Dataset Information

De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for Brain Development and Metabolism, Causing an Intellectual-Disability Syndrome.

ABSTRACT: The overall understanding of the molecular etiologies of intellectual disability (ID) and developmental delay (DD) is increasing as next-generation sequencing technologies identify genetic variants in individuals with such disorders. However, detailed analyses conclusively confirming these variants, as well as the underlying molecular mechanisms explaining the diseases, are often lacking. Here, we report on an ID syndrome caused by de novo heterozygous loss-of-function (LoF) mutations in SON. The syndrome is characterized by ID and/or DD, malformations of the cerebral cortex, epilepsy, vision problems, musculoskeletal abnormalities, and congenital malformations. Knockdown of son in zebrafish resulted in severe malformation of the spine, brain, and eyes. Importantly, analyses of RNA from affected individuals revealed that genes critical for neuronal migration and cortex organization (TUBG1, FLNA, PNKP, WDR62, PSMD3, and HDAC6) and metabolism (PCK2, PFKL, IDH2, ACY1, and ADA) are significantly downregulated because of the accumulation of mis-spliced transcripts resulting from erroneous SON-mediated RNA splicing. Our data highlight SON as a master regulator governing neurodevelopment and demonstrate the importance of SON-mediated RNA splicing in human development.

SUBMITTER: Kim JH

PROVIDER: S-EPMC5011044 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for Brain Development and Metabolism, Causing an Intellectual-Disability Syndrome.

Kim Jung-Hyun JH Shinde Deepali N DN Reijnders Margot R F MRF Hauser Natalie S NS Belmonte Rebecca L RL Wilson Gregory R GR Bosch Daniëlle G M DGM Bubulya Paula A PA Shashi Vandana V Petrovski Slavé S Stone Joshua K JK Park Eun Young EY Veltman Joris A JA Sinnema Margje M Stumpel Connie T R M CTRM Draaisma Jos M JM Nicolai Joost J Yntema Helger G HG Lindstrom Kristin K de Vries Bert B A BBA Jewett Tamison T Santoro Stephanie L SL Vogt Julie J Bachman Kristine K KK Seeley Andrea H AH Krokosky Alyson A Turner Clesson C Rohena Luis L Hempel Maja M Kortüm Fanny F Lessel Davor D Neu Axel A Strom Tim M TM Wieczorek Dagmar D Bramswig Nuria N Laccone Franco A FA Behunova Jana J Rehder Helga H Gordon Christopher T CT Rio Marlène M Romana Serge S Tang Sha S El-Khechen Dima D Cho Megan T MT McWalter Kirsty K Douglas Ganka G Baskin Berivan B Begtrup Amber A Funari Tara T Schoch Kelly K Stegmann Alexander P A APA Stevens Servi J C SJC Zhang Dong-Er DE Traver David D Yao Xu X MacArthur Daniel G DG Brunner Han G HG Mancini Grazia M GM Myers Richard M RM Owen Laurie B LB Lim Ssang-Taek ST Stachura David L DL Vissers Lisenka E L M LELM Ahn Eun-Young Erin EYE

American journal of human genetics 20160818 3

The overall understanding of the molecular etiologies of intellectual disability (ID) and developmental delay (DD) is increasing as next-generation sequencing technologies identify genetic variants in individuals with such disorders. However, detailed analyses conclusively confirming these variants, as well as the underlying molecular mechanisms explaining the diseases, are often lacking. Here, we report on an ID syndrome caused by de novo heterozygous loss-of-function (LoF) mutations in SON. Th ...[more]

PMID: 27545680

Similar Datasets

Project description:BackgroundAutism spectrum disorder (ASD) is often accompanied by intellectual disability (ID). Despite extensive studies, however, the genetic basis for this comorbidity is still not clear. In this study, we tried to develop an analyzing pipeline for de novo mutations and possible pathways related to ID phenotype in ASD. Whole-exome sequencing (WES) was performed to screen de novo mutations and candidate genes in 79 ASD children together with their parents (trios). The de novo altering genes and relative pathways which were associated with ID phenotype were analyzed. The connection nodes (genes) of above pathways were selected, and the diagnostic value of these selected genes for ID phenotype in the study population was also evaluated.ResultsWe identified 89 de novo mutant genes, of which 34 genes were previously reported to be associated with ASD, including double hits in the EGF repeats of NOTCH1 gene (p.V999M and p.S1027L). Interestingly, of these 34 genes, 22 may directly affect intelligence quotient (IQ). Further analyses revealed that these IQ-related genes were enriched in protein synthesis, energy metabolism, and amino acid metabolism, and at least 9 genes (CACNA1A, ALG9, PALM2, MGAT4A, PCK2, PLEKHA1, PSME3, ADI1, and TLE3) were involved in all these three pathways. Seven patients who harbored these gene mutations showed a high prevalence of a low IQ score (< 70), a non-verbal language, and an early diagnostic age (< 4 years). Furthermore, our panel of these 9 genes reached a 10.2% diagnostic rate (5/49) in early diagnostic patients with a low IQ score and also reached a 10% diagnostic yield in those with both a low IQ score and non-verbal language (4/40).ConclusionWe found some new genetic disposition for ASD accompanied with intellectual disability in this study. Our results may be helpful for etiologic research and early diagnoses of intellectual disability in ASD. Larger population studies and further mechanism studies are warranted.

Dataset Information

De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for Brain Development and Metabolism, Causing an Intellectual-Disability Syndrome.

Publications

De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for Brain Development and Metabolism, Causing an Intellectual-Disability Syndrome.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets