Patient with three euchromatic supernumerary marker chromosomes derived from chromosomes 1, 12, and 18: characterization and evaluation of the aberrations.

The genetic relevance of small supernumerary marker chromosomes (sSMCs) depends on their content of euchromatin. In case of mosaicism, the phenotype of the carrier furthermore is influenced by the distribution of the marker in the body. In the majority of reported cases no correlation of the degree of mosaicism in the tissue(s) analyzed and the phenotype could be detected.

SIL1 mutations and clinical spectrum in patients with Marinesco-Sjogren syndrome.

Marinesco-Sjögren syndrome is a rare autosomal recessive multisystem disorder featuring cerebellar ataxia, early-onset cataracts, chronic myopathy, variable intellectual disability and delayed motor development. More recently, mutations in the SIL1 gene, which encodes an endoplasmic reticulum resident co-chaperone, were identified as the main cause of Marinesco-Sjögren syndrome. Here we describe the results of SIL1 mutation analysis in 62 patients presenting with early-onset ataxia, cataracts and myopathy or combinations of at least two of these.

IGF1R mutation analysis in short children with Silver-Russell syndrome features.

The insulin-like growth factor 1 receptor (IGF1R) is a key factor in intrauterine and postnatal growth by mediating the biological function of IGF-I. Mutations of IGF1R gene are usually associated with growth retardation, but the clinical picture of IGF1R mutation carriers is heterogeneous. Indeed, these patients show clinical signs compatible with Silver-Russell syndrome (SRS), and some IGF1R mutation carriers have been identified in SRS cohorts.

Multi-exon deletion in the XDH gene as a cause of classical xanthinuria.

Xanthinuria Type I is caused by mutations in the xanthine dehydrogenase gene (XDH). We report on a patient suffering from xanthinuria. Genomic DNA was screened for point mutations and imbalances in the XDH gene by sequencing and microarray typing.

Genome-wide paternal uniparental disomy mosaicism in a woman with Beckwith-Wiedemann syndrome and ovarian steroid cell tumour.

Uniparental disomy (UPD) of single chromosomes is a well-known molecular aberration in a group of congenital diseases commonly known as imprinting disorders (IDs). Whereas maternal and/or paternal UPD of chromosomes 6, 7, 11, 14 and 15 are associated with specific IDs (Transient neonatal diabetes mellitus, Silver-Russell syndrome, Beckwith-Wiedemann syndrome (BWS), upd(14)-syndromes, Prader-Willi syndrome, Angelman Syndrome), the other autosomes are not. UPD of the whole genome is not consistent with life, in case of non-mosaic genome-wide paternal UPD (patUPD) it leads to hydatidiform mole.

Heterogeneous growth patterns in carriers of chromosome 7p12.2 imbalances affecting GRB10.

Chromosomal duplications and deletions in 7p12.2 have been described in patients with growth disturbance phenotypes, that is, Silver-Russell and Beckwith-Wiedemann syndrome (SRS, BWS). The region harbors the imprinted GRB10/Grb10 gene which has been postulated to belong to a major fetal growth pathway.

Clinical significance of copy number variations in the 11p15.5 imprinting control regions: new cases and review of the literature.

Among the clusters of imprinted genes in humans, one of the most relevant regions involved in human growth is localised in 11p15. Opposite epigenetic and genomic disturbances in this chromosomal region contribute to two distinct imprinting disorders associated with disturbed growth, Silver-Russell and Beckwith-Wiedemann syndromes. Due to the complexity of the 11p15 imprinting regions and their interactions, the interpretation of the copy number variations in that region is complicated.

2p21 Deletions in hypotonia-cystinuria syndrome.

The significant role of the SLC3A1 gene in the aetiology of cystinuria is meanwhile well established and more than 130 point mutations have been reported. With the reports on genomic deletions including at least both SLC3A1 and the neighboured PREPL gene the spectrum of cystinuria mutations and of clinical symptoms could recently be enlarged: patients homozygous for these deletions suffer from a general neonatal hypotonia and growth retardation in addition to cystinuria. The hypotonia in these hypotonia-cystinuria (HCS) patients has been attributed to the total loss of the PREPL protein.

Epigenetic and genetic diagnosis of Silver-Russell syndrome.

Silver-Russell syndrome (SRS) is a congenital imprinting disorder characterized by intrauterine and postnatal growth restriction and further characteristic features. SRS is genetically heterogenous: 7-10% of patients carry a maternal uniparental disomy of chromosome 7; >38% show a hypomethylation in imprinting control region 1 in 11p15; and a further class of mutations are copy number variations affecting different chromosomes, but mainly 11p15 and 7. The diagnostic work-up should thus aim to detect these three molecular subtypes.

Molecular karyotyping as a relevant diagnostic tool in children with growth retardation with Silver-Russell features.

Objective: To determine the contribution of submicroscopic chromosomal imbalances to the etiology of Silver-Russell syndrome (SRS) and SRS-like phenotypes.

Study Design: We performed molecular karyotyping in 41 patients with SRS or SRS-like features without known chromosome 7 and 11 defects using the Affymetrix SNP Array 6.0 system (Affymetrix, High Wycombe, United Kingdom).

Duplication 3q13.11q23: Longitudinal study in a patient over a period of more than 7 years and refinements of the breakpoints.

In 2006, we reported the first case with a pure duplication of proximal 3q. In these rare aberrations, detailed clinical and developmental investigations at different ages are required to provide sufficient phenotypic documentation. Clinical and psychological differences were therefore regularly documented in our case.

Use of multilocus methylation-specific single nucleotide primer extension (MS-SNuPE) technology in diagnostic testing for human imprinted loci.

A number of diseases have been found to be linked to aberrant methylation of specific genes. However, most of the routine diagnostic techniques to detect epigenetic disturbances are restricted to single loci. Additionally, a precise quantification of the methylation status is often hampered.

Segmental maternal uniparental disomy 7q associated with DLK1/GTL2 (14q32) hypomethylation.

Aberrant methylation at different imprinted loci has been reported for several congenital imprinting disorders, that is, Silver-Russell syndrome (SRS), but the coincidental occurrence of aberrant methylation and uniparental disomy (UPD) has not yet been described. We report on a patient initially diagnosed with SRS carrying a segmental maternal UPD of chromosome 7 [upd(7q)mat]. By further screening the patient's DNA for methylation defects on other chromosomes we identified a hypomethylation of the paternally methylated DLK1/GTL2 locus in 14q32, an epigenotype typically associated with the upd(14)mat phenotype.

Disturbed methylation at multiple imprinted loci: an increasing observation in imprinting disorders.

The widely accepted association between aberrant methylation at specific imprinted loci and distinct imprinting disorders has recently been brought into question by the identification of methylation defects at multiple loci (multilocus methylation defect [MLMD]). Strikingly, in different imprinting disorders, the same MLMD patterns can be observed. The cause for this ambiguous epigenotype-phenotype correlation is currently unknown.

Primary pulmonary hypertension, congenital heart defect, central nervous system malformations, hypo- and aplastic toes: another case of Yunis-Varón syndrome or report of a new entity.

Here we describe a patient with a new malformation syndrome which shows similarities with Yunis-Varon syndrome (YVS). Prenatal presentation included polyhydramnios, increased nuchal translucency, and bilateral hydrothoraces requiring pigtail insertion. Postnatal presentation revealed primary pulmonary hypertension (PPH), persistent hydrothoraces, one atrial and two ventricular septal defects, hypoplasia of the corpus callosum and cerebellar vermis, dilated interhemispheric ventricles, severe developmental delay with general muscular hypotonia, retinal anomalies, sparse scalp hair, sparse eyebrows and eyelashes, hypo- and aplastic nails, low-set dysplastic ears, loose nuchal skin, hypo- and aplastic distal phalanges of the toes as well as postnatal failure to thrive.

Testing of buccal swab DNA does not increase the detection rate for imprinting control region 1 hypomethylation in Silver-Russell syndrome.

Silver-Russell syndrome (SRS) is a congenital imprinting disorder mainly characterized by growth restriction, a triangular shaped face, a relative macrocephaly, and asymmetry of the body and the limbs. In 7%-10% of the patients a maternal uniparental disomy of chromosome 7 (upd(7)mat) can be observed; a hypomethylation of the imprinting control region 1 (ICR1) in 11p15 is present in >38% of patients. Methylation-specific multiplex ligation-dependent probe amplification is a well-established method for the detection of (epi)mutations in 11p15.

Genetic and epigenetic findings in Silver-Russell syndrome.

Silver-Russell syndrome (SRS) is a genetically and clinically heterogeneous disease which is mainly characterized by pre- and postnatal growth restriction. The typical SRS phenotype furthermore includes a relative macrocephaly, a triangular shaped face, body asymmetry, clinodactyly of the fifth finger and other less constant features. In about ~50% of patients (epi)genetic alterations involving chromosomes 7 and 11 can be detected.

Silver-Russell syndrome: genetic basis and molecular genetic testing.

Imprinted genes with a parent-of-origin specific expression are involved in various aspects of growth that are rooted in the prenatal period. Therefore it is predictable that many of the so far known congenital imprinting disorders (IDs) are clinically characterised by growth disturbances. A noteable imprinting disorder is Silver-Russell syndrome (SRS), a congenital disease characterised by intrauterine and postnatal growth retardation, relative macrocephaly, a typical triangular face, asymmetry and further less characteristic features.

Chromosome 11p15 duplication in Silver-Russell syndrome due to a maternally inherited translocation t(11;15).

The role of 11p15 disturbances in the aetiology of Silver-Russell syndrome (SRS) is well established: in addition to hypomethylation of the H19/IGF2 differentially methylated regions, five patients with a duplication of maternal 11p15 material have been described. We report on a boy with SRS carrying a maternally inherited duplication of chromosome 11p15. The patient showed the typical clinical picture of SRS including severe intrauterine and postnatal growth restriction, relative macrocephaly, a prominent forehead, a triangular face, down-turned corners of the mouth and fifth digit clinodactyly.

Identification of a 21q22 duplication in a Silver-Russell syndrome patient further narrows down the Down syndrome critical region.

Several duplications of chromosome 21q helped to narrow down the Down syndrome (DS) critical region (DSCR) to chromosomal band 21q22 with an approximate length of 5.4 Mb. Recently, it has been suggested that the facial gestalt of DS has been linked to the distal part of the DSCR whereas the proximal region harboring DSCR1/RCAN and DSCAM should be associated with the cardiac abnormalities.

MBD3 mutations are not responsible for ICR1 hypomethylation in Silver-Russell syndrome.

Silver-Russell syndrome (SRS) is a sporadic and heterogeneous disease that is mainly associated with intrauterine and postnatal growth retardation. The most frequent known aberration in SRS patients is a hypomethylation of the imprinting control region 1 (ICR1) in 11p15 ( approximately 38%). Up to now the basic mechanisms leading to this imprinting defect are unknown.

LOT1 (ZAC1/PLAGL1) as member of an imprinted gene network does not harbor Silver-Russell specific variants.

Silver-Russell syndrome (SRS) is a heterogeneous disease associated with intrauterine and postnatal growth retardation (IUGR/PNGR), asymmetry and craniofacial dysmorphisms. In 7-10% of patients with SRS, maternal uniparental disomy of chromosome 7 can be detected; more than 38% carry hypomethylation of the imprinting region 1 in 11p15. These chromosomes harbor the imprinted genes IGF2, H19, LIT1 and MEST.

Screening for genomic variants in ZFP57 in Silver-Russell syndrome patients with 11p15 epimutations.

Silver-Russell syndrome (SRS) describes a uniform malformation syndrome characterized by intrauterine and postnatal growth restriction and morphological abnormalities including a small triangular face, relative macrocephaly, asymmetry of the head and limbs, and clinodactyly V. In >38% of SRS cases a hypomethylation of the H19/IGF2 DMR in 11p15 can be detected. Recently, ZFP57 mutations have been identified as a cause of hypomethylation of multiple imprinted loci.