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PubMed2005

Paternal isodisomy for chromosome 2 as the cause of Crigler-Najjar type I syndrome.

Crigler-Najjar syndrome type I (CN-I) is a rare and severe autosomal recessive metabolic disease due to a total deficiency of bilirubin uridine diphosphate glucuronosyltransferase located on chromosome 2. We report on a child with CN-I due to a phenylalanine residue deletion inherited only from the father carrying this deletion at the heterozygous state. Cytogenetic analyses showed no deletion of the chromosomal 2q37 region. Microsatellite analysis of the child and his parents was consistent with paternal isodisomy for chromosome 2 in the child. This report demonstrates that uniparental disomy may be at the origin of very rare diseases transmitted as autosomal recessive traits and emphasizes the need for parental DNA analysis in such cases.

Base Sequence↗
PubMed2005

Complete paternal uniparental isodisomy of chromosome 1 resulting in Herlitz junctional epidermolysis bullosa.

Herlitz junctional epidermolysis bullosa (JEB) is an autosomal recessive mechanobullous disorder that results from loss-of-function mutations in the genes encoding the basement membrane component, laminin 5. Typically, there are frameshift, splice site or nonsense mutations on both alleles of either the LAMA3, LAMB3 or LAMC2 genes, with affected individuals inheriting one mutated allele from each parent. In this report, we describe a patient with Herlitz JEB in whom DNA analysis revealed homozygosity for the recurrent nonsense mutation R635X in LAMB3, located on chromosome 1q32.2. However, screening of parental DNA showed that although the patient's father was a heterozygous carrier of this mutation, the mother's DNA showed only wild-type sequence. Subsequent genotype analysis using 13 microsatellite markers spanning chromosome 1 revealed that the affected child was homozygous for the entire series of markers tested and that all of the alleles originated from the father. These results indicate that the Herlitz JEB phenotype in this patient is due to complete paternal isodisomy of chromosome 1 and reduction to homozygosity of the mutant LAMB3 gene locus. This is the fourth case of uniparental disomy to be described in Herlitz JEB, but it represents the first example of complete paternal isodisomy for chromosome 1 with a pathogenic mutation in the LAMB3 gene. These findings have important implications for mutation screening in JEB and for genetic counselling.

Chromosome Mapping↗
PubMed2002

Maternal uniparental isodisomy 20 in a foetus with trisomy 20 mosaicism: clinical, cytogenetic and molecular analysis.

The clinical significance of trisomy 20 mosaicism detected prenatally remains uncertain due to the rarity of liveborn cases with inconsistent clinical findings, and lack of long-term follow-up and outcome. We describe a case of true trisomy 20 mosaicism in a liveborn girl with maternal uniparental isodisomy of chromosome 20 in the diploid blood cells. Trisomy 20 mosaicism was originally detected in amniotic fluid (98%) and was confirmed in the term placenta (100%), as well as in the blood (10%) and urine sediment (100%) of the neonate. There was intrauterine and postnatal growth retardation, but otherwise the newborn manifested no gross abnormalities. At 9 months of age moderate psychomotor retardation, central hypotonia with peripheral hypertonia, numerous minor morphogenetic variants, marked kyphosis, and extensive Mongolian spot were observed. To our knowledge this represents the first case of trisomy 20 mosaicism detected prenatally and confirmed in different tissues of the newborn, where uniparental disomy was demonstrated in the diploid cell line. The clinical and laboratory findings in our patient are compared with those of five previously reported cases of UPD20, suggesting that maternal UPD20 might be associated with a characteristic phenotype.

Chromosomes, Human, Pair 20↗
PubMed2003

Angelman syndrome: a review of the clinical and genetic aspects.

Angelman syndrome (AS) is a neurodevelopmental disorder characterised by severe learning difficulties, ataxia, a seizure disorder with a characteristic EEG, subtle dysmorphic facial features, and a happy, sociable disposition. Most children present with delay in developmental milestones and slowing of head growth during the first year of life. In the majority of cases speech does not develop. Patients with AS have a characteristic behavioural phenotype with jerky movements, frequent and sometimes inappropriate laughter, a love of water, and sleep disorder. The facial features are subtle and include a wide, smiling mouth, prominent chin, and deep set eyes. It is caused by a variety of genetic abnormalities involving the chromosome 15q11-13 region, which is subject to genomic imprinting. These include maternal deletion, paternal uniparental disomy, imprinting defects, and point mutations or small deletions within the UBE3A gene, which lies within this region. UBE3A shows tissue specific imprinting, being expressed exclusively from the maternal allele in brain. The genetic mechanisms identified so far in AS are found in 85-90% of those with the clinical phenotype and all interfere with UBE3A expression.

Angelman Syndrome↗
PubMed2006

Use of single nucleotide polymorphism-based mapping arrays to detect copy number changes and loss of heterozygosity in multiple myeloma.

The genetics of multiple myeloma is a vastly studied field in which techniques such as classical cytogenetics, fluorescence in situ hybridization, and comparative genomic hybridization have been used. More recently, single nucleotide polymorphism (SNP)-based mapping arrays have become available that allow the identification of regions of gain or loss as small as 2.5 kb. In addition to the increased resolution of SNP-based arrays, the detection of loss of heterozygosity is also possible. This allows the identification of loss of heterozygosity regions that arise through monosomy and recombination, resulting in uniparental disomy, which cannot be detected by conventional genetic methods. In this review, we discuss the benefits of SNP-based arrays along with some of the drawbacks and how that data can be used in conjunction with expression data to identify genes with altered expression in regions of interest.

Chromosome Mapping↗
PubMedDate not supplied

Mosaic trisomy 15 and hemihypertrophy.

We report a case of mosaic trisomy 15 with mental retardation, facial dysmorphism, and hemihypertrophy, but no manifestations of Prader-Willi or Angelman syndromes. Mosaic trisomy 15 (11%) was discovered at the amniocentesis. Uniparental disomy for chromosome 15 was excluded by molecular analysis. Post-natal blood karyotype and examination were normal. Mosaic was confirmed on skin fibroblasts, placenta and cord. Evolution was marked by progressive right hemi-hypertrophy, and developmental delay. Our case is the first patient reported with hemihypertrophy associated with mosaic trisomy 15. The relevant literature is reviewed.

Adult↗
PubMed2003

How clinicians add to knowledge of development.

Studies of human birth defects and developmental disorders have made major contributions to our understanding of development. Rare human syndromes have allowed identification of important developmental genes, and revealed mechanisms such as uniparental disomy and unstable trinucleotide repeats that were not suspected from animal studies. Some aspects of development, in particular cognitive development, can only be studied in human beings. Basic developmental mechanisms are very highly conserved across a very wide range of animals, making for a rich interplay between animal and human studies. Often, clinical studies identify a gene, or suggest a hypothesis, that can then be investigated in animals.

Animals↗
PubMed2005

Diagnostic proceeding in Silver-Russell syndrome.

BACKGROUND: Silver-Russell syndrome (SRS) describes a uniform malformation syndrome characterized by pre- and postnatal growth restriction (<3rd percentile) and a typical craniofacial gestalt. The basic defect of SRS is currently unknown, and the number of meaningful genetic tests available is therefore limited. Different chromosomal aberrations have been identified, including in the chromosomal region 7p12-p14. Detailed analyses of numerous candidate genes have not revealed any relevant insights with respect to the etiology of the disease.However, maternal uniparental disomy (UPD) of chromosome 7 (matUPD7), the inheritance of both homologues of chromosome 7 only from the mother, is observed in approximately 10% of SRS patients. Here, we report on our experiences of UPD testing in patients referred to our laboratory with the clinical diagnosis of SRS. A diagnostic algorithm for SRS is suggested. METHODS: Eighty-six patients with the clinical diagnosis of SRS were screened for matUPD7 by microsatellite typing. In 13 cases, the clinical data were consistent with the diagnosis of SRS. The other 73 patients were referred for UPD testing with the suspected diagnosis of SRS, but clinical data were scarce. RESULTS: In total, we identified three new cases of matUPD7: one patient belonged to the cohort of 13 clinically characterized patients; the other two patients were referred with the suspected diagnosis of SRS but initially without detailed reports. DNA studies revealed uniparental heterodisomy 7 in two patients, while the results in the third case were consistent with uniparental isodisomy. CONCLUSIONS: MatUPD7 is predominantly detectable in patients showing SRS features, and testing should therefore be restricted to this group of growth-restricted patients. Generally, a combination of cytogenetic and molecular genetic tests can be offered in SRS, aiming at the detection of chromosomal rearrangements and matUPD7 in >10% of SRS patients.

Abnormalities, Multiple↗
PubMed2003

A fluorescent method for detecting low-grade 11patUPD mosaicism in Beckwith-Wiedemann syndrome.

The quantitative evaluation of mosaicism for uniparental disomy (UPD) involving a restricted chromosomal region requires the availability of a sensitive and reproducible method that is capable of detecting even a small percentage of disomic cells and avoiding false positive and false negative results. The occurrence of UPD is usually monitored by means of the parent-proband segregation analysis of microsatellites mapping to the target region. We here describe the quantitative blood cell evaluation of segmental mosaic UPD11, a marker of Beckwith-Wiedemann syndrome, by means of the segregation analysis of 11p15 microsatellites using both radioactive and fluorescence-based techniques. As the greater amplification efficiency of the shorter allele in heterozygous subjects may bias the correct evaluation of disomy, the mean short/long allele ratio was established at three loci of each of 30 normal heterozygous subjects, as well as the peak As/Al area in the presence of 50% of each allele. The interval was defined using a 5% level of significance. The results show that the fluorescence-based technique is superior to radioactivity in detecting the subtle allelic imbalances present in low-grade mosaicism conditions.

Alleles↗
PubMed2005

Forty-two supernumerary marker chromosomes (SMCs) in 43,273 prenatal samples: chromosomal distribution, clinical findings, and UPD studies.

Fluorescence in situ hybridization (FISH) analyses were performed on supernumerary marker chromosomes (SMCs) detected in 43,273 prenatal diagnoses over a period of 11 years, 1993-2003. A total of 42 pregnancies with SMC were identified, indicating a prevalence of one in 1032. A total of 15 SMCs were endowed with detectable euchromatin (prevalence, 1/2884), including six SMCs containing the cat eye critical region (CECR) on chromosome 22q11.21 (1/7212). De novo SMCs were found in 29 pregnancies (1/1492), including 14 euchromatic SMCs (48.2%). Follow-up studies were available for 24 cases. Nine pregnancies (37.5%) were terminated; two children (8.3%) were born with Pallister-Killian syndrome and cat eye syndrome (CES), respectively; 13 children (54.1%) showed apparently normal development. Familial SMCs were identified in 13 pregnancies (1/3328) from 11 unrelated women. They were all acrocentric. In all, 10 were heterochromatic and one was an extra der(22)t(11;22) chromosome. A total of 12 cases were available for follow-up. One pregnancy was terminated due to anhydramnios, spina bifida, and cystic-dysplastic kidneys; one child suffered from a der(22) syndrome; 10 children (83.3%) appeared unaffected. Studies for uniparental disomy were performed on seven pregnancies and revealed a case of maternal heterodisomy for chromosome 22. So far this is the largest FISH study of prenatally ascertained SMCs and the first study with detailed data on the prevalence. Findings illustrate the spectrum and clinical outcomes of prenatally diagnosed SMCs, and indicate a higher frequency of SMCs than generally assumed.

Abnormalities, Multiple↗
PubMed2006

Changing rates of genetic subtypes of Prader-Willi syndrome in the UK.

The genetically determined neurodevelopmental disorder, Prader-Willi syndrome (PWS), has two main genetic subtypes: a 15q11-q13 deletion affecting the paternally inherited chromosome 15 and chromosome 15 maternal uniparental disomy (mUPD) in which two maternal copies of chromosome 15 are inherited but no paternal copy. It has been accepted that these subtypes occur in approximately 70 and 25% of cases, respectively. This is the first report of a greater proportion (50%) of those with PWS due to mUPD in children presently under 5 years living in the UK. Increasing maternal age at conception is likely to explain the changing proportions in this generation of mothers.

Adult↗
PubMed2002

Embryonic stem cells and somatic cells differ in mutation frequency and type.

Pluripotent embryonic stem (ES) cells have been used to produce genetically modified mice as experimental models of human genetic diseases. Increasingly, human ES cells are being considered for their potential in the treatment of injury and disease. Here we have shown that mutation in murine ES cells, heterozygous at the selectable Aprt locus, differs from that in embryonic somatic cells. The mutation frequency in ES cells is significantly lower than that in mouse embryonic fibroblasts, which is similar to that in adult cells in vivo. The distribution of spontaneous mutagenic events is remarkably different between the two cell types. Although loss of the functional allele is the predominant mutation type in both cases, representing about 80% of all events, mitotic recombination accounted for all loss of heterozygosity events detected in somatic cells. In contrast, mitotic recombination in ES cells appeared to be suppressed and chromosome loss/reduplication, leading to uniparental disomy (UPD), represented more than half of the loss of heterozygosity events. Extended culture of ES cells led to accumulation of cells with adenine phosphoribosyltransferase deficiency and UPD. Because UPD leads to reduction to homozygosity at multiple recessive disease loci, including tumor suppressor loci, in the affected chromosome, the increased risk of tumor formation after stem cell therapy should be viewed with concern.

Adenine Phosphoribosyltransferase↗
PubMed2005

Allele-specific methylation of a functional CTCF binding site upstream of MEG3 in the human imprinted domain of 14q32.

The gene MEG3 is located in the imprinted human chromosomal region on 14q32. Imprinting of a structurally homologous region IGF2/H19 on 11p15 is mediated through cytosine methylation-controlled binding of the protein CTCF to target sites upstream of H19. We identified five new CTCF binding sites around the promoter of MEG3. Using an electrophoretic mobility shift assay, we showed that these sites bind CTCF in vitro. Using one of these sites, chromatin immunoprecipitation (ChIP) analysis confirmed CTCF binding in-vivo, and differential allele-specific methylation was demonstrated in seven individuals with either maternal or paternal uniparental disomy 14 (UPD14). The site was unmethylated on the maternally inherited chromosomes 14 and methylated on the paternally inherited chromosomes 14, suggesting parent-specific methylation of sequences upstream of MEG3. We speculate that this CTCF-binding region may provide a mechanism for the transcriptional regulation of MEG3 and DLK1.

Alleles↗
PubMed2002

The mouse Zac1 locus: basis for imprinting and comparison with human ZAC.

We identified a maternally methylated CpG island at the mouse Zac1 locus on chromosome (Chr.) 10 in a screen for imprinted genes. The homologous human gene ZAC (also known as LOT1 and PLAGLI) is a candidate gene for transient neonatal diabetes (TNDM), an imprinted disorder associated with paternal duplication for 6q24 and characterized by intrauterine growth retardation and insulin dependence. A mouse model would be indispensable to investigate the basis of the disorder, however, there is apparently no similar phenotype in mice with the corresponding chromosome anomaly. To begin to understand this difference, we have undertaken a comparative analysis of the mouse and human genes. We show that the CpG island is far upstream of the coding body of mouse Zac1, that Zac1 transcripts initiate in a conserved region in the CpG island, and transcripts undergo complex splicing--all properties shared with the human gene. CpG island methylation is present in oocyte DNA and constitutes a germline-specific epigenetic mark. Mice with uniparental disomy (UPD) for Chr. 10 exhibit appropriate parent-of-origin dependent expression of Zac1, indicating that the absence of phenotypes comparable to aspects of human TNDM is not because imprinting of Zac1 is relaxed in these UPD mice.

5' Flanking Region↗
PubMed2002

Epigenetic alterations of H19 and LIT1 distinguish patients with Beckwith-Wiedemann syndrome with cancer and birth defects.

Beckwith-Wiedemann syndrome (BWS) is a congenital cancer-predisposition syndrome associated with embryonal cancers, macroglossia, macrosomia, ear pits or ear creases, and midline abdominal-wall defects. The most common constitutional abnormalities in BWS are epigenetic, involving abnormal methylation of either H19 or LIT1, which encode untranslated RNAs on 11p15. We hypothesized that different epigenetic alterations would be associated with specific phenotypes in BWS. To test this hypothesis, we performed a case-cohort study, using the BWS Registry. The cohort consisted of 92 patients with BWS and molecular analysis of both H19 and LIT1, and these patients showed the same frequency of clinical phenotypes as those patients in the Registry from whom biological samples were not available. The frequency of altered DNA methylation of H19 in patients with cancer was significantly higher, 56% (9/16), than the frequency in patients without cancer, 17% (13/76; P=.002), and cancer was not associated with LIT1 alterations. Furthermore, the frequency of altered DNA methylation of LIT1 in patients with midline abdominal-wall defects and macrosomia was significantly higher, 65% (41/63) and 60% (46/77), respectively, than in patients without such defects, 34% (10/29) and 18% (2/11), respectively (P=.012 and P=.02, respectively). Additionally, paternal uniparental disomy (UPD) of 11p15 was associated with hemihypertrophy (P=.003), cancer (P=.03), and hypoglycemia (P=.05). These results define an epigenotype-phenotype relationship in BWS, in which aberrant methylation of H19 and LIT1 and UPD are strongly associated with cancer risk and specific birth defects.

Abdomen↗
PubMed2006

Complete maternal isodisomy of chromosome 3 in a child with recessive dystrophic epidermolysis bullosa but no other phenotypic abnormalities.

The mechanobullous disease Hallopeau-Siemens recessive dystrophic epidermolysis bullosa (HS-RDEB) results from mutations in the type VII collagen gene (COL7A1) on chromosome 3p21.31. Typically, there are frameshift, splice site, or nonsense mutations on both alleles. In this report, we describe a patient with HS-RDEB, who was homozygous for a new frameshift mutation, 345insG, in exon 3 of COL7A1. However, sequencing of parental DNA showed that although the patient's mother was a heterozygous carrier of this mutation, the father's DNA contained only wild-type sequence. Microsatellite marker analysis confirmed paternity and genotyping of 28 microsatellites spanning chromosome 3 revealed that the affected child was homozygous for every marker tested with all alleles originating from a single maternal chromosome 3. Thus, the HS-RDEB phenotype in this patient is due to complete maternal isodisomy of chromosome 3 and reduction to homozygosity of the mutant COL7A1 gene locus. To our knowledge, there are no published reports of uniparental disomy (UPD) in HS-RDEB; moreover, this case represents only the third example of UPD of chromosome 3 to be reported. The severity of the HS-RDEB in this case was similar to other affected individuals and no additional phenotypic abnormalities were observed, suggesting an absence of maternally imprinted genes on chromosome 3.

Adult↗
PubMed2004

Combined cytogenetic and molecular analyses for the diagnosis of Prader-Willi/Angelman syndromes.

Prader-Willi (PWS) and Angelman (AS) are syndromes of developmental impairment that result from the loss of expression of imprinted genes in the paternal (PWS) or maternal (AS) 15q11-q13 chromosome. Diagnosis on a clinical basis is difficult in newborns and young infants; thus, a suitable molecular test capable of revealing chromosomal abnormalities is required. We used a variety of cytogenetic and molecular approaches, such as, chromosome G banding, fluorescent in situ hybridization, a DNA methylation test, and a set of chromosome 15 DNA polymorphisms to characterize a cohort of 27 PWS patients and 24 suspected AS patients. Molecular analysis enabled the reliable diagnosis of 14 PWS and 7 AS patients, and their classification into four groups: (A) 6 of these 14 PWS subjects (44 %) had deletions of paternal 15q11-q13; (B) 4 of the 7 AS patients had deletions of maternal 15q11-q13; (C) one PWS patient (8 %) had a maternal uniparental disomy (UPD) of chromosome 15; (D) the remaining reliably diagnoses of 7 PWS and 3 AS cases showed abnormal methylation patterns of 15q11-q13 chromosome, but none of the alterations shown by the above groups, although they may have harbored deletions undetected by the markers used. This study highlights the importance of using a combination of cytogenetic and molecular tests for a reliable diagnosis of PWS or AS, and for the identification of genetic alterations.

Adolescent↗
PubMed2006

Complete maternal uniparental isodisomy of chromosome 4 in a subject with major depressive disorder detected by high density SNP genotyping arrays.

Uniparental isodisomy (iUPD) is a rare genetic condition caused by non-disjunction during meiosis that ultimately leads to a duplication of either the maternal or paternal chromosome in the affected individual. Two types of disorders can result, those due to imprinted genes and those due to homozygosity of recessive disease-causing mutations. Here, we describe the third known case of complete chromosome 4 iUPD of maternal origin. This condition became apparent during whole genome linkage studies of psychiatric disorders in the Portuguese population. The proband is an adult female with normal fertility and no major medical complaints, but a history of major depressive disorder and multiple suicide attempts. The proband's siblings and parents had normal chromosome 4 genotypes and no history of mood disturbance. A brief review of other studies lends support for the possibility that genes on chromosome 4 might confer risk for mood disorders. We conclude that chromosome 4 maternal uniparental disomy (UPD) is a rare disorder that may present with a major depressive phenotype. The lack of a common disease phenotype between this and two other cases of chromosome 4 iUPD [Lindenbaum et al. [1991] Am J Med Genet 49(Suppl 285):1582; Spena et al. [2004] Eur J Hum Genet 12:891-898) would suggest that there is no vital maternal gene imprinting on chromosome 4. However, since there is no reported case of paternal chromosome 4 UPD, paternal gene imprinting on chromosome 4 cannot be excluded.

Adult↗