The imprinted 11p15 region is organized in two domains, each of them under the control of its own imprinting control region (ICR1 for the IGF2/H19 domain and ICR2 for the KCNQ1OT1/CDKN1C domain). Disruption of 11p15 imprinting results in two fetal growth disorders with opposite phenotypes: the Beckwith-Wiedemann (BWS) and the Silver-Russell (SRS) syndromes. Various 11p15 genetic and epigenetic defects have been demonstrated in BWS and SRS. Among them, isolated DNA methylation defects account for approximately 60% of patients. To investigate whether cryptic copy number variations (CNVs) involving only part of one of the two imprinted domains account for 11p15 isolated DNA methylation defects, we designed a single nucleotide polymorphism array covering the whole 11p15 imprinted region and genotyped 185 SRS or BWS cases with loss or gain of DNA methylation at either ICR1 or ICR2. We describe herein novel small gain and loss CNVs in six BWS or SRS patients, including maternally inherited cis-duplications involving only part of one of the two imprinted domains. We also show that ICR2 deletions do not account for BWS with ICR2 loss of methylation and that uniparental isodisomy involving only one of the two imprinted domains is not a mechanism for SRS or BWS. arabic 22 English 137
- Demars, J., S. Rossignol, I. Netchine, K. S. Lee, Mansur Ennuri Moftah Shmela, L. Faivre, J. Weill, S. Odent, S. Azzi, P. Callier, J. Lucas, C. Dubourg, J. Andrieux, Y. Le Bouc, A. El-Osta , C. Gicquel(10-2011)

The imprinted expression of the IGF2 and H19 genes is controlled by the imprinting control region 1 (ICR1) located at chromosome 11p15.5. This methylation-sensitive chromatin insulator works by binding the zincfinger protein CTCF in a parent-specific manner. DNA methylation defects involving the ICR1 H19/IGF2 domain result in two growth disorders with opposite phenotypes: an overgrowth disorder, the Beckwith– Wiedemann syndrome (maternal ICR1 gain of methylation in 10% of BWS cases) and a growth retardation disorder, the Silver–Russell syndrome (paternal ICR1 loss of methylation in 60% of SRS cases). Although a few deletions removing part of ICR1 have been described in some familial BWS cases, little information is available regarding the mechanism of ICR1 DNA methylation defects. We investigated the CTCF gene and the ICR1 domain in 21 BWS patients with ICR1 gain of methylation and 16 SRS patients with ICR1 loss of methylation. We identified four constitutional ICR1 genetic defects in BWS patients, including a familial case. Three of those defects are newly identified imprinting defects consisting of small deletions and a single mutation, which do not involve one of the CTCF binding sites. Moreover, two of those defects affect OCT-binding sequences which are suggested to maintain the unmethylated state of the maternal allele. A single-nucleotide variation was identified in a SRS patient. Our data extends the spectrum of constitutive genetic ICR1 abnormalities and suggests that extensive and accurate analysis of ICR1 is required for appropriate genetic counseling in BWS patients with ICR1 gain of methylation.
Demars, J., Mansur Ennuri Moftah Shmela, S. Rossignol, J. Okabe, I. Netchine, S. Azzi, S. Cabrol, C. Le Caignec, A. David , Y. Le Bouc, A. El-Osta , C. Gicquel(9-2010)

Carpal conformation is thought to contribute to the frequency of carpal pathology so non-invasive measurement of carpal morphometry would be useful to identify joints at risk. However, there are scant radiographic morphometrical details for the carpals of Thoroughbred (TB) and Standardbred (SB) racehorses even though these breeds differ in the incidence of carpal damage. This study aimed to identify morphometrical similarities and differences in carpal conformation in TB and SB. Thirty carpal dorsopalmar radiographs (DP) were collected from 15 TB and 15 SB. All DP radiographs were at zero degrees or within the acceptable range of rotation. Twelve carpal radiographic parameters were selected and measured on each radiograph. Statistical analysis found significant differences in four carpal parameters. These parameters revealed that the middle carpal joint in SB was significantly more angled distomedially whereas the radial distal metaphysis showed a greater distolateral inclination in TB. The radiocarpal and the carpometacarpal articulations exhibited common features in the two groups of horses. These carpal traits in TB and SB highlight their potential association with loading distribution and pathology. Measuring carpi from untrained and injured horses is necessary to establish breed specific features for the ideal carpal conformation in each of these breeds.
Aiman Hussein Saleh Oheida, Abdulrhman Mohamed Salah Alrtib, Aiman Abdulghader Salim Shalgum, Mansur Ennuri Moftah Shmela, Mohamed A Marzok, Helen M S Davies(4-2019)