Comparative analysis of isodisomic and heterodisomic segments in cases with maternal uniparental disomy 14 suggests more than one imprinted region

The results of molecular investigations of 21 cases with complete or segmental maternal uniparental disomy (UPD) 14 published in the literature were compared with respect to isodisomic and heterodisomic segments. The aim of the study was to find hints toward imprinted regions other than the recently defined imprinted segment 14q32. Three regions with no isodisomic molecular marker were found. The most distal of these regions located on 14q32.12 and 14q32.13 supports the hypothesis of genomic imprinting as the cause of the maternal UPD 14 phenotype by synteny to the maternally imprinted region on mouse distal chromosome 12 and correlation with the recently defined imprinting cluster on human chromosome 14q32. The other two heterodisomic areas located on 14q11.2-->14q12 and 14q21.1-->14q31.2 are hints toward one or more additional regions of genomic imprinting on human chromosome 14.     

Relationship of sleep abnormalities to patient genotypes in Prader-Willi syndrome

To assess whether sleep abnormalities are related to the genetic abnormalities in Prader-Willi Syndrome (PWS), we performed polysomnographic studies (nighttime and daytime) and determined the chromosome 15 genotypes in eight patients with PWS. Four patients demonstrated sleep onset REM periods (SOREM), and five met the objective polysomnographic criteria for severe or moderate excessive daytime sleepiness (EDS). Three of the four patients with SOREM displayed a paternally derived deletion of chromosome 15q11-q13, whereas the fourth exhibited maternal uniparental heterodisomy in this chromosomal region (UPD). Two of the four patients that did not display SOREM carried paternally derived deletions; the remaining two demonstrated UPD. Four of the five patients with EDS displayed paternal deletions, and the fifth exhibited UPD. One of three patients without evidence of EDS demonstrated paternal deletion; the remaining two showed UPD. Although neither EDS nor SOREM was not consistently associated with a specific genetic abnormality, these phenotypes may be more common in patients with paternal deletions than in those with UPD. Sleep abnormalities in PWS cannot be explained by a single genetic model. © 1996 Wiley-Liss, Inc.     

Trisomy 15 mosaicism and uniparental disomy (UPD) in a liveborn infant

We describe a liveborn infant with uniparental disomy (UPD) with trisomy 15 mosaicism. Third trimester amniocentesis yielded a 46,XX/47,XX,+15 karyotype. Symmetrical growth retardation, distinct craniofacies, congenital heart disease, severe hypotonia and minor skeletal anomalies were noted. The infant died at 6 weeks of life. Peripheral lymphocyte chromosomes were “normal” 46,XX in 100 cells. Parental lymphocyte chromosomes were normal. Skin biopsy showed 47,XX,+15 in 80% of fibroblasts and results were equivalent in fibroblasts from autopsy lung tissue. Molecular analysis revealed maternal uniparental heterodisomy for chromosome 15 in the 46,XX cell line. We describe an emerging phenotype of trisomy 15 mosaicism, confirm that more than one tissue should be studied in all cases of suspected mosaicism, and suggest that UPD be considered in all such cases. © 1996 Wiley-Liss, Inc.     

Maternal uniparental disomy of chromosome 4 in a patient with limb-girdle muscular dystrophy 2E confirmed by SNP array technology

The limb-girdle muscular dystrophies (LGMDs) are a heterogenous group of diseases characterized by shoulder-girdle and pelvic muscle weakness and wasting. LGMD 2E is an autosomal recessively inherited form of the disease caused by mutations in the β-sarcoglycan (SGCB) gene located at 4q12. In this report, we describe a patient who demonstrates non-Mendelian inheritance of a homozygous missense mutation in SGCB resulting in disease expression. A combination of single-nucleotide polymorphism (SNP) array technology and microsatellite analysis revealed the occurrence of maternal uniparental disomy (UPD) for chromosome 4 in the patient. As a consequence of segmental isodisomy at 4q12, the patient inherited two identical SGCB alleles carrying a missense mutation predicted to result in abnormal protein function. SNP array technology proved to be an elegant means to determine the most probable mechanism of UPD formation in this case, and enabled us to determine the location of recombination events along chromosome 4. In our patient, UPD likely arose from a trisomy rescue event due to maternal meiotic non-disjunction that we speculate may have been caused by abnormal recombination at the pericentromeric region. Maternal UPD 4 is a rare finding, and to our knowledge this is the first reported case of UPD in association with LGMD.     

Congenital hyperinsulinism and mosaic abnormalities of the ploidy

Background

Congenital hyperinsulinism and Beckwith‐Wiedemann syndrome both lead to β islet hyperplasia and neonatal hypoglycaemia. They may be related to complex genetic/epigenetic abnormalities of the imprinted 11p15 region. The possibility of common pathophysiological determinants has not been thoroughly investigated.

Objective

To report abnormalities of the ploidy in two unrelated patients with congenital hyperinsulinism.

Methods

Two patients with severe congenital hyperinsulinism, one overlapping with Beckwith‐Wiedemann syndrome, had pancreatic histology, ex vivo potassium channel electrophysiological studies, and mutation detection of the encoding genes. The parental genetic contribution was explored using genome‐wide polymorphism, fluorescent in situ hybridisation (FISH), and blood group typing studies.

Results

Histological findings diverged from those described in focal congenital hyperinsulinism or Beckwith‐Wiedemann syndrome. No potassium channel dysfunction and no mutation of its encoding genes (SUR1, KIR6.2) were detected. In patient 1 with congenital hyperinsulinism and Beckwith‐Wiedemann syndrome, paternal isodisomy for the whole haploid set was homogeneous in the pancreatic lesion, and mosaic in the leucocytes and skin fibroblasts (hemihypertrophic segment). Blood group typing confirmed the presence of two erythroid populations (bi‐parental v paternal only contribution). Patient 2 had two pancreatic lesions, both revealing triploidy with paternal heterodisomy. Karyotype and FISH analyses done on the fibroblasts and leucocytes of both patients were unremarkable (diploidy).

Conclusions

Diploid (biparental/paternal‐only) mosaicism and diploid/triploid mosaicism were present in two distinct patients with congenital hyperinsulinism. These chromosomal abnormalities led to paternal disomy for the whole haploid set in pancreatic lesions (with isodisomy or heterodisomy), thereby extending the range and complexity of the mechanisms underlying congenital hyperinsulinism, associated or not with Beckwith‐Wiedemann syndrome.     

Male infant with paternal uniparental diploidy mosaicism and a 46,XX/46,XY karyotype

A male patient with mosaic paternal uniparental diploidy (PUD) is presented. After birth, the patient presented with hypoglycemia, hemihypertrophy, umbilical hernia, and hepatomegaly. Afterward pancreatic hypertrophy, liver hemangiomas, and cysts were detected sonographically. At the age of 3.5 months, hepatoblastoma was diagnosed. To investigate suspected Beckwith‐Wiedemann syndrome (BWS), extensive genetic analyses were performed using DNA from chorionic villus sampling, amniocentesis, and peripheral blood lymphocytes (chromosome analysis, methylation‐specific multiplex ligation‐dependent probe amplification assays, microsatellite analyses, and single nucleotide polymorphism array analysis). These analyses led to the detection of mosaic PUD. In peripheral blood lymphocytes, a male cell line (46,XY[27]/46,XX[5]) predominated, suggesting a mixture of uniparental isodisomy and heterodisomy. The genetic analyses suggest that the mosaic PUD status was attributable to fertilization of an oocyte by two sperms, with subsequent triploidy rescue giving rise to haploidy, which in turn was rescued. Notably, in the majority of the 28 mosaic PUD patients reported to date, BWS was initially suspected. Mosaic PUD status is associated with a higher risk for a broad range of malignant and benign tumors than in BWS. As tumors can also occur after childhood surveillance into adolescence is indicated. Mosaic PUD must therefore be considered in patients with suspected BWS.     

An analysis of the distribution of hetero- and isodisomic regions of chromosome 7 in five mUPD7 Silver-Russell syndrome probands

Silver-Russell syndrome (SRS) shares common features of intrauterine growth retardation (IUGR) and a number of dysmorphic features including lateral asymmetry in about 50% of subjects. Its genetic aetiology is complex and most probably heterogeneous. Approximately 7% of patients with SRS have been found to have maternal uniparental disomy of chromosome 7 (mUPD7). Genomic DNA samples from five SRS patients with mUPD7 have been analysed for common regions of isodisomy using 40 polymorphic markers distributed along the length of chromosome 7. No regions of common isodisomy were found among the five patients. It is most likely that imprinted gene(s) rather than recessive mutations cause the common phenotype. Heterodisomy of markers around the centromere indicated that the underlying cause of the mUPD7 is a maternal meiosis I non-disjunction error in these five subjects.     

An analysis of common isodisomic regions in five mUPD 16 probands

Intrauterine growth retardation (IUGR) with or without additional abnormalities is recognised as a common feature of maternal uniparental disomy for chromosome 16 (mUPD 16) and is usually associated with confined placental mosaicism (CPM). Although it is likely that the CPM largely contributes to the IUGR, postnatal growth retardation and other common abnormalities may also be attributed to the mUPD. Five cases with mUPD 16 and CPM were analysed for common regions of isodisomy using polymorphic markers distributed along the length of the chromosome. In each case the aberration was consistent with a maternal meiosis I error. Complete isodisomy was not detected in any of the patients although two patients were found to be mixed with both iso- and heterodisomy. Interestingly, the patient with the greater region of isodisomy was the most severely affected. The fact that there were no common regions of isodisomy in any of the patients supports the hypothesis that imprinted genes, rather than recessive mutations, may play a role in the shared phenotypes.     

Visualization of uniparental inheritance, Mendelian inconsistencies, deletions, and parent of origin effects in single nucleotide polymorphism trio data with SNPtrio

A variety of alterations occur in chromosomal DNA, many of which can be detected using high density single nucleotide polymorphism (SNP) microarrays. These include deletions and duplications (assessed by observing changes in copy number) and regions of homozygosity. The analysis of SNP data from trios can provide an additional category of information about the nature and origin of inheritance patterns, including uniparental disomy (UPD), loss of transmitted allele (LTA), and nonparental relationship. The main purpose of SNPtrio is to locate regions of uniparental inheritance (UPI) and Mendelian inconsistency (MI), identify the type (paternal vs. maternal, iso- vs. hetero-), and assess the associated statistical probability of occurrence by chance. SNPtrio's schema permits the identification of hemizygous or homozygous deletions as well as UPD. We validated the performance of SNPtrio on three platforms (Affymetrix 10 K and 100 K arrays and Illumina 550 K arrays) using SNP data obtained from DNA samples of patients known to have UPD and diagnosed with Prader-Willi syndrome, Angelman syndrome, Beckwith-Wiedemann syndrome, pseudohypoparathyroidism, and a complex chromosome 2 abnormality. We further validated SNPtrio using DNA from patients previously shown to have microdeletions that were verified by fluorescence in situ hybridization (FISH). SNPtrio successfully identified previously known UPD and deletion regions, and generated associated probability values. SNPtrio analysis of trisomy 21 (Down syndrome) cases and their parents permitted identification of the parent of origin of the extra chromosomal copy. SNPtrio is freely accessible at http://pevsnerlab.kennedykrieger.org/SNPtrio.htm (Last accessed: 20 June 2007).