Periventricular heterotopia and white matter abnormalities in a girl with mosaic ring chromosome 6

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Abstract

Ring chromosome 6 is a rare chromosome abnormality that arises typically de novo. The phenotypes can be highly variable, ranging from almost normal to severe malformations and neurological defects. We report a case of a 3-year-old girl with mosaic ring chromosome 6 who presented with being small for gestational age and intellectual disability, and whose brain MRI later revealed periventricular heterotopia and white matter abnormalities. Mosaicism was identified in peripheral blood cells examined by standard G-bands, mos 46,XX,r(6)(p25q27)[67]/45,XX,-6[25]/46,XX,dic r(6:6)(p25q27:p25q27)[6]/47,XX,r(6)(p25q27) × 2[2]. Using array-comparative genomic hybridization, we identified terminal deletion of 6q27 (1.5 Mb) and no deletion on 6p. To our knowledge, this is the first report of periventricular heterotopia and white matter abnormalities manifested in a patient with ring chromosome 6. These central nervous system malformations are further discussed in relation to molecular genetics.

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rnaset2 mutant zebrafish model familial cystic leukoencephalopathy and reveal a role for RNase T2 in degrading ribosomal RNA.

Noémie Haud, Firat Kara, Simone Diekmann … (2011)

T2-family acidic endoribonucleases are represented in all genomes. A physiological role for RNase T2 has yet to be defined for metazoa. RNASET2 mutation in humans is linked with a leukoencephalopathy that arises in infancy characterized by cortical cysts and multifocal white matter lesions. We now show localization of RNASET2 within lysosomes. Further, we demonstrate that loss of rnaset2 in mutant zebrafish results in accumulation of undigested rRNA within lysosomes within neurons of the brain. Further, by using high field intensity magnetic resonance microimaging, we reveal white matter lesions in these animals comparable to those observed in RNASET2-deficient infants. This correlates with accumulation of Amyloid precursor protein and astrocytes at sites of neurodegeneration. Thus we conclude that familial cystic leukoencephalopathy is a lysosomal storage disorder in which rRNA is the best candidate for the noxious storage material.

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Does "ring syndrome" exist? An analysis of 207 case reports on patients with a ring autosome.

G Kosztolányi (1987)

Analysis of 207 case reports on patients with ring autosome showed that: Forty patients, a fifth of the total, had extreme growth failure together with an otherwise almost-normal appearance, viz. no major malformation, no specific deletion syndrome, no or only a few unspecific minor anomalies. This phenotype may be regarded as the "ring syndrome", a term proposed by Cote et al. (1981) since it is independent of what chromosome is involved. Severe growth failure, the sole major physical abnormality in the "ring syndrome", was seen significantly more often among patients with ring of larger chromosomes than among patients with a smaller ring, indicating that the greater the chromosome involved in ring formation, the higher is the probability of severe growth failure. Larger ring chromosomes showed significantly more often instability than smaller rings, suggesting that there may be a correlation between ring instability and the size of the chromosome involved. Growth failure was present in significantly more patients with a "labile" ring than with a "stable" ring, indicating that a correlation may exist between ring instability and growth failure. It is suggested that the "ring syndrome" observed in many cases with ring autosome may result from end-to-end fusion of chromosome ends, an event not involving deletion in the genetic sense. It is also suggested that the "ring syndrome" is caused by a continuous generation of secondary aneuploid cells with increased mortality, i.e. structural ring instability which seems to be a function of the size of the chromosome involved. Thus, formation of a ring chromosome in certain cases might be regarded as a "structural mutation", i.e. an alteration in the structure of the genetic material per se, rather than a loss or gain of genetic dosages.

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Periventricular heterotopia in 6q terminal deletion syndrome: role of the C6orf70 gene.

Valerio Conti, Aurelie Carabalona, Emilie Pallesi-Pocachard … (2013)

Periventricular nodular heterotopia is caused by defective neuronal migration that results in heterotopic neuronal nodules lining the lateral ventricles. Mutations in filamin A (FLNA) or ADP-ribosylation factor guanine nucleotide-exchange factor 2 (ARFGEF2) cause periventricular nodular heterotopia, but most patients with this malformation do not have a known aetiology. Using comparative genomic hybridization, we identified 12 patients with developmental brain abnormalities, variably combining periventricular nodular heterotopia, corpus callosum dysgenesis, colpocephaly, cerebellar hypoplasia and polymicrogyria, harbouring a common 1.2 Mb minimal critical deletion in 6q27. These anatomic features were mainly associated with epilepsy, ataxia and cognitive impairment. Using whole exome sequencing in 14 patients with isolated periventricular nodular heterotopia but no copy number variants, we identified one patient with periventricular nodular heterotopia, developmental delay and epilepsy and a de novo missense mutation in the chromosome 6 open reading frame 70 (C6orf70) gene, mapping in the minimal critical deleted region. Using immunohistochemistry and western blots, we demonstrated that in human cell lines, C6orf70 shows primarily a cytoplasmic vesicular puncta-like distribution and that the mutation affects its stability and subcellular distribution. We also performed in utero silencing of C6orf70 and of Phf10 and Dll1, the two additional genes mapping in the 6q27 minimal critical deleted region that are expressed in human and rodent brain. Silencing of C6orf70 in the developing rat neocortex produced periventricular nodular heterotopia that was rescued by concomitant expression of wild-type human C6orf70 protein. Silencing of the contiguous Phf10 or Dll1 genes only produced slightly delayed migration but not periventricular nodular heterotopia. The complex brain phenotype observed in the 6q terminal deletion syndrome likely results from the combined haploinsufficiency of contiguous genes mapping to a small 1.2 Mb region. Our data suggest that, of the genes within this minimal critical region, C6orf70 plays a major role in the control of neuronal migration and its haploinsufficiency or mutation causes periventricular nodular heterotopia.

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Author and article information

Contributors

Satsuki Nishigaki: +81-6-6645-3815 , nishigaki.satsuki@med.osaka-cu.ac.jp

Takashi Hamazaki: hammer@med.osaka-cu.ac.jp

Mika Saito: mika-s@med.osaka-cu.ac.jp

Toshiyuki Yamamoto: yamamoto.toshiyuki@twmu.ac.jp

Toshiyuki Seto: setot@med.osaka-cu.ac.jp

Haruo Shintaku: shintakuh@med.osaka-cu.ac.jp

Journal

Journal ID (nlm-ta): Mol Cytogenet

Journal ID (iso-abbrev): Mol Cytogenet

Title: Molecular Cytogenetics

Publisher: BioMed Central (London )

ISSN (Electronic): 1755-8166

Publication date (Electronic): 26 July 2015

Publication date PMC-release: 26 July 2015

Publication date Collection: 2015

Volume: 8

Electronic Location Identifier: 54

Affiliations

[ ]Department of Pediatrics, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585 Japan

[ ]Institute for Integrated Medical Sciences, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ward, Tokyo, 162-8666 Japan

Article

Publisher ID: 162

DOI: 10.1186/s13039-015-0162-3

PMC ID: 4514952

SO-VID: aafa78af-2e46-4f80-a882-356d59ab3fbe

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 16 April 2015

Date accepted : 12 July 2015

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ScienceOpen disciplines: Genetics

Keywords: ring chromosome 6,brain mri,periventricular heterotopia,white matter abnormality,array-comparative genomic hybridization,small for gestational age

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ScienceOpen disciplines: Genetics

Keywords: ring chromosome 6, brain mri, periventricular heterotopia, white matter abnormality, array-comparative genomic hybridization, small for gestational age

Periventricular heterotopia and white matter abnormalities in a girl with mosaic ring chromosome 6

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Most cited references 15

rnaset2 mutant zebrafish model familial cystic leukoencephalopathy and reveal a role for RNase T2 in degrading ribosomal RNA.

Does "ring syndrome" exist? An analysis of 207 case reports on patients with a ring autosome.

Periventricular heterotopia in 6q terminal deletion syndrome: role of the C6orf70 gene.

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