Cognet M.,University of Paris Descartes |
Nougayrede A.,University of Paris Descartes |
Malan V.,University of Paris Descartes |
Callier P.,Service de Gene tique |
And 15 more authors.
European Journal of Human Genetics | Year: 2011
Feingold syndrome (FS) is a syndromic microcephaly entity for which MYCN is the major disease-causing gene. We studied the expression pattern of MYCN at different stages of human embryonic development and collected a series of 17 FS and 12 isolated oesophageal atresia (IOA) cases. An MYCN gene deletion/mutation was identified in 47% of FS cases exclusively. We hypothesized that mutations or deletions of highly conserved non-coding elements (HCNEs) at the MYCN locus could lead to its misregulation and thereby to FS and/or IOA. We subsequently sequenced five HCNEs at the MYCN locus and designed a high-density tiling path comparative genomic hybridization array of 3.3Mb at the MYCN locus. We found no mutations or deletions in this region, supporting the hypothesis of genetic heterogeneity in FS. © 2011 Macmillan Publishers Limited.
Habib W.A.,French Institute of Health and Medical Research |
Habib W.A.,Paris-Sorbonne University |
Habib W.A.,Armand Trousseau Hospital |
Azzi S.,French Institute of Health and Medical Research |
And 24 more authors.
Human Molecular Genetics | Year: 2014
Isolated gain of methylation (GOM) at the IGF2/H19 imprinting control region 1 (ICR1) accounts for about 10% of patients with BWS. A subset of these patients have genetic defects within ICR1, but the frequency of these defects has not yet been established in a large cohort ofBWSpatients with isolated ICR1 GOM. Here, we carried out a genetic analysis in a large cohort of 57BWSpatients with isolated ICR1GOMand analyzed the methylation status of the entire domain. We found a new point mutation in two unrelated families and a 21 bp deletion in another unrelated child, both of which were maternally inherited and affected the OCT4/SOX2 binding site in the A2 repeat of ICR1. Based on data from this and previous studies, we estimate that cis genetic defects account for about 20% of BWS patients with isolated ICR1 GOM. Methylation analysis at eight loci of the IGF2/H19 domain revealed that sites surrounding OCT4/SOX2 binding site mutations were fully methylated and methylation indexes declined as a function of distance from these sites. This was not the case inBWSpatients without genetic defects identified. Thus, GOM does not spread uniformly across the IGF2/H19 domain, suggesting that OCT4/ SOX2 protects against methylation at local sites. These findings add new insights to the mechanismof the regulation of the ICR1 domain. Our data show that mutations and deletions within ICR1 are relatively common. Systematic identification is therefore necessary to establish appropriate genetic counseling for BWS patients with isolated ICR1 GOM. © The Author 2014. Published by Oxford University Press. All rights reserved.