Mutations specific to the Rac-GEF domain of<i>TRIO</i>cause intellectual disability and microcephaly

Pengelly, Reuben J.; Greville‐Heygate, Stephanie; Schmidt, Susanne; Seaby, Eleanor G.; Jabalameli, M. Reza; Mehta, Sarju G.; Parker, Michael; Goudie, David; Fagotto‐Kaufmann, Christine; Mercer, Catherine; Debant, Anne; Ennis, Sarah; Baralle, Diana

doi:10.1136/jmedgenet-2016-103942

Cited by 79 publications

(117 citation statements)

References 32 publications

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“…Of note, mutations in TRIO (MIM: 601893), a gene that encodes a RAC1 GEF, have been shown to result in mild intellectual disability. 43,44 Interestingly, missense mutations in RAC-GEF domain of TRIO result in a more severe phenotype with global developmental delay, microcephaly, and reduced RAC1 activity. 43 Furthermore, biallelic mutations in HACE1 (MIM: 610876), a known interactor of RAC1, have been recently shown to result in an autosomal-recessive syndrome with macrocephaly.…”

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confidence: 99%

“…43,44 Interestingly, missense mutations in RAC-GEF domain of TRIO result in a more severe phenotype with global developmental delay, microcephaly, and reduced RAC1 activity. 43 Furthermore, biallelic mutations in HACE1 (MIM: 610876), a known interactor of RAC1, have been recently shown to result in an autosomal-recessive syndrome with macrocephaly. 45 Notably, overexpression of a WAVE mutant has been demonstrated to partially rescue axon growth in Rac1 knock-out neurons, 19 suggesting that some of the conditions in this group could be potentially treatable.…”

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confidence: 99%

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RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes

Reijnders

Ansor

Kousi

et al. 2017

The American Journal of Human Genetics

137

154

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RAC1 is a widely studied Rho GTPase, a class of molecules that modulate numerous cellular functions essential for normal development. RAC1 is highly conserved across species and is under strict mutational constraint. We report seven individuals with distinct de novo missense RAC1 mutations and varying degrees of developmental delay, brain malformations, and additional phenotypes. Four individuals, each harboring one of c.53G>A (p.Cys18Tyr), c.116A>G (p.Asn39Ser), c.218C>T (p.Pro73Leu), and c.470G>A (p.Cys157Tyr) variants, were microcephalic, with head circumferences between À2.5 to À5 SD. In contrast, two individuals with c.151G>A (p.Val51Met) and c.151G>C (p.Val51Leu) alleles were macrocephalic with head circumferences of þ4.16 and þ4.5 SD. One individual harboring a c.190T>G (p.Tyr64Asp) allele had head circumference in the normal range. Collectively, we observed an extraordinary spread of $10 SD of head circumferences orchestrated by distinct mutations in the same gene. In silico modeling, mouse fibroblasts spreading assays, and in vivo overexpression assays using zebrafish as a surrogate model demonstrated that the p.Cys18Tyr and p.Asn39Ser RAC1 variants function as dominant-negative alleles and result in microcephaly, reduced neuronal proliferation, and cerebellar abnormalities in vivo. Conversely, the p.Tyr64Asp substitution is constitutively active. The remaining mutations are probably weakly dominant negative or their effects are context dependent. These findings highlight the importance of RAC1 in neuronal development. Along with TRIO and HACE1, a sub-category of rare developmental disorders is emerging with RAC1 as the central player. We show that ultra-rare disorders caused by private, non-recurrent missense mutations that result in varying phenotypes are challenging to dissect, but can be delineated through focused international collaboration.Developmental disorders (DDs) are etiologically extremely heterogeneous and affect 2%-5% of individuals.

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confidence: 99%

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confidence: 99%

RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes

Reijnders

Ansor

Kousi

et al. 2017

The American Journal of Human Genetics

137

154

View full text Add to dashboard Cite

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“…The TRIO gene has been recently associated with mild to borderline intellectual disability, delay in acquisition of motor and language skills, and neurobehavioral problems. Other findings can include microcephaly, variable digital and dental abnormalities, and suggestive facial features (Ba et al, 2016;Pengelly et al, 2016). Only few individuals carrying pathogenic mutations in this gene have been reported to date, thus the clinical manifestations of the TRIOrelated disorder is still evolving.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Intellectual disability and Autism comorbidity through gene panel sequencing

Aspromonte

Bellini

Gasparini

et al. 2019

Preprint

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Intellectual disability (ID) and autism spectrum disorder (ASD) are clinically and genetically heterogeneous diseases. Recent whole exome sequencing studies indicated that genes associated with different neurological diseases are shared across disorders and converge on common functional pathways. Using the Ion Torrent platform, we developed a low-cost next generation sequencing (NGS) gene panel that has been transferred into clinical practice, replacing single disease gene analyses for the early diagnosis of individuals with ID/ASD. The gene panel was designed using an innovative in silico approach based on disease networks and mining data from public resources to score disease-gene associations. We analyzed 150 unrelated individuals with ID and/or ASD and a confident diagnosis has been reached in 26 cases (17%). Likely pathogenic mutations have been identified in another 15 patients, reaching a total diagnostic yield of 27%.Our data also support the pathogenic role of genes recently proposed to be involved in ASD.Although many of the identified variants need further investigation to be considered diseasecausing, our results indicate the efficiency of the targeted gene panel on the identification of novel and rare variants in patients with ID and ASD.

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“…share additional features in common with the phenotypic spectrum of DE, including microcephaly, and digit malformations 47,48 .…”

Section: Apart From Intellectual Disability Individuals With Heterozmentioning

confidence: 99%

Capture-based DNA methylation sequencing facilitates diagnosis and reveals potential pathogenic mechanisms in teratogenic diabetes exposure

Bhatt

Azamian

et al. 2017

Preprint

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Diabetic embryopathy (DE) describes a spectrum of birth defects associated with a teratogenic exposure to maternal diabetes in utero. These defects strongly overlap the phenotypes of known genetic syndromes; however, the pathogenic mechanisms underlying DE remain uncertain and there are no definitive tests that distinguish the diagnosis. Here, we explore the potential of DNA methylation as both a diagnostic biomarker and a means of informing disease pathogenesis in DE. Capture-based bisulfite sequencing was used to compare patterns of DNA methylation at 2,800,516 sites genome-wide in seven DE neonates and 11 healthy neonates, including five with in utero diabetes exposure. DE infants had significantly lower global DNA methylation (ANOVA, Tukey HSD p=0.045) than diabetes-unexposed, healthy controls (UH), with multiple sites showing large (mean methylation difference = 16.6%) and significant (p<0.001) differential methylation between the two groups. We found that a subset of 237 highly differentially methylated loci could accurately distinguish DE infants from both UH and diabetes-exposed healthy infants (sensitivity 80% -100%). Differentially methylated sites were enriched in intergenic (p<3.52x10 -15 ) and intronic (p<0.001) regions found proximal to genes either associated with Mendelian syndromes that overlap the DE phenotype (e.g. TRIO, ANKRD11), or known to influence early organ development (e.g. BRAX1, RASA3). Further, by integrating information on cis-sequence variation, we found that 39.3% of loci with evidence for allele-specific methylation also showed differential methylation between DE and controls.Our study suggests a role for aberrant DNA methylation and cis-sequence variation in the pathogenesis of DE, and highlights the diagnostic potential of DNA methylation for teratogenic birth defects.

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Mutations specific to the Rac-GEF domain ofTRIOcause intellectual disability and microcephaly

Cited by 79 publications

References 32 publications

RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes

RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes

Characterization of Intellectual disability and Autism comorbidity through gene panel sequencing

Capture-based DNA methylation sequencing facilitates diagnosis and reveals potential pathogenic mechanisms in teratogenic diabetes exposure

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