De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome
Copyright policy )De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome
Brain malformations are individually rare but collectively common causes of developmental disabilities. Many forms of malformation occur sporadically and are associated with reduced reproductive fitness, pointing to a causative role for de novo mutations. Here, we report a study of Baraitser-Winter syndrome, a well-defined disorder characterized by distinct craniofacial features, ocular colobomata and neuronal migration defect. Using whole-exome sequencing of three proband-parent trios, we identified de novo missense changes in the cytoplasmic actin-encoding genes ACTB and ACTG1 in one and two probands, respectively. Sequencing of both genes in 15 additional affected individuals identified disease-causing mutations in all probands, including two recurrent de novo alterations (ACTB, encoding p.Arg196His, and ACTG1, encoding p.Ser155Phe). Our results confirm that trio-based exome sequencing is a powerful approach to discover genes causing sporadic developmental disorders, emphasize the overlapping roles of cytoplasmic actin proteins in development and suggest that Baraitser-Winter syndrome is the predominant phenotype associated with mutation of these two genes.
- KU Leuven Belgium
- Radboud University Nijmegen Netherlands
- Cornell University United States
- University of Groningen Netherlands
- Assistance Publique -Hopitaux De Paris France
Male, anzsrc-for: 060410 Neurogenetics, PTOSIS, Developmental Disabilities, NCMLS 6: Genetics and epigenetic pathways of disease IGMD 3: Genomic disorders and inherited multi-system disorders, Congenital, 2.1 Biological and endogenous factors, Child, EMC MGC-02-96-01, 11 Medical and Health Sciences, Sequence Deletion, Pediatric, 2 Aetiology, Genetics & Heredity, NCMLS 6: Genetics and epigenetic pathways of disease DCN MP - Plasticity and memory, Brain, Syndrome, Coloboma, GROWTH, Female, Abnormalities, Multiple, Sequence Analysis, Life Sciences & Biomedicine, Adult, Adolescent, DNA Copy Number Variations, 3001 Agricultural biotechnology, Molecular Sequence Data, DNA-SEQUENCING DATA, NOONAN-SYNDROME, Mutation, Missense, 610, Nervous System Malformations, 3105 Genetics, Article, Intellectual Disability, Genetics, Humans, MALFORMATIONS, Abnormalities, Multiple, anzsrc-for: 060403 Developmental Genetics (incl. Sex Determination), Amino Acid Sequence, IGMD 3: Genomic disorders and inherited multi-system disorders DCN MP - Plasticity and memory, Science & Technology, anzsrc-for: 111403 Paediatrics, IDENTIFICATION, Base Sequence, GAMMA-ACTIN, DNA, Sequence Analysis, DNA, 06 Biological Sciences, IRIS COLOBOMA, Actins, BETA-ACTIN, anzsrc-for: 11 Medical and Health Sciences, Mutation, anzsrc-for: 06 Biological Sciences, Congenital Structural Anomalies, 3102 Bioinformatics and computational biology, PAX9 Transcription Factor, Missense, Sequence Alignment, MENTAL-RETARDATION, Developmental Biology
Male, anzsrc-for: 060410 Neurogenetics, PTOSIS, Developmental Disabilities, NCMLS 6: Genetics and epigenetic pathways of disease IGMD 3: Genomic disorders and inherited multi-system disorders, Congenital, 2.1 Biological and endogenous factors, Child, EMC MGC-02-96-01, 11 Medical and Health Sciences, Sequence Deletion, Pediatric, 2 Aetiology, Genetics & Heredity, NCMLS 6: Genetics and epigenetic pathways of disease DCN MP - Plasticity and memory, Brain, Syndrome, Coloboma, GROWTH, Female, Abnormalities, Multiple, Sequence Analysis, Life Sciences & Biomedicine, Adult, Adolescent, DNA Copy Number Variations, 3001 Agricultural biotechnology, Molecular Sequence Data, DNA-SEQUENCING DATA, NOONAN-SYNDROME, Mutation, Missense, 610, Nervous System Malformations, 3105 Genetics, Article, Intellectual Disability, Genetics, Humans, MALFORMATIONS, Abnormalities, Multiple, anzsrc-for: 060403 Developmental Genetics (incl. Sex Determination), Amino Acid Sequence, IGMD 3: Genomic disorders and inherited multi-system disorders DCN MP - Plasticity and memory, Science & Technology, anzsrc-for: 111403 Paediatrics, IDENTIFICATION, Base Sequence, GAMMA-ACTIN, DNA, Sequence Analysis, DNA, 06 Biological Sciences, IRIS COLOBOMA, Actins, BETA-ACTIN, anzsrc-for: 11 Medical and Health Sciences, Mutation, anzsrc-for: 06 Biological Sciences, Congenital Structural Anomalies, 3102 Bioinformatics and computational biology, PAX9 Transcription Factor, Missense, Sequence Alignment, MENTAL-RETARDATION, Developmental Biology
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