Abstract
TRIO is a Dbl family guanine nucleotide exchange factor (GEF) and an important regulator of neuronal development. Most truncating and missense variants affecting the Dbl homology domain of TRIO are associated with a neurodevelopmental disorder with microcephaly (MIM617061). Recently, de novo missense variants affecting the spectrin repeat region of TRIO were associated with a novel phenotype comprising severe developmental delay and macrocephaly (MIM618825). Here, we provide more evidence on this new TRIO-associated phenotype by reporting two severely affected probands with de novo missense variants in TRIO affecting the spectrin repeat region upstream of the typically affected GEF1 domain of the protein.
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References
Rauch A et al (2012) Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Lancet 380(9854):1674–1682
Deciphering Developmental Disorders (2017) Prevalence and architecture of de novo mutations in developmental disorders. Nature 542(7642):433–438
Vissers LE, Gilissen C, Veltman JA (2016) Genetic studies in intellectual disability and related disorders. Nat Rev Genet 17(1):9–18
Pengelly RJ et al (2016) Mutations specific to the Rac-GEF domain of TRIO cause intellectual disability and microcephaly. J Med Genet 53(11):735–742
Ba W et al (2016) TRIO loss of function is associated with mild intellectual disability and affects dendritic branching and synapse function. Hum Mol Genet 25(5):892–902
Katrancha SM et al (2017) Neurodevelopmental disease-associated de novo mutations and rare sequence variants affect TRIO GDP/GTP exchange factor activity. Hum Mol Genet 26(23):4728–4740
Sadybekov A et al (2017) An autism spectrum disorder-related de novo mutation hotspot discovered in the GEF1 domain of Trio. Nat Commun 8(1):601
Awasaki T et al (2000) The Drosophila trio plays an essential role in patterning of axons by regulating their directional extension. Neuron 26(1):119–131
Schmidt S, Debant A (2014) Function and regulation of the Rho guanine nucleotide exchange factor Trio. Small GTPases 5:e29769
Herring BE, Nicoll RA (2016) Kalirin and Trio proteins serve critical roles in excitatory synaptic transmission and LTP. Proc Natl Acad Sci U S A 113(8):2264–2269
Debant A et al (1996) The multidomain protein Trio binds the LAR transmembrane tyrosine phosphatase, contains a protein kinase domain, and has separate rac-specific and rho-specific guanine nucleotide exchange factor domains. Proc Natl Acad Sci U S A 93(11):5466–5471
Liu X et al (1998) NMR structure and mutagenesis of the N-terminal Dbl homology domain of the nucleotide exchange factor Trio. Cell 95(2):269–277
Bellanger JM et al (1998) Role of the multifunctional Trio protein in the control of the Rac1 and RhoA gtpase signaling pathways. C R Seances Soc Biol Fil 192(2):367–374
Bellanger JM et al (2000) The Rac1- and RhoG-specific GEF domain of Trio targets filamin to remodel cytoskeletal actin. Nat Cell Biol 2(12):888–892
Katrancha SM et al (2019) Trio haploinsufficiency causes neurodevelopmental disease-associated deficits. Cell Rep 26(10):2805-2817 e9
Samocha KE et al (2014) A framework for the interpretation of de novo mutation in human disease. Nat Genet 46(9):944–950
Lek M et al (2016) Analysis of protein-coding genetic variation in 60,706 humans. Nature 536(7616):285–291
Genovese G et al (2016) Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia. Nat Neurosci 19(11):1433–1441
Petrovski S et al (2013) Genic intolerance to functional variation and the interpretation of personal genomes. PLoS Genet 9(8):e1003709
O’Brien SP et al (2000) Skeletal muscle deformity and neuronal disorder in Trio exchange factor-deficient mouse embryos. Proc Natl Acad Sci U S A 97(22):12074–12078
Zong W et al (2015) Trio gene is required for mouse learning ability. Brain Res 1608:82–90
Barbosa S et al (2020) Opposite modulation of RAC1 by mutations in TRIO is associated with distinct, domain-specific neurodevelopmental disorders. Am J Hum Genet 106(3):338–355
Mercer CL, Keeton B, Dennis NR (2008) Familial multiple ventricular extrasystoles, short stature, craniofacial abnormalities and digital hypoplasia: a further case of Stoll syndrome? Clin Dysmorphol 17(2):91–93
Hempel M et al (2015) De novo mutations in CHAMP1 cause intellectual disability with severe speech impairment. Am J Hum Genet 97(3):493–500
Kortum F et al (2015) Mutations in KCNH1 and ATP6V1B2 cause Zimmermann-Laband syndrome. Nat Genet 47(6):661–667
Koehler K et al (2013) Mutations in GMPPA cause a glycosylation disorder characterized by intellectual disability and autonomic dysfunction. Am J Hum Genet 93(4):727–734
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We would like to thank the probands and their families for participating in this study.
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The study conformed to the tenets of the Declaration of Helsinki and was approved by the Ethics Committee of the Hamburg Medical Chamber [PV3802].
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Kloth, K., Graul-Neumann, L., Hermann, K. et al. More evidence on TRIO missense mutations in the spectrin repeat domain causing severe developmental delay and recognizable facial dysmorphism with macrocephaly. Neurogenetics 22, 221–224 (2021). https://doi.org/10.1007/s10048-021-00648-3
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DOI: https://doi.org/10.1007/s10048-021-00648-3