Baraitser–Winter cerebrofrontofacial syndrome

Yates, T. Michael; Turner, Claire; Firth, Helen V.; Berg, Jonathan; Pilz, Daniela T.

doi:10.1111/cge.12864

Cited by 23 publications

(16 citation statements)

References 40 publications

(105 reference statements)

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“…None of our individuals were detected to have agyria/pachygyria or coloboma, which are frequent in BRWS. 30 , 31 This further emphasizes that ACTB loss-of-function mutations cause a specific syndrome distinct from BRWS.…”

Section: Main Textmentioning

confidence: 94%

ACTB Loss-of-Function Mutations Result in a Pleiotropic Developmental Disorder

Cuvertino

Stuart

Chandler

et al. 2017

The American Journal of Human Genetics

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ACTB encodes β-actin, an abundant cytoskeletal housekeeping protein. In humans, postulated gain-of-function missense mutations cause Baraitser-Winter syndrome (BRWS), characterized by intellectual disability, cortical malformations, coloboma, sensorineural deafness, and typical facial features. To date, the consequences of loss-of-function ACTB mutations have not been proven conclusively. We describe heterozygous ACTB deletions and nonsense and frameshift mutations in 33 individuals with developmental delay, apparent intellectual disability, increased frequency of internal organ malformations (including those of the heart and the renal tract), growth retardation, and a recognizable facial gestalt (interrupted wavy eyebrows, dense eyelashes, wide nose, wide mouth, and a prominent chin) that is distinct from characteristics of individuals with BRWS. Strikingly, this spectrum overlaps with that of several chromatin-remodeling developmental disorders. In wild-type mouse embryos, β-actin expression was prominent in the kidney, heart, and brain. ACTB mRNA expression levels in lymphoblastic lines and fibroblasts derived from affected individuals were decreased in comparison to those in control cells. Fibroblasts derived from an affected individual and ACTB siRNA knockdown in wild-type fibroblasts showed altered cell shape and migration, consistent with known roles of cytoplasmic β-actin. We also demonstrate that ACTB haploinsufficiency leads to reduced cell proliferation, altered expression of cell-cycle genes, and decreased amounts of nuclear, but not cytoplasmic, β-actin. In conclusion, we show that heterozygous loss-of-function ACTB mutations cause a distinct pleiotropic malformation syndrome with intellectual disability. Our biological studies suggest that a critically reduced amount of this protein alters cell shape, migration, proliferation, and gene expression to the detriment of brain, heart, and kidney development.

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Section: Main Textmentioning

confidence: 94%

ACTB Loss-of-Function Mutations Result in a Pleiotropic Developmental Disorder

Cuvertino

Stuart

Chandler

et al. 2017

The American Journal of Human Genetics

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“…Previous studies focusing on subcortical neuronal heterotopia have shown relationships between cortical lamination and the genetic abnormalities associated with the mechanisms of migration impairment in agyric/pachygyria syndromes (Marcorelles et al, 2010; Verloes et al, 2014; Yates et al, 2017). In this study with associated callosal agenesis and heterotopia, we have demonstrated an array of underlying pathologies, such as impairments in the proliferation of the progenitor cells, a noticeable reduction of neurons, and growth cones without leading edges in the CGE.…”

Section: Discussionmentioning

confidence: 99%

Post-mortem Characterisation of a Case With an ACTG1 Variant, Agenesis of the Corpus Callosum and Neuronal Heterotopia

et al. 2019

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Cytoplasmic Actin Gamma 1 ( ACTG1 ) gene variant are autosomal dominant and can cause CNS anomalies (Baraitser Winter Malformation Syndrome; BWMS). ACTG1 anomalies in offspring include agenesis of the corpus callosum (ACC) and neuronal heterotopia which are ectopic nodules of nerve cells that failed to migrate appropriately. Subcortical and periventricular neuronal heterotopia have been described previously in association with ACC. In this case report, we investigated a neonatal brain with an ACTG1 gene variant and a phenotype of ACC, and neuronal heterotopia (ACC-H) which was diagnosed on antenatal MR imaging and was consistent with band heterotopia seen on post-mortem brain images. Histologically clusters of neurons were seen in both the subcortical and periventricular white matter (PVWM) brain region that coincided with impaired abnormalities in glial formation. Immunohistochemistry was performed on paraffin-embedded brain tissue blocks from this case with ACTG1 variant and an age-matched control. Using tissue sections from the frontal lobe, we examined the distribution of neuronal cells (HuC/HuD, calretinin, and parvalbumin), growth cone (drebrin), and synaptic proteins (synaptophysin and SNAP-25). Additionally, we investigated how the ACTG1 variant altered astroglia (nestin, GFAP, vimentin); oligodendroglia (OLIG2) and microglia (Iba-1) in the corpus callosum, cortex, caudal ganglionic eminence, and PVWM. As predicted in the ACTG1 variant case, we found a lack of midline radial glia and glutamatergic fibers. We also found disturbances in the cortical region, in glial cells and a lack of extracellular matrix components in the ACTG1 variant. The caudal ganglionic eminence and the PVWM regions in the ACTG1 variant lacked several cellular components that were identified in a control case. Within the neuronal heterotopia, we found evidence of glutamatergic and GABAergic neurons with apparent synaptic connections. The data presented from this case study with BWMS with variants in the ACTG1 gene provides insight as to the composition of neuronal heterotopia, and how disturbances of important migratory signals may dramatically affect ongoing brain development.

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“…Most birth defects have unknown causes (Nelson & Holmes, ); however, there is strong evidence that genetic factors contribute to their etiologies. To date, much of what is known about the genetics of birth defects includes effects of high‐risk alleles that cause rare multiple malformation syndromes (Belmont, Mohapatra, Towbin, & Ware, ; de Munnik et al, ; Lewin, Glass, & Power, ; Maslen, ; Mori & Bruneau, ; Yates, Turner, Firth, Berg, & Pilz, ). Such alleles occur at very low frequency in the general population and explain relatively little of the population burden of birth defects.…”

Section: Other Considerations and Future Directionsmentioning

confidence: 99%

Genome‐wide association studies of structural birth defects: A review and commentary

Lupo

Mitchell

Jenkins

2019

Birth Defects Research

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Background While there is strong evidence that genetic risk factors play an important role in the etiologies of structural birth defects, compared to other diseases, there have been relatively few genome‐wide association studies (GWAS) of these conditions. We reviewed the current landscape of GWAS conducted for birth defects, noting novel insights, and future directions. Methods This article reviews the literature with regard to GWAS of structural birth defects. Key defects included in this review include oral clefts, congenital heart defects (CHDs), biliary atresia, pyloric stenosis, hypospadias, craniosynostosis, and clubfoot. Additionally, other issues related to GWAS are considered, including the assessment of polygenic risk scores and issues related to genetic ancestry, as well as utilizing genome‐wide single nucleotide polymorphism array data to evaluate gene–environment interactions and Mendelian randomization. Results For some birth defects, including oral clefts and CHDs, several novel susceptibility loci have been identified and replicated through GWAS, including 8q24 for oral clefts, DGKK for hypospadias, and 4p16 for CHDs. Relatively common birth defects for which there are currently no published GWAS include neural tube defects, anotia/microtia, anophthalmia/microphthalmia, gastroschisis, and omphalocele. Conclusions Overall, GWAS have been successful in identifying several novel susceptibility genes and genomic regions for structural birth defects. These findings have provided new insights into the etiologies of these phenotypes. However, GWAS have been underutilized for understanding the genetic etiologies of several birth defects.

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Baraitser–Winter cerebrofrontofacial syndrome

Cited by 23 publications

References 40 publications

ACTB Loss-of-Function Mutations Result in a Pleiotropic Developmental Disorder

ACTB Loss-of-Function Mutations Result in a Pleiotropic Developmental Disorder

Post-mortem Characterisation of a Case With an ACTG1 Variant, Agenesis of the Corpus Callosum and Neuronal Heterotopia

Genome‐wide association studies of structural birth defects: A review and commentary

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