inoue, K. ; Miyatake, S. ; Tsurusaki, Y. ; Nakashima, M. ; Saitsu, H. ; Goto, Y.-i. ; Miyake, N. ; Matsumoto, N.
  • Assuntos: Child, Preschool ; Disease ; Exome ; Female ; Genes, X-Linked ; Genetic disorders ; Haplotypes ; High-Throughput Nucleotide Sequencing ; Histone Demethylases - genetics ; Humans ; Infant ; intellectual disability ; Intellectual Disability - genetics ; Intellectual Disability - physiopathology ; KDM5C ; Male ; Maternal Inheritance - genetics ; Mosaicism ; Mothers ; Mutation ; Mutation - genetics ; Pedigree ; Phenotype ; reversion error ; Siblings ; somatic mutation
  • É parte de: Clinical genetics, 2016-09, Vol.90 (3), p.276-281
  • Notas: istex:9F4C5F2CF5492EB771F6C3DEA7A9BF26D3A8D2DA
    Comprehensive Research on Disability Health and Welfare
    Research on Measures for Intractable Diseases
    Practical Research Project for Rare/Intractable Diseases
    Ministry of Education, Culture, Sports, Science and Technology of Japan - No. 24118007
    Initiative on Rare and Undiagnosed Diseases in Pediatrics - No. 15gk0110012h0101
    ArticleID:CGE12767
    Fig. S1. Brain MRI of patient III-3 at 4 years old. Cerebellar atrophy was observed, predominantly in the upper segment. The white arrow indicates the region of cerebellar atrophy. Fig. S2. Brain MRI and hand X-ray images of patient III-4 at 1 year and 11 months axial sections of T1-weighted (a) and T2-weighted (b) images are shown. Slight hypoplasia of the apical portion of the lateral lobe was noted. (c) Sagittal section of a T1-weighted image shows unremarkable findings in the brain. (d) X-ray image of the right hand. Bone age was estimated at younger than 6 months. Fig. S3. Evolutionary conservation of c.631-c.633 nucleotides in KDM5C. Conservation of c.631, c.632 and c.633 is highlighted in blue, yellow and orange, respectively. Seven orthologous sequences were aligned by Clustal W (http://www.clustal.org/clustal2/). Fig. S4. KDM5C mutations visualized using the Integrative Genomics Viewer using WES data from all the family members. KDM5C is positioned on the reverse strand. Purple and pink horizontal lines indicate forward and reverse sequence reads, respectively. Orange and blue arrows show positions of the c.633delG and c.631delC mutations, respectively. Black hyphens represent base deletions. Fig. S5. Occurrence of two KDM5C mutations in the mother (II-2). The heterozygous germline mutation, c.631delC, is predicted to have occurred before the first cell division of the fertilized egg. The somatic mutation, c.633delG, may have arisen after the two cell stage but before the specification of primordial germ cells (PGCs, dark green). Colored circles indicate the inner cell mass (light green), epiblast (pink), hypoblast (blue), and future endoderm (yellow) and mesoderm cells (purple). Fig. S6. Schematic representation of KDM5C mutations. Filled and open circles denote protein-truncating and missense mutations. Mutations in black and red are reported and newly found mutations, respectively. Functional domains are indicated as colored boxes based on a prediction by NCBI Conserved Domain Database (http://www.ncbi.nlm.nih.gov/cdd/). The protein contains a jumonji N (JmjN) domain, an AT-rich interactive domain (ARID), two plant homeodomains (PHDs), a jumonji C (JmjC) domain and a C5HC2 zinc finger domain. Table S1. Clinical features of three affected individuals with KDM5C mutations Table S2. Numbers of sequence reads covering KDM5C mutations by whole-exome sequencing of the familial members Table S3. The probability estimation of two KDM5C mutations in this family Table S4. Comparison of coding-variant numbers in KDM5C, MECP2, and KMT2D
    ark:/67375/WNG-T2HBSRLT-N
    Strategic Research Program for Brain Science - No. 11105137
    ObjectType-Article-1
    SourceType-Scholarly Journals-1
    ObjectType-Feature-2
    content type line 23
  • Descrição: Genetic reversion is the phenomenon of spontaneous gene correction by which gene function is partially or completely rescued. However, it is unknown whether this mechanism always correctly repairs mutations, or is prone to error. We investigated a family of three boys with intellectual disability, and among them we identified two different mutations in KDM5C, located at Xp11.22, using whole‐exome sequencing. Two affected boys have c.633delG and the other has c.631delC. We also confirmed de novo germline (c.631delC) and low‐prevalence somatic (c.633delG) mutations in their mother. The two mutations are present on the same maternal haplotype, suggesting that a postzygotic somatic mutation or a reversion error occurred at an early embryonic stage in the mother, leading to switched KDM5C mutations in the affected siblings. This event is extremely unlikely to arise spontaneously (with an estimated probability of 0.39–7.5 × 10−28), thus a possible reversion error is proposed here to explain this event. This study provides evidence for reversion error as a novel mechanism for the generation of somatic mutations in human diseases. Genetic analysis of the family with intellectual disability harboured different X‐linked KDM5C mutations.
  • Editor: Oxford, UK: Blackwell Publishing Ltd
  • Idioma: Inglês
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  • Realização: ABCD-USP USP   Logos de Redes Sociais: Freepik

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