Comprehensive genetic analysis confers high diagnostic yield in 16 Japanese patients with corpus callosum anomalies

Miyamoto, Sachiko; Kato, Mitsuhiro; Hiraide, Takuya; Shiohama, Tadashi; Goto, Tomohide; Hojo, Akira; Ebata, Akio; Suzuki, Manabu; Kobayashi, Kozue; Chong, Pin Fee; Kira, Ryutaro; Matsushita, Hiroko; Ikeda, Hiroko; Hoshino, Kyoko; Matsufuji, Mayumi; Moriyama, Nobuyuki; Furuyama, Masayuki; Yamamoto, Tatsuya; Nakashima, Mitsuko; Saitsu, Hirotomo

doi:10.1038/s10038-021-00932-y

Cited by 9 publications

(7 citation statements)

References 37 publications

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“…Recently, an additional female patient has been described carrying the c.2827C>T pathogenic variant, in a study concerning genetic ethiologies of corpus callosum abnormalities. Like the other 2 patients, this affected individual also presented global developmental delay and mildly thin body of the corpus callosum, in addition to a hypoplastic frontal lobe and a dilatation of the lateral ventricles [Miyamoto et al, 2021].…”

Section: Discussionmentioning

confidence: 65%

Expanding the Phenotypic Spectrum of HIVEP2-Related Intellectual Disability: Description of Two Portuguese Patients and Review of the Literature

Quental

Borges

Santos³

et al. 2022

Mol Syndromol

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Introduction: Pathogenic variants in HIVEP2 have been associated with a neurodevelopmental disorder mainly characterized by intellectual disability, severe language impairment, and motor developmental delay. Since its first description in 2016, only 15 patients have been described in the literature. Methods: Here, we report 2 additional unrelated Portuguese children presenting intellectual disability and motor delay in whom de novo nonsense pathogenic variants in HIVEP2 have been identified by next-generation sequencing analysis. Results: In patient 1, the variant c.2827C>T, p.(Arg943*) was detected, whereas patient 2 carried the variant c.6667C>T, p.(Arg2223*). Interestingly, patient 1 presented with a rapid growth of the occipitofrontal diameter in the first months of life due to external hydrocephalus, a feature that, as far as we know, has never been reported in patients with HIVEP2 pathogenic variants. Conclusion: This report expands the phenotypic spectrum of this rare syndrome and provides deeper insights by comparing the clinical features of our patients with previously reported affected individuals.

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Section: Discussionmentioning

confidence: 65%

Expanding the Phenotypic Spectrum of HIVEP2-Related Intellectual Disability: Description of Two Portuguese Patients and Review of the Literature

Quental

Borges

Santos³

et al. 2022

Mol Syndromol

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“…We describe the first documented occurrence of an inherited CDK8 ‐associated disease variant in a child–parent pair (child: NM_001260.3; parent: NM_001260.2). All documented cases of CDK8 ‐related syndromes to date have arisen de novo (Table S1) (Aggarwal et al, 2020; Calpena et al, 2019; Halfmeyer et al, 2023; Maron et al, 2023; Miyamoto et al, 2021; Uehara et al, 2020); 13 different heterozygous variants have been identified in 18 unrelated patients. This case documents parental inheritance of a CDK8 pathogenic variant which can affect genetic counseling and recurrence risk in other family members.…”

Section: Discussionmentioning

confidence: 99%

Expanding the phenotypic spectrum for CDK8‐related disease: A case report

Comeau,

Belliveau,

Bouhamdani

et al. 2024

American J of Med Genetics Pt A

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BackgroundCyclin‐dependent kinase 8 (CDK8) is part of a regulatory kinase module that regulates the activity of the Mediator complex. The Mediator, a large conformationally flexible protein complex, goes on to regulate RNA polymerase II activity, consequently affecting transcriptional regulation. Thus, inactivating mutations of the genes within the kinase module cause aberrant transcriptional regulation and disease, namely, CDK8‐related intellectual developmental disorder with hypotonia and behavioral abnormalities (IDDHBA).Case PresentationWe describe, for the first time, a likely pathogenic heterozygous CDK8 variant c.599G>A, p.(Arg200Gln) inherited from the biological mother. The clinical presentation of the child and mother is within the described clinical spectrum for IDDHBA; however, undocumented progressive contractures of the hips and knees as well as scoliosis were also observed in the child. This phenotype was not found in the mother, highlighting a heterogenous presentation for the same variant within the same family. Furthermore, the described clinical presentation may further support the notion of a module‐ or Mediator‐related syndrome with varying clinical presentation.ConclusionThis case report documents the first inherited case of IDDHBA and expands the phenotypic spectrum for CDK8‐related disease to include undocumented progressive contractures of the hips and knees as well as scoliosis, which may support the notion of a module‐ or Mediator‐related syndrome with varying clinical presentation.

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“…1A-B, File S1 "clinical_table", File S2 "clinical reports"). A clinical description of previously reported individuals, although incomplete, was available only for Ind5812-H2054P (Miyamoto et al 2021a), Ind11-I2031T (Mignot et al 2016) and Ind10-I2031N (Yan et al 2019a) and was extracted from the respective publications (File S1 "clinical_table"). Facial dysmorphic features of Ind1-2129del4 and Ind2-2188ter were determined independently by two clinical geneticists and for the previously described cases, when available, from the respective clinical report or analysis of the published pictures (File S1 "clinical_table", File S2 "clinical reports").…”

Section: Clinical Informationmentioning

confidence: 99%

The missing link: ARID1B non-truncating variants causing Coffin-Siris syndrome due to protein aggregation

Bosch,

Güse,

Kirchner

et al. 2024

Preprint

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ARID1B is the most frequently mutated gene in Coffin-Siris syndrome (CSS). To date, the vast majority of causative variants reported in ARID1B are truncating, leading to nonsense-mediated mRNA decay. In the absence of experimental data, only few ARID1B amino acid substitutions have been classified as pathogenic, mainly based on clinical data and their de novo occurrence, while most others are currently interpreted as variants of unknown significance. The present study substantiates the pathogenesis of ARID1B non-truncating/NMD-escaping variants located in the SMARCA4-interacting EHD2 and DNA-binding ARID domains. Overexpression assays in cell lines revealed that the majority of EHD2 variants lead to protein misfolding and formation of cytoplasmic aggresomes surrounded by vimentin cage-like structures and co-localizing with the microtubule organisation center. ARID domain variants exhibited not only aggresomes, but also nuclear aggregates, demonstrating robust pathological effects. Protein levels were not compromised, as shown by quantitative western blot analysis. In silico structural analysis predicted the exposure of amylogenic segments in both domains due to the nearby variants, likely causing this aggregation. Genome-wide transcriptome and methylation analysis in affected individuals revealed expression and methylome patterns consistent with those of the pathogenic haploinsufficiency ARID1B alterations in CSS cases. These results further support pathogenicity and indicate two approaches for disambiguation of such variants in everyday practice. The few affected individuals harbouring EHD2 non-truncating variants described to date exhibit mild CSS clinical traits. In summary, this study paves the way for the re-evaluation of previously unclear ARID1B non-truncating variants and opens a new era in CSS genetic diagnosis.

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Comprehensive genetic analysis confers high diagnostic yield in 16 Japanese patients with corpus callosum anomalies

Cited by 9 publications

References 37 publications

Expanding the Phenotypic Spectrum of <b><i>HIVEP2</i></b>-Related Intellectual Disability: Description of Two Portuguese Patients and Review of the Literature

Expanding the Phenotypic Spectrum of <b><i>HIVEP2</i></b>-Related Intellectual Disability: Description of Two Portuguese Patients and Review of the Literature

Expanding the phenotypic spectrum for CDK8‐related disease: A case report

The missing link: ARID1B non-truncating variants causing Coffin-Siris syndrome due to protein aggregation

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