Psychiatric features and variable neurodevelopment outcome in four females with IQSEC2 spectrum disorder

Accogli, Andrea; Jarvis, G. Eric; Schiavetto, Alessandra; Lai, Laurence; Amirali, Lila; Cruz, Daniel Alexander Jimenez; Rivière, Jean‐Baptiste; Trakadis, Yannis

doi:10.1007/s12041-020-01204-y

Cited by 5 publications

(9 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…There is an emerging clinical picture of ID, epileptic encephalopathy with speech and language deficits and autism due to a broad range of variants in the IQSEC2 gene, including the missense variants in the PH domain that we report here. When we include the five novel cases presented in this study, there are 29 distinct nonsynonymous missense variants in the IQSEC2 gene reported in 34 unrelated cases and families 2,3,12,14‐20 . Most of these variants occur in known functional domains.…”

Section: Discussionmentioning

confidence: 99%

“…When we include the five novel cases presented in this study, there are 29 distinct nonsynonymous missense variants in the IQSEC2 gene reported in 34 unrelated cases and families. 2,3,12,[14][15][16][17][18][19][20] Most of these variants occur in known functional domains. Within the catalytic Sec7 domain, nine missense variants with three recurrent variants across eight separate cases or families, impact a total of 44 affected individuals (39 males and five females).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

IQSEC2‐related encephalopathy in males due to missense variants in the pleckstrin homology domain

et al. 2022

View full text Add to dashboard Cite

Pathogenic variants in IQ motif and SEC7 domain containing protein 2 (IQSEC2) gene cause a variety of neurodevelopmental disorders, with intellectual disability as a uniform feature. We report five cases, each with a novel missense variant in the pleckstrin homology (PH) domain of the IQSEC2 protein. Male patients all present with moderate to profound intellectual disability, significant delays or absent language and speech and variable seizures. We describe the phenotypic spectrum associated with missense variants in PH domain of IQSEC2, further delineating the genotype-phenotype correlation for this X-linked gene.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

IQSEC2‐related encephalopathy in males due to missense variants in the pleckstrin homology domain

et al. 2022

View full text Add to dashboard Cite

show abstract

“…To date, hundreds of different IQSEC2 pathogenic structural or intragenic coding variants have been reported ( Accogli et al, 2020 ; Barrie et al, 2020 ; Lopergolo et al, 2021 ; Mignot et al, 2019 ; Radley et al, 2019 ; Shoubridge et al, 2019 , 2022 ; Wayhelova et al, 2020 ; Fig. 3, E and F ; and Fig.…”

Section: Resultsmentioning

confidence: 99%

“…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.) and nonsyndromic forms of intellectual disability (ID; Accogli et al, 2020 ; Barrie et al, 2020 ; Levy et al, 2023 ; Lopergolo et al, 2021 ; Mignot et al, 2019 ; Radley et al, 2019 ; Shoubridge et al, 2019 , 2022 ; Wayhelova et al, 2020 ). These mutations are spread throughout the protein-coding sequence of the gene.…”

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

View full text Add to dashboard Cite

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.

show abstract

“…IQSEC2 encodes GEFs for the ARF family of GTP-binding proteins (Shoubridge et al, 2019 ). Multiple IQSEC2 mutations have been reported (Jackson et al, 2019 ; Accogli et al, 2020 ; Brant et al, 2021 ) and may lead to global severe developmental delay and epilepsy. Our study found four novel IQSEC2 mutations related to overall developmental delay and seizures.…”

Section: Discussionmentioning

confidence: 99%

IQSEC2-related encephalopathy in male children: Novel mutations and phenotypes

Liu

Zhang

Lin

et al. 2022

Front. Mol. Neurosci.

View full text Add to dashboard Cite

The isoleucine–glutamine (IQ) motif and Sec7 domain-containing protein 2 (IQSEC2) gene, located at Xp11. 2, are associated with nervous system diseases, such as epilepsy, autism, and intellectual disabilities. Gender-related differences in the severity of phenotype severity have been described previously. Here, we report the details of seven male children with IQSEC2 mutations from different families. During this investigation, we explored the relationship between the genotype and phenotype of IQSEC2 mutations; to do so, we recruited seven children with pathogenic/likely pathogenic IQSEC2 mutations who were diagnosed with global developmental delay and/or epilepsy. Their clinical features were assessed, and Trio-based whole-exome sequencing (trio WES) was conducted in seven pedigrees. A variety of algorithms and computational tools were used to calculate the pathogenicity, protein stability, conservation, side chain properties, and protein-protein interactions of mutated proteins. The seven patients ranged in age from 18 months to 5 years. Among them, six children were found to have both developmental delay and epilepsy, and one child only exhibited developmental delay. Four novel mutations (c.316C > T, c.443_4 44dup, c.3235T > C, and c.1417G > T) were newly reported. Two patients did not have truncated aberrant proteins caused by missense mutations. Still, they did have severe phenotypes, such as early-onset epilepsy in infancy, because the mutations were located in domains like the pleckstrin homology and IQ calmodulin-binding motif domains. The bioinformatics analysis also proved that missense mutations may be located in the functional region, which affects protein stability and is harmful. In summary, severe phenotypes, such as early-onset epilepsy in infancy, occur in male patients with a missense mutation in specific domains (e.g., pleckstrin homology and IQ calmodulin-binding motif domains). Some female individuals with IQSEC2 mutations may be asymptomatic because of the skewed inactivation of the X chromosome.

show abstract

Psychiatric features and variable neurodevelopment outcome in four females with IQSEC2 spectrum disorder

Cited by 5 publications

References 30 publications

IQSEC2‐related encephalopathy in males due to missense variants in the pleckstrin homology domain

IQSEC2‐related encephalopathy in males due to missense variants in the pleckstrin homology domain

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

IQSEC2-related encephalopathy in male children: Novel mutations and phenotypes

Contact Info

Product

Resources

About