Disruption of the IQSEC2 transcript in a female with X;autosome translocation t(X;20)(p11.2;q11.2) and a phenotype resembling X-linked infantile spasms (ISSX) syndrome

Morleo, Manuela; Iaconis, Daniela; Chitayat, David; Peluso, Ilaria; Marzella, R.; Renieri, Alessandra; Mari, Francesca; Bazzoli, Franco

doi:10.3892/mmr.1.1.33

Cited by 10 publications

(2 citation statements)

References 22 publications

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“…She presented with mental retardation, lack of speech, hand stereotypies, poor eye‐contact, and microcephaly, which resembles those of RTT. Besides, there is significant overlap between the expression profile of Iqsec2 and Cdkl5 in murine adult brain, suggesting a possible functional link between them (Morleo et al, ). These findings provided supports that IQSEC2 is responsible for Rett or Rett‐like syndrome.…”

Section: Discussionmentioning

confidence: 99%

Rett and Rett‐like syndrome: Expanding the genetic spectrum to KIF1A and GRIN1 gene

Wang

Zhang

Chen

et al. 2019

Molec Gen & Gen Med

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BackgroundThis study aimed to investigate the new genetic etiologies of Rett syndrome (RTT) or Rett‐like phenotypes.MethodsTargeted next‐generation sequencing (NGS) was performed on 44 Chinese patients with RTT or Rett‐like phenotypes, in whom genetic analysis of MECP2, CDKL5, and FOXG1 was negative.ResultsThe detection rate was 31.8% (14/44). A de novo pathogenic variant (c.275_276ins AA, p. Cys92*) of KIF1A was identified in a girl with all core features of typical RTT. A patient with atypical RTT was detected having de novo GRIN1 pathogenic variant (c.2337C > A, p. Val793Phe). Additionally, compound heterozygous pathogenic variants of PPT1 gene were detected in a girl, who initially displayed typical RTT features, but progressed into neuronal ceroid lipofuscinoses (NCL) afterwards. Pathogenic variants in KCNQ2, MEF2C, WDR45, TCF4, IQSEC2, and SDHA were also found in our cohort.ConclusionsIt is the first time that pathogenic variants of GRIN1 and KIF1A were linked to RTT and Rett‐like profiles. Our findings expanded the genetic heterogeneity of Chinese RTT or Rett‐like patients, and also suggest that some patients with genetic metabolic disease such as NCL, might displayed Rett features initially, and clinical follow‐up is essential for the diagnosis.

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Section: Discussionmentioning

confidence: 99%

Rett and Rett‐like syndrome: Expanding the genetic spectrum to KIF1A and GRIN1 gene

Wang

Zhang

Chen

et al. 2019

Molec Gen & Gen Med

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“…Iqsec2 is located at chromosome Xp11.22 and is a member of a family of three genes ( Iqsec1-3 ). It was initially proposed as a candidate X-linked intellectual disability (XLID) gene in a study of a patient with a de novo chromosomal translocation ( Morleo et al, 2008 ). Since then, >100 pathogenic variants of Iqsec2 have been reported, leading to both syndromic (e.g., seizures, speech deficits, autistic or other psychiatric behaviors, etc.)…”

Section: Introductionmentioning

confidence: 99%

Ca2+-induced release of IQSEC2/BRAG1 autoinhibition under physiological and pathological conditions

Bai,

Li,

Qin

et al. 2023

Journal of Cell Biology

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IQSEC2 (aka BRAG1) is a guanine nucleotide exchange factor (GEF) highly enriched in synapses. As a top neurodevelopmental disorder risk gene, numerous mutations are identified in Iqsec2 in patients with intellectual disabilities accompanied by other developmental, neurological, and psychiatric symptoms, though with poorly understood underlying molecular mechanisms. The atomic structures of IQSECs, together with biochemical analysis, presented in this study reveal an autoinhibition and Ca2+-dependent allosteric activation mechanism for all IQSECs and rationalize how each identified Iqsec2 mutation can alter the structure and function of the enzyme. Transgenic mice modeling two pathogenic variants of Iqsec2 (R359C and Q801P), with one activating and the other inhibiting the GEF activity of the enzyme, recapitulate distinct clinical phenotypes in patients. Our study demonstrates that different mutations on one gene such as Iqsec2 can have distinct neurological phenotypes and accordingly will require different therapeutic strategies.

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Mutations in epilepsy and intellectual disability genes in patients with features of Rett syndrome

Olson

Tambunan

LaCoursiere

et al. 2015

American J of Med Genetics Pt A

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Rett syndrome and neurodevelopmental disorders with features overlapping this syndrome frequently remain unexplained in patients without clinically identified MECP2 mutations. We recruited a cohort of 11 patients with features of Rett syndrome and negative initial clinical testing for mutations in MECP2. We analyzed their phenotypes to determine whether patients met formal criteria for Rett syndrome, reviewed repeat clinical genetic testing, and performed exome sequencing of the probands. Using 2010 diagnostic criteria, three patients had classical Rett syndrome, including two for whom repeat MECP2 gene testing had identified mutations. In a patient with neonatal onset epilepsy with atypical Rett syndrome, we identified a frameshift deletion in STXBP1. Among seven patients with features of Rett syndrome not fulfilling formal diagnostic criteria, four had suspected pathogenic mutations, one each in MECP2, FOXG1, SCN8A, and IQSEC2. MECP2 mutations are highly correlated with classical Rett syndrome. Genes associated with atypical Rett syndrome, epilepsy, or intellectual disability should be considered in patients with features overlapping with Rett syndrome and negative MECP2 testing. While most of the identified mutations were apparently de novo, the SCN8A variant was inherited from an unaffected parent mosaic for the mutation, which is important to note for counseling regarding recurrence risks.

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Disruption of the IQSEC2 transcript in a female with X;autosome translocation t(X;20)(p11.2;q11.2) and a phenotype resembling X-linked infantile spasms (ISSX) syndrome

Cited by 10 publications

References 22 publications

Rett and Rett‐like syndrome: Expanding the genetic spectrum to KIF1A and GRIN1 gene

Rett and Rett‐like syndrome: Expanding the genetic spectrum to KIF1A and GRIN1 gene

Ca2+-induced release of IQSEC2/BRAG1 autoinhibition under physiological and pathological conditions

Mutations in epilepsy and intellectual disability genes in patients with features of Rett syndrome

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