Identification of a Duplication of Xq28 Associated with Bilateral Periventricular Nodular Heterotopia

Fink, Jürgen; Dobyns, William B.; Guerrini, Renzo; Hirsch, Betsy A.

doi:10.1086/514863

Cited by 78 publications

(46 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…15 Virtually, all of these mutations are frameshift or truncating and likely to be subject to nonsense-mediated RNA decay. There have been two reports of surviving male patients with PVNH associated with duplications of the Xq28 region, 15,16 suggesting that the amount of FLNA is critical for neuronal migration, and either increased or decreased expression can interfere with the normal migration process. This hypothesis is also supported by animal studies.…”

Section: Discussionmentioning

confidence: 99%

Xq28 duplication presenting with intestinal and bladder dysfunction and a distinctive facial appearance

et al. 2008

View full text Add to dashboard Cite

Xq28 duplications encompassing MECP2 have been described in male patients with a severe neurodevelopmental disorder associated with hypotonia and spasticity, severe learning disability and recurrent pneumonia. We identified an Xq28 duplication in three families where several male patients had presented with intestinal pseudo-obstruction or bladder distension. The affected boys had similar dysmorphic facial appearances. Subsequently, we ascertained seven further families where the proband presented with similar features. We demonstrated duplications of the Xq28 region in five of these additional families. In addition to MECP2, these duplications encompassed several other genes already known to be associated with diseases including SLC6A8, L1CAM and Filamin A (FLNA). The two remaining families were shown to have intragenic duplications of FLNA only. We discuss which elements of the Xq28 duplication phenotype may be associated with the various genes in the duplication. We propose that duplication of FLNA may contribute to the bowel and bladder phenotype seen in these seven families.

show abstract

Section: Discussionmentioning

confidence: 99%

Xq28 duplication presenting with intestinal and bladder dysfunction and a distinctive facial appearance

et al. 2008

View full text Add to dashboard Cite

show abstract

“…Twenty G banded metaphase cells were analyzed. Sequential G banding to fluorescence in situ hybridization (FISH) was performed on prepared metaphase cells from bone marrow by using a technique previously reported (22). FISH was performed with an MLL gene probe (ONCOR) mapped to band 11q23.…”

Section: Methodsmentioning

confidence: 99%

Somatic mosaicism in Fanconi anemia: Evidence of genotypic reversion in lymphohematopoietic stem cells

Gregory

Wagner

Verlander

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

207

137

View full text Add to dashboard Cite

Somatic mosaicism has been observed previously in the lymphocyte population of patients with Fanconi anemia (FA). To identify the cellular origin of the genotypic reversion, we examined each lymphohematopoietic and stromal cell lineage in an FA patient with a 2815-2816ins19 mutation in FANCA and known lymphocyte somatic mosaicism. DNA extracted from individually plucked peripheral blood T cell colonies and marrow colony-forming unit granulocyte-macrophage and burst-forming unit erythroid cells revealed absence of the maternal FANCA exon 29 mutation in 74.0%, 80.3%, and 86.2% of colonies, respectively. These data, together with the absence of the FANCA exon 29 mutation in Epstein-Barr virus-transformed B cells and its presence in fibroblasts, indicate that genotypic reversion, most likely because of back mutation, originated in a lymphohematopoietic stem cell and not solely in a lymphocyte population. Contrary to a predicted increase in marrow cellularity resulting from reversion in a hematopoietic stem cell, pancytopenia was progressive. Additional evaluations revealed a partial deletion of 11q in 3 of 20 bone marrow metaphase cells. By using interphase fluorescence in situ hybridization with an MLL gene probe mapped to band 11q23 to identify colonyforming unit granulocyte-macrophage and burst-forming unit erythroid cells with the 11q deletion, the abnormal clone was exclusive to colonies with the FANCA exon 29 mutation. Thus, we demonstrate the spontaneous genotypic reversion in a lymphohematopoietic stem cell. The subsequent development of a clonal cytogenetic abnormality in nonrevertant cells suggests that ex vivo correction of hematopoietic stem cells by gene transfer may not be sufficient for providing life-long stable hematopoiesis in patients with FA. F anconi anemia (FA) is an autosomal recessive disorder characterized by congenital abnormalities, bone marrow failure, and a predisposition to malignancies, including myelodysplastic syndrome and acute myelogenous leukemia (1). Seven FA complementation groups (FA-A through FA-G) have been reported (2), with FA-A (Online Mendelian Inheritance in Man, OMIM no. 227650) constituting approximately two-thirds of the patients. The FANCA, FANCC, FANCE, FANCF, and FANCG genes have been cloned and mapped to chromosomes 16q24. 3, 9q22.3, 6p21.2-21.3, 11p15, and 9p13, respectively (3-8). However, the specific function of these genes remains unclear.FA cells are uniquely hypersensitive to DNA cross-linking agents such as diepoxybutane (DEB) and mitomycin C (MMC) (9). This cellular phenotype can be demonstrated in cultured T cells, B cells, fibroblasts, and fetal cells cultured from amniotic fluid or chorionic villi (10). Hypersensitivity of phytohemagglutinin (PHA)-stimulated peripheral blood lymphocytes (PBLs) to DEB is used routinely as a diagnostic test for the syndrome (11). At a DEB concentration that has a minimal effect on normal PBLs (0.1 g͞ml), 80-100% of PBLs analyzed will have chromatid breaks and exchanges in the typical FA patient. However, in a small grou...

show abstract

“…When needed for specific localization of the hybridization signals, sequential Gbanding to FISH was performed as previously described. 26 …”

Section: Methodsmentioning

confidence: 99%

Cytogenetic and molecular heterogeneity of 7q36/12p13 rearrangements in childhood AML

et al. 2002

View full text Add to dashboard Cite

The t(7;12)(q36;p13) is a recurrent abnormality in acute myeloid leukemia (AML) of childhood. The involved gene on chromosome 12 is TEL; the 7q36 partner gene has not been identified. We describe morphologic, molecular and cytogenetic characterization of two cases of 7q36/12p13-associated AML that provide important insights regarding the consequences of this rearrangement. First, the molecular organization of the breakpoint regions differ significantly: one case is a reciprocal 7;12 translocation (RTR); the other has an insertion of 7q into 12p (INS). While 12p13 breakpoints in both patients interrupt TEL intron 1, the centromere to telomere orientation of the 7q36 sequences relative to the TEL sequences are inverted in INS compared to RTR. This difference makes it difficult to postulate a mechanism whereby both patients could produce a common fusion transcript. Further, no evidence was obtained for any TEL-containing fusion transcripts. Finally, we report the first cloning of a 7;12 genomic breakpoint (from RTR) and find that it maps to a site 30 kbp proximal to the HLXB9 gene in 7q36. Together, these data suggest that, unlike most leukemia-associated chromosomal rearrangements, the important consequence of the t(7;12) is likely not the generation of a novel fusion transcript, but instead the inactivation of TEL and/or a gene at 7q36.

show abstract

Identification of a Duplication of Xq28 Associated with Bilateral Periventricular Nodular Heterotopia

Cited by 78 publications

References 25 publications

Xq28 duplication presenting with intestinal and bladder dysfunction and a distinctive facial appearance

Xq28 duplication presenting with intestinal and bladder dysfunction and a distinctive facial appearance

Somatic mosaicism in Fanconi anemia: Evidence of genotypic reversion in lymphohematopoietic stem cells

Cytogenetic and molecular heterogeneity of 7q36/12p13 rearrangements in childhood AML

Contact Info

Product

Resources

About