Periventricular heterotopia with white matter abnormalities associated with 6p25 deletion

Cellini, Elena; Disciglio, Vittoria; Novara, Francesca; Barkovich, James; Mencarelli, Maria Antonietta; Hayek, Joussef; Renieri, Alessandra; Zuffardi, Orsetta; Guerrini, Renzo

doi:10.1002/ajmg.a.35416

Cited by 30 publications

(20 citation statements)

References 12 publications

(20 reference statements)

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“…Interestingly, several reports have linked white matter abnormalities and stroke to copy-number variations in the relevant chromosomal region, 6p25 (Cellini et al, 2012;Kapoor et al, 2011;Rosenberg et al, 2013;van der Knaap et al, 2006;Vernon et al, 2013). Interpretations are complicated by the fact that FOXC1 are located only 214 kb downstream (centromeric) of FOXF2, and recently genetic variants centromeric of FOXC1 were associated with white matter hyperintensities (French et al, 2014).…”

Section: Discussionmentioning

confidence: 95%

Foxf2 Is Required for Brain Pericyte Differentiation and Development and Maintenance of the Blood-Brain Barrier

et al. 2015

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Pericytes are critical for cerebrovascular maturation and development of the blood-brain barrier (BBB), but their role in maintenance of the adult BBB, and how CNS pericytes differ from those of other tissues, is less well understood. We show that the forkhead transcription factor Foxf2 is specifically expressed in pericytes of the brain and that Foxf2(-/-) embryos develop intracranial hemorrhage, perivascular edema, thinning of the vascular basal lamina, an increase of luminal endothelial caveolae, and a leaky BBB. Foxf2(-/-) brain pericytes were more numerous, proliferated faster, and expressed significantly less Pdgfrβ. Tgfβ-Smad2/3 signaling was attenuated, whereas phosphorylation of Smad1/5 and p38 were enhanced. Tgfβ pathway components, including Tgfβ2, Tgfβr2, Alk5, and integrins αVβ8, were reduced. Foxf2 inactivation in adults resulted in BBB breakdown, endothelial thickening, and increased trans-endothelial vesicular transport. On the basis of these results, FOXF2 emerges as an interesting candidate locus for stroke susceptibility in humans.

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Section: Discussionmentioning

confidence: 95%

Foxf2 Is Required for Brain Pericyte Differentiation and Development and Maintenance of the Blood-Brain Barrier

et al. 2015

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“…In multiple case reports of patients with 6p25 deletions, individuals with ARS and other developmental abnormalities were found to also have white matter hyperintensities on MRI from as early as 18 months [47]. These reports provided early evidence for involvement of the FOXC1 gene in SVD.…”

Section: Foxc1-deletion Related Svdmentioning

confidence: 92%

Monogenic causes of stroke: now and the future

Tan

Markus

2015

J Neurol

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Most stroke is multifactorial with multiple polygenic risk factors each conferring small increases in risk interacting with environmental risk factors, but it can also arise from mutations in a single gene. This review covers single-gene disorders which lead to stroke as a major phenotype, with a focus on those which cause cerebral small vessel disease (SVD), an area where there has been significant recent progress with findings that may inform us about the pathogenesis of SVD more broadly. We also discuss the impact that next generation sequencing technology (NGST) is likely to have on clinical practice in this area. The most common form of monogenic SVD is cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, due to the mutations in the NOTCH3 gene. Several other inherited forms of SVD include cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy, retinal vasculopathy with cerebral leukodystrophy, collagen type IV α1 and α2 gene-related arteriopathy and FOXC1 deletion related arteriopathy. These monogenic forms of SVD, with overlapping clinical phenotypes, are beginning to provide insights into how the small arteries in the brain can be damaged and some of the mechanisms identified may also be relevant to more common sporadic SVD. Despite the discovery of these disorders, it is often challenging to clinically and radiologically distinguish between syndromes, while screening multiple genes for causative mutations that can be costly and time-consuming. The rapidly falling cost of NGST may allow quicker diagnosis of these rare causes of SVD, and can also identify previously unknown disease-causing variants.

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“…The 6p deletion in our patient is much smaller (0.4 Mb) when compared to other patients reported in the literature, who had deletions from 2.1 to 8.1 Mb, resulting in a higher number of hemyzigous genes and more severe phenotypes [Descipio, 2007;Martinet et al, 2008;Cellini et al, 2012;Nakane et al, 2013]. The 6p deletion in our patient encompassed only 3 genes: IRF4 (interferon regulatory factor 4) [OMIM 601900], EXOC2 (exocyst complex component 2) [OMIM 615329], HUS1B [HUS1 checkpoint homolog b (S. pombe)] [OMIM 609713] and a pseudogene LOC100421511 (MAP/microtubule affinity-regulating kinase 2 pseudogene).…”

Section: Discussionmentioning

confidence: 67%

“…Considering that our patient shows the 3 classes of immunoglobulins, a single copy of the IRF4 gene, or the redundancy of function of IRF4 and IRF8 genes may maintain the operation of classswitch recombination. Despite the hemizigosity of the IRF4 gene, which appears to have an important role in the immunological system, the immunodeficiency showed by our patient appears to be a result of the 22q11.2 deletion, since the patients described with pure 6p deletion do not show immune defects [Descipio, 2007;Cellini et al, 2012]. Considering the restricted number of genes deleted in 6p25.3 and their functions, we can attribute the patient's phenotype to the 22q11.2 deletion.…”

Section: Discussionmentioning

confidence: 89%

“…Impairment of the central nervous system and developmental delay of variable degrees are observed in all patients described [Martinet et al, 2008]. The clinical phenotype of these patients is probably caused by haploinsufficiency of one or more genes located in 6p25 [Cellini et al, 2012] and based on the patient described by Anderlid et al [2003]; the critical region of the 6pter deletion syndrome was narrowed down to a 2.1-Mb interval.…”

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confidence: 99%

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22q11.2 Deletion Syndrome due to a Translocation t(6;22) in a Patient Conceived via in vitro Fertilization

et al. 2015

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We report on a patient conceived via in vitro fertilization (IVF) with a 22q11.2 deletion due to an unusual unbalanced translocation involving chromosomes 6 and 22 in a karyotype with 45 chromosomes. Cytogenomic studies showed that the patient has a 3.3-Mb deletion of chromosome 22q and a 0.4-Mb deletion of chromosome 6p, which resulted in haploinsufficiency of the genes responsible for the 22q11.2 deletion syndrome and also of the <i>IRF4</i> gene, a member of the interferon regulatory factor family of transcription factors, which is expressed in the immune system cells. The rearrangement could be due to the manipulation of the embryo or as a sporadic event unrelated to IVF. Translocation involving chromosome 22 in a karyotype with 45 chromosomes is a rare event, with no previous reports involving chromosomes 6p and 22q.

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Periventricular heterotopia with white matter abnormalities associated with 6p25 deletion

Cited by 30 publications

References 12 publications

Foxf2 Is Required for Brain Pericyte Differentiation and Development and Maintenance of the Blood-Brain Barrier

Foxf2 Is Required for Brain Pericyte Differentiation and Development and Maintenance of the Blood-Brain Barrier

Monogenic causes of stroke: now and the future

22q11.2 Deletion Syndrome due to a Translocation t(6;22) in a Patient Conceived via in vitro Fertilization

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