Distinct Methylation Changes at the IGF2-H19 Locus in Congenital Growth Disorders and Cancer

Background: Differentially methylated regions (DMRs) are associated with many imprinted genes. In mice methylation at a DMR upstream of the H19 gene known as the Imprint Control region (IC1) is acquired in the male germline and influences the methylation status of DMRs 100 kb away in the adjacent Insulin-like growth factor 2 (Igf2) gene through long-range interactions. In humans, germline-derived or post-zygotically acquired imprinting defects at IC1 are associated with aberrant activation or repression of IGF2, resulting in the congenital growth disorders Beckwith-Wiedemann (BWS) and Silver-Russell (SRS) syndromes, respectively. In Wilms tumour and colorectal cancer, biallelic expression of IGF2 has been observed in association with loss of methylation at a DMR in IGF2. This DMR, known as DMR0, has been shown to be methylated on the silent maternal IGF2 allele presumably with a role in repression. The effect of IGF2 DMR0 methylation changes in the aetiology of BWS or SRS is unknown. Methodology/Principal Findings: We analysed the methylation status of the DMR0 in BWS, SRS and Wilms tumour patients by conventional bisulphite sequencing and pyrosequencing. We show here that, contrary to previous reports, the IGF2 DMR0 is actually methylated on the active paternal allele in peripheral blood and kidney. This is similar to the IC

A new syndrome with ocular, skeletal and renal involvement

A patient with retinitis pigmentosa, hypertension with interstitial nephropathy, short limb dwarfism with Madelung deformity of the forearms and an unclassified type of brachydactyly is described. Such bone dysplasia has never been reported to date either as a single entity or associated with renal and retinal diseases

Central nervous system developmental disorder in Noonan syndrome: a genomic approach

Noonan syndrome (NS \u2013 OMIM 163950) is a multisystemic dominant disorder with a prevalence of 1/1000-1/2500 live births. It is clinically and genetically heterogeneous, with mutations in several genes of the RAS/MAPK pathway detectable in up to 75% of cases. Pathogenesis of central nervous system (CNS) developmental anomalies has not been thus far fully enlightened. We have applied the multiple hit hypothesis to study in deep the pathogenic mechanisms implicated in NS related CNS anomalies. In this oligogenic model, point mutations and genomic rearrangements cooperate in an additive manner in the pathologic development of CNS. Using array CGH technology, we analyzed 15 samples of selected patients with molecularly confirmed diagnosis of NS and a severe impairment of CNS. We found 37 rare CNVs (one/several per patient) most of them inherited from an healthy parent. According to the Database of Genomic Variants 12/37 were never reported and 25/37 were reported in very few cases. Based on the function of the genes mapping in the identified CNVs, 10/37 (27%) were probably involved in the pathogenesis of CNS anomalies observed in our patients. We provided first data supporting the hypothesis that CNS involvement in NS does not depend exclusively on single gene mutations but also on the concurrent presence of other genomic penetrant variants. These results represent an initial assumption for the application of the multi-hit hypothesis in the dissection of the NS pathogenesis. Further studies on larger cohorts are deserved to better define the meaning and the clinical implications of these findings

A child with macrocephaly: case report of a patient with megalencephalic leukoencephalopathy with subcortical cysts and a compound heterozygosity for two mutations in the MLC1 gene

Megalencephaly is as a rule accompanied by macrocephaly, an occipitofrontal circumference (OFC) greater than the 98th percentile. Megalencephaly is divided into an anatomic type (developmental) and a metabolic type. Metabolic megalencephaly refers to various storage and degenerative encephalopathies. The differential diagnosis includes Alexander's disease, Canavan's disease, glutaric aciduria type 1, GM1 and GM2 gangliosidosis, merosin-deficient variant of congenital muscular dystrophy and megalencephalic leukoencephalopathy with subcortical cysts (MLC). The distinctive features of this syndrome are enlarged cranial circumference, present at birth or starting in the first year of life, and magnetic resonance imaging (MRI) evidence of diffuse with matter abnormalities with subcortical cysts in the tips of the temporal lobes and in frontoparietal subcortical areas. Mutations in the MLC1 gene have been found as causative of MLC in 60-70 % of affected subjects, without genotype-phenotype correlation. The child we describe presented with progressive macrocephaly not associated with dysmorphic features and large abdominoscrotal hydrocele. At the age of 8 months, encephalic Mill showed anomalies suggestive for MLC and brainstem auditory evoked potentials (BAEP) documented alterations of signal conduction in right tracts. At the time, clinical neurologic examination was normal. Extensive metabolic assays were within normal range. Sequence analysis for MLC1 gene revealed a compound heterozygosity for two mutations in MLC1 gene, inherited from healthy non consanguineous parent