Whole-exome sequencing is a powerful approach for establishing the etiological diagnosis in patients with intellectual disability and microcephaly

Rump, Patrick; Jazayeri, Omid; Dijk-Bos, K. K. van; Johansson, Lennart; Essen, Anthonie J. van; Verheij, J.; Veenstra‐Knol, Hermine E.; Redeker, E.; Mannens, Marcel M.A.M.; Swertz, Morris A.; Alizadeh, Behrooz Z.; Ravenswaaij-Arts, Conny M. A. van; Sinke, Richard J.; Sikkema‐Raddatz, Birgit

doi:10.1186/s12920-016-0167-8

Cited by 74 publications

(83 citation statements)

References 37 publications

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“…[28][29][30][31] The genes causing microcephaly have been widely acknowledged to link closely to the mitotic apparatus that take part in DNA replication, centriole duplication, chromosome condensation, spindle assembly, and mitotic checkpoint activation. [28][29][30][31] The genes causing microcephaly have been widely acknowledged to link closely to the mitotic apparatus that take part in DNA replication, centriole duplication, chromosome condensation, spindle assembly, and mitotic checkpoint activation.…”

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confidence: 99%

The UFM1 cascade times mitosis entry associated with microcephaly

Deng

et al. 2019

FASEB j.

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Posttranslational modifications enhance the functional diversity of the proteome by modifying the substrates. The UFM1 cascade is a novel ubiquitin‐like modification system. The mutations in UFM1, its E1 (UBA5) and E2 (UFC1), have been identified in patients with microcephaly. However, its pathological mechanisms remain unclear. Herein, we observed the disruption of the UFM1 cascade in Drosophila neuroblasts (NBs) decreased the number of NBs, leading to a smaller brain size. The lack of ufmylation in NBs resulted in an increased mitotic index and an extended G2/M phase, indicating a defect in mitotic progression. In addition, live imaging of the embryos revealed an impaired E3 ligase (Ufl1) function resulted in premature entry into mitosis and failed cellularization. Even worse, the embryonic lethality occurred as early as within the first few mitotic cycles following the depletion of Ufm1. Knockdown of ufmylation in the fixed embryos exhibited severe phenotypes, including detached centrosomes, defective microtubules, and DNA bridge. Furthermore, we observed that the UFM1 cascade could alter the level of phosphorylation on tyrosine‐15 of CDK1 (pY15‐CDK1), which is a negative regulator of the G2 to M transition. These findings yield unambiguous evidence suggesting that the UFM1 cascade is a microcephaly‐causing factor that regulates the progression of the cell cycle at mitosis phase entry.

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confidence: 99%

The UFM1 cascade times mitosis entry associated with microcephaly

Deng

et al. 2019

FASEB j.

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“…The application of sequence variation detection methods (i. e. whole exome or whole genome sequencing) for the identification of molecular ID causes is a powerful tool for the diagnostic evaluation of patients with highly heterogeneous DD/ID phenotypes (27–28). The introduction of these next generation sequencing methods has advanced the detection of new ID genes though the confirmation of the candidate genomic loci still remains complicated and requires many more research studies and functional studies of the genomic variants.…”

Section: Discussionmentioning

confidence: 99%

Identification of genetic causes of congenital neurodevelopmental disorders using genome wide molecular technologies

Preikšaitienė¹,

Ambrozaitytė²,

Maldžienė³

et al. 2016

AML

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Background.Intellectual disability affects about 1–2% of the general population worldwide, and this is the leading socio-economic problem of health care. The evaluation of the genetic causes of intellectual disability is challenging because these conditions are genetically heterogeneous with many different genetic alterations resulting in clinically indistinguishable phenotypes. Genome wide molecular technologies are effective in a research setting for establishing the new genetic basis of a disease. We describe the first Lithuanian experience in genome-wide CNV detection and whole exome sequencing, presenting the results obtained in the research project UNIGENE.Materials and methods.The patients with developmental delay/intellectual disability have been investigated (n = 66). Diagnostic screening was performed using array-CGH technology. FISH and real time-PCR were used for the confirmation of gene-dose imbalances and investigation of parental samples. Whole exome sequencing using the next generation high throughput NGS technique was used to sequence the samples of 12 selected families.Results.14 out of 66 patients had pathogenic copy number variants, and one patient had novel likely pathogenic aberration (microdeletion at 4p15.2). Twelve families have been processed for whole exome sequencing. Two identified sequence variants could be classified as pathogenic (in MECP2, CREBBP genes). The other families had several candidate intellectual disability gene variants that are of unclear clinical significance and must be further investigated for possible effect on the molecular pathways of intellectual disability.Conclusions.The genetic heterogeneity of intellectual disability requires genome wide approaches, including detection of chromosomal aberrations by chromosomal microarrays and whole exome sequencing capable of uncovering single gene mutations. This study demonstrates the benefits and challenges that accompany the use of genome wide molecular technologies and provides genotype-phenotype information on 32 patients with chromosomal imbalances and ID candidate sequence variants.

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“…Patients with CASK gene mutations has pontocerebellar hypoplasia, microcephaly and severe mental retardation. Cases of ataxia, nystagmus and sensorineural deafness have been described 1,4,5,8,[10][11][12] . We could observe pontocerebellar hypoplasia on the magnetic resonance imaging, as well as altered conduction of the pontomesencephalic pathways in brainstem auditory evoked potentials (AEP).…”

Section: Discussionmentioning

confidence: 99%

Hipoplasia pontocerebelosa secundaria a deleción en el gen CASK: Caso clínico

Rivas

Blanco

Torreira

et al. 2017

Rev. chil. pediatr.

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Introduction: Pontocerebellar hypoplasia (PCH) is a reduction of the size of the cerebellum and pons secondary to an alteration in its development, and can be caused by neurodegenerative diseases of genetic origin, of which there are known 10 subtypes (PCH 1-10), cortical malformations, metabolic and genetic diseases. Objective: To present the case of a child with microcephaly, PCH and West syndrome, in which the genetic study allowed to make the diagnosis of a deletion on chromosome X. Case report: This is a female infant of 7-month at diagnosis, without family or obstetric history of interest, head circumference at birth -1.5 standard deviations (SD). She had little weight and growth in head circumference progression. In addition, physical examination revealed no fixating gaze, hypotonia with preserved deep tendon reflexes. Progressively developed refractary seizures. Brainsteam Auditory Evoked Potential demonstrated involvement of pontomesencefphalic ways and neuroimaging Pontocerebellar hypoplasia. The genetic study (aCGH) showed heterozygous deletion on the X chromosome, affecting the CASK gene. Conclusions: Given the wide differential diagnosis proposed at the PCH, new cytogenetic techniques have improved the classification of HPC and in some cases establish their etiology, so in these cases can provide appropriate genetic counseling to families.

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Whole-exome sequencing is a powerful approach for establishing the etiological diagnosis in patients with intellectual disability and microcephaly

Cited by 74 publications

References 37 publications

The UFM1 cascade times mitosis entry associated with microcephaly

The UFM1 cascade times mitosis entry associated with microcephaly

Identification of genetic causes of congenital neurodevelopmental disorders using genome wide molecular technologies

Hipoplasia pontocerebelosa secundaria a deleción en el gen CASK: Caso clínico

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