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PubMed2002

A second case of intrauterine growth retardation and primary hypospadias associated with a trisomy 22 placenta but with biparental inheritance of chromosome 22 in the fetus.

We report a case of severe intrauterine growth retardation (IUGR) and hypospadias in association with trisomy 22 diagnosed following chorionic villus sampling (CVS). Subsequent analysis of amniotic fluid cultures showed a normal male karyotype, 46,XY. As a previous case had been reported with similar abnormalities, in association with maternal uniparental disomy (UPD) 22, molecular studies were also performed. Microsatellite marker studies showed biparental inheritance. Follow-up studies after delivery showed a normal cell line in lymphocytes with the trisomy appearing to be confined to the placenta. The present case concurs with other earlier reports that maternal UPD for chromosome 22 has no impact on the phenotype. The features seen in the fetus are most likely the result of placental dysfunction due to trisomy, tissue-specific mosaicism and/or the effects of local growth restriction.

Adult↗

PubMed2003

Antenatal manifestation of congenital pancreatoblastoma in a fetus with Beckwith-Wiedemann syndrome.

Antenatal detection of an isolated abdominal cyst was found to be a pancreatoblastoma in a female fetus with Beckwith-Wiedemann syndrome. Prenatal and post-natal features and management of this very rare tumour are discussed. Molecular investigation disclosed a mosaic paternal 11p15 uniparental disomy in the tumoral cells. The prognosis of a congenital pancreatoblastoma is good if complete surgical excision is achieved. However, the association with Beckwith-Wiedemann syndrome requires a prolonged follow-up because of the increased risk of developing malignant tumours.

Beckwith-Wiedemann Syndrome↗

PubMed2003

A further case of confined placental mosaicism for trisomy 2 associated with adverse pregnancy outcome.

OBJECTIVES: To add to the knowledge base concerning confined placental mosaicism for trisomy 2. METHODS: Cytogenetic study of a late CVS referred for hyperechogenic bowel and raised AFP, and cytogenetic and molecular genetic study of a follow-up amniocentesis. Ultrasound monitoring at regular intervals following the CVS result. RESULTS: All cells examined from direct and cultured CVS showed a 47,XY,+2 karyotype. Amniocentesis showed a mosaic 47,XY,+2[8]/46,XY[81] karyotype. Uniparental disomy (UPD) studies on the amniotic fluid showed normal biparental inheritance. The pregnancy developed oligohydramnios and IUGR and resulted in a 26-week liveborn male infant with a 46,XY karyotype, which died after 3 days because of complications of severe prematurity. Placental villi post delivery showed only the 47,XY,+2 cell line. CONCLUSIONS: This case represents a further example of confined placental mosaicism (CPM) for trisomy 2 associated with oligohydramnios, IUGR and poor pregnancy outcome.

Adult↗

PubMed2026

Severe Early-Onset Fetal Growth Restriction: The Yield of Antenatal and Postnatal Genetic Testing.

OBJECTIVES: We evaluated the diagnostic yield of karyotype (KT) and chromosomal microarray (CMA) with isolated severe FGR diagnosed before 32 weeks' gestation. Exome and genome sequencing (ES/GS) level data were available in a subset of this population. METHOD: We performed a retrospective review of singleton pregnancies (delivered 2022-2025) with estimated fetal weight or abdominal circumference < 3rd percentile before 32 weeks' gestation, no sonographic structural anomalies, and diagnostic testing (KT, CMA, ES, or GS) via amniocentesis or cord blood. Cases with abnormal cell-free DNA were excluded. RESULTS: Forty cases were included (mean diagnosis 26.8 weeks). Testing was performed via amniocentesis in 42% and cord blood in 58%. All KT (27/40) were normal. CMA (39/40) identified one pathogenic CNV (2.5%) and three (7.5%) variants of uncertain significance (VUS). Four (10%) showed ≥ 1 region of absence of heterozygosity (AOH) > 10Mb; one revealed maternal uniparental disomy of chromosome 6. Sequencing (N = 10) detected one VUS in COL1A1. Acute viral infection was not observed in any of the cases. CONCLUSIONS: CMA was diagnostic in 2/39 (5.1%) cases, a pathogenic CNV implicating the SHOX gene, and maternal UPD 6, which were consistent with FGR. There was a remarkable rate (10%) of AOH. Further investigation, including placental studies and genome sequencing, may elucidate whether AOH is a contributing factor for FGR.

Humans↗

PubMed2026

Comparison of Medium-Coverage Whole-Genome Sequencing and Chromosomal Microarray in Prenatal Testing of Absence of Heterozygosity.

OBJECTIVE: Absence of heterozygosity (AOH) is a clinically significant genomic feature often associated with uniparental disomy and parental consanguinity in the prenatal settings. Chromosomal microarray analysis (CMA) is commonly used for AOH detection, while sequencing-based approaches may provide complementary genomic information within a single assay. This study evaluated the performance of medium-coverage whole-genome sequencing (CNV-plus) for the detection of prenatal AOH. METHODS: We analyzed 45 prenatal samples (35-CMA-positive, 10-CMA-negative). Concordance between CNV-plus and CMA was assessed at regional, genome-wide, and sample levels, with particular emphasis on the effect of AOH segment size. RESULTS: CNV-plus detected 56 AOH regions compared with 65 by CMA, yielding 68 matched segments. Segment-level sensitivity was 86.8%, showing clear size dependence: 53.3% for 5-10 Mb regions and 96.2% for regions > 10 Mb. Genome-wide overlap was high (global Jaccard index = 0.871), although boundary resolution differed between methods. At the sample level, CNV-plus achieved 97.1% sensitivity and 100% specificity, with no significant difference from CMA. CONCLUSIONS: CNV-plus demonstrates good concordance with CMA for detecting larger AOH regions in prenatal samples and may serve as a complementary approach when considering its size-dependent performance.

Humans↗

PubMed2004

Issues arising from the prenatal diagnosis of some rare trisomy mosaics--the importance of cryptic fetal mosaicism.

OBJECTIVES: To add to the knowledge of fetal mosaicism, confined placental mosaicism (CPM), and uniparental disomy (UPD), in rare trisomies detected at prenatal diagnosis. METHODS: The origin of rare trisomy mosaics, mostly (8/11) seen in amniocytes, was examined in 11 cases by follow-up karyotyping and the study of microsatellite inheritance. RESULTS: Of the rare trisomies presented, three were mosaic trisomy 16 (two of which were CPM), and the remainder comprised single cases of mosaic trisomies of 8, 9, 10, 11, 12, 14, 5 and 15--the last two being CPM. Cases varied in parental derivation and meiotic versus post-zygotic origin but no case involved UPD. There was evidence for cryptic fetal mosaicism in three cases (5, 7, 11)--involving chromosomes 11, 14 and 16. CONCLUSIONS: These cases contribute further data to phenotypes associated with rare trisomies and the relative influences on the phenotype of CPM, UPD and fetal mosaicism. From sparse published data, we estimate that approximately 10% of apparent CPM cases for a rare trisomy (i.e. aneuploid CVS, normal amniocytes) may actually be cryptic fetal mosaics undetected in cultured amniocytes. In many cases, this cryptic mosaicism may be of limited clinical significance, but in others, the associated phenotypic effects may be obvious. There is no general approach to resolve this issue; the finding of even a few similar aneuploid cells in different amniocyte culture vessels may be clinically significant. It may be useful to study such an amniocyte culture with FISH with the relevant centromeric probe. Careful follow-up is recommended, particularly for infants where apparent correction of autosomal trisomy has occurred.

Adult↗

PubMed1997

Monoallelic expression of human PEG1/MEST is paralleled by parent-specific methylation in fetuses.

We have isolated the human PEG1/MEST gene and have investigated its imprinting status and parental-specific methylation. FISH mapping assigned the gene to chromosome 7q32, and homologous sequences were identified on the short arm of human chromosomes 3 and 5. Through the use of a newly identified intragenic polymorphism, expression analysis revealed that PEG1/MEST is monoallelically transcribed in all fetal tissues examined. In two informative cases, expression was shown to be confined to the paternally derived allele. In contrast to the monoallelic expression observed in fetal tissues, biallelic expression was evident in adult blood lymphocytes. Biallelic expression in blood is supported by the demonstration of PEG1/MEST transcripts in a lymphoblastoid cell line with maternal uniparental disomy 7. The human PEG1/MEST gene spans a genomic region of approximately 13 kb. Sequence analysis of the 5' region of PEG1/MEST revealed the existence of a 620-bp-long CpG island that extends from the putative promoter region into intron 1. We demonstrate that this CpG island is methylated in a parent-of-origin-specific manner. All MspI/HpaII sites were unmethylated on the active paternal allele but methylated on the inactive maternal one.

Adult↗

PubMed1998

Genomic organization of the UBE3A/E6-AP gene and related pseudogenes.

The UBE3A gene encodes the E6-AP ubiquitin-protein ligase and has recently been shown to be mutated in Angelman syndrome patients who lack 15q11-q13 deletions or chromosome 15 paternal uniparental disomy. Previous UBE3A cDNA analysis has shown a coding region of approximately 2.6 kb and a 3'-untranslated region (UTR) of < 50 bp, whereas Northern analysis has indicated mRNA sizes of 5-8 kb. We have analyzed additional cDNA clones and provide evidence for an additional 0.5 kb of 5'-UTR and > 2 kb of 3'-UTR. We have established the genomic organization of UBE3A and the sequence of intron-exon borders. We have also mapped two highly homologous processed pseudogenes, UBE3AP1 and UBE3AP2, to chromosomes 2 and 21, respectively, and determined their genomic organization. These results will form the basis for studies of mutation and imprinting of UBE3A.

Base Sequence↗

PubMed2000

Construction of a physical and transcript map flanking the imprinted MEST/PEG1 region at 7q32.

MEST/PEG1, a gene expressed paternally in mesodermal derivatives in early embryonic stages, is the first imprinted gene mapped to chromosome 7q32. Since imprinted genes are clustered in general at a chromosomal region, we speculated that a similar imprinted-gene cluster may exist at chromosome region 7q32 and that the functions of some such genes may contribute to the phenotype of Silver-Russell syndrome including maternal uniparental disomy for chromosome 7 (maternal UPD7). As an initial step toward the isolation of imprinted genes at 7q32, we adopted an integrated approach involving the construction of a PAC contig and ESTs mapping in the vicinity of MEST. Here, we have constructed a complete contig of PAC and BAC clones and a transcript map spanning the entire approximately 1-Mb region between D7S530 and D7S649. We developed 60 novel STSs and precisely mapped 47 genes/ESTs. This map contains a putative autistic disorder locus that has been suggested to be localized near markers D7S530 and D7S684. This integrated physical and transcript map provides a valuable resource for identification of an imprinted gene(s) in this region as well as a candidate gene(s) for autistic disorder.

Base Sequence↗

PubMed2000

A novel imprinted gene, HYMAI, is located within an imprinted domain on human chromosome 6 containing ZAC.

Transient neonatal diabetes mellitus (TNDM) is a rare disease characterized by intrauterine growth retardation, dehydration, and failure to thrive due to a lack of normal insulin secretion. This disease is associated with paternal uniparental disomy or paternal duplication of chromosome 6, suggesting that the causative gene(s) for TNDM is imprinted. Recently, Gardner et al. (1999, J. Med. Genet. 36: 192-196) proposed that a candidate gene for TNDM lies within chromosome 6q24.1-q24.3. To find human imprinted genes, we performed a database search for EST sequences that mapped to this region, followed by RT-PCR analysis using monochromosomal hybrid cells with a human chromosome 6 of defined parental origin. Here we report the identification of a novel imprinted gene, HYMAI. This gene exhibits differential DNA methylation between the two parental alleles at an adjacent CpG island and is expressed only from the paternal chromosome. A previously characterized imprinted gene, ZAC/LOT1, is located 70 kb downstream of HYMAI and is also expressed only from the paternal allele. In the pancreas, both genes are moderately expressed. HYMAI and ZAC/LOT1 are therefore candidate genes involved in TNDM. Furthermore, the human chromosome 6q24 region is syntenic to mouse chromosome 10 and represents a novel imprinted domain.

Alleles↗

PubMed2001

Maternal and paternal chromosomes 7 show differential methylation of many genes in lymphoblast DNA.

Genomic imprinting, the differential expression of paternal and maternal alleles, involves many chromosomal regions and plays a role in development and growth. Differential methylation of maternal and paternal alleles is a hallmark of imprinted genes, and thus methylation assays are widely used to support the identification of novel imprinted genes. Either blood or lymphoblast DNAs are most often used in these assays, even though methylation levels may change in cell culture. We undertook a systematic survey of parent-of-origin-specific methylation of chromosome 7 genes and ESTs by comparing DNA samples from cases of maternal and paternal uniparental disomy for chromosome 7 using DNA from fresh blood and lymphoblast cell lines. Our results revealed that up to 41% of genes and ESTs show parent-of-origin-specific methylation differences in lymphoblast DNA after only a short time in culture, whereas methylation differences were not seen in blood DNA. The methylation changes occurred most commonly on paternal chromosome 7, whereas alterations on maternal chromosome 7 were more infrequent and weaker. These findings indicate that methylation patterns may change significantly during cell culture in a parent-of-origin-dependent manner and suggest that methylation is maintained differently on maternal and paternal chromosomes 7.

Adolescent↗

PubMed2002

Molecular genetic studies of human chromosome 7 in Russell-Silver syndrome.

Russell-Silver syndrome (RSS) is a form of congenital short stature characterized by severe growth retardation and variable dysmorphic features. In some RSS individuals, alterations in imprinted genes may be involved because approximately 7% of sporadic patients have been observed to have maternal uniparental disomy (mUPD) of chromosome 7. RSS patients with structural abnormalities of chromosome 7 have also been described. In these individuals the chromosome rearrangement could disrupt the balance of imprinted genes, contribute to a recessive form of RSS, or lead to haploinsufficiency of a crucial developmental gene product. Because the mechanism and molecular defects on chromosome 7 causing RSS are still unknown, we tested our collection of 77 RSS families for mUPD7 and were able to identify three new cases. We also characterized two RSS patients with de novo cytogenetic abnormalities involving the short arm of chromosome 7. One had a partial duplication [46, XX, dup(7)(p12 p14)] and the second contained a paracentric inversion [46, XY, inv(7)(p14 p21)]. Fluorescence in situ hybridization (FISH) mapping revealed that the breakpoints on 7p14 were localized to the same novel gene, C7orf10, which encompasses >700 kb of DNA. We also identified other transcription units from this immediate region, but all seem to be biallelically expressed when using a somatic cell hybrid assay.

Abnormalities, Multiple↗

PubMed1999

Human diseases and genomic imprinting.

In summary, there are a number of conditions where genomic imprinting effects are recognized to be associated clinical disorders of importance in humans. There may be many more. Genomic imprinting should be suspected in any disorder with overgrowth, undergrowth, or behavior abnormalities. Disorders with unusual pattern of inheritance should be studied for the possibility that genomically imprinted gene(s) are involved. Understanding the mechanisms of genomic imprinting has major ramifications in terms of recurrence risk, prediction of whether offspring will be affected, and risk of malignancy. Of particular concern is the potential for uniparental disomy when trisomy is found during prenatal diagnosis.

Aneuploidy↗

PubMed1993

Molecular study of chromosome 15 in 22 patients with Angelman syndrome.

DNA studies in 22 families with Angelman syndrome (AS) were performed using the chromosome 15 marker loci D15S9, D15S10, D15S11, D15S12, D15S13, D15S18, D15S24, D15S86, the alpha-actin gene and the GABA beta 3 receptor gene (GABRB3). Uniparental disomy of chromosome 15 was excluded in all patients. Eighteen AS patients (82%) showed a molecular deletion of chromosome 15q11-q13 with one or more of these markers. No duplications of junction fragments, bridging deletions or duplication breakpoints were observed. The GABRB3 gene was deleted in all deletion-positive patients tested. Analysis of maternal DNA indicated that each deletion was a de novo event. All deletions were of maternal origin; this is in agreement with genomic imprinting in AS.

Actins↗

PubMed1996

A clinical and molecular study of mosaicism for trisomy 17.

Trisomy 17 has never been reported in a live birth. We present a case of mosaic trisomy 17 in a male presenting with mental retardation, seizures, attention deficit hyperactivity and autistic disorders, hearing loss, growth retardation, microcephaly, and minor anomalies. Although peripheral blood lymphocyte chromosomes were normal, trisomy 17 was present in the skin fibroblasts. The percentage of abnormal cells appears to have increased from 18% in an initial skin biopsy at age 3 years 8 months to 80% at age 8 years 8 months. Molecular analysis using 13 highly polymorphic markers spanning the length of chromosome 17 demonstrated the extra chromosome 17 in the skin to be of paternal origin. Three alleles were never seen in the trisomic cell line, suggesting that the extra chromosome arose through a mitotic duplication error after conception. Uniparental disomy was excluded in the euploid blood sample. Although Smith-Magenis syndrome involves a deletion of proximal 17p, some of the clinical features of this mosaic trisomy 17 patient, such as decreased REM sleep and increased tolerance to pain, are suggestive of phenotypic features observed in Smith-Magenis syndrome. We speculate that there are dosage-sensitive genes located in 17p11.2 that produce these phenotypes for either deficiencies or over-expression of their gene products.

Abnormalities, Multiple↗

PubMed1992

Molecular diagnosis of the Prader-Willi and Angelman syndromes by detection of parent-of-origin specific DNA methylation in 15q11-13.

The Prader-Willi syndrome (PWS) and the Angelman syndrome (AS) are distinct genetic disorders that are caused by a deletion of chromosome region 15q11-13 or by uniparental disomy for chromosome 15. Whereas PWS results from the absence of a paternal copy of 15q11-13, the absence of a maternal copy of 15q11-13 leads to AS. We have found that an MspI/HpaII restriction site at the D15S63 locus in 15q11-13 is methylated on the maternally derived chromosome, but unmethylated on the paternally derived chromosome. Based on this difference, we have devised a rapid diagnostic test for patients suspected of having PWS and AS.

Adult↗

PubMed1995

DNA diagnosis of Prader-Willi and Angelman syndromes with the probe PW71 (D15S63).

Previously, 158 nuclear families with probands suspected of having either Prader Willi (PWS) or Angelman syndrome (AS) were analyzed with polymorphic DNA markers from the 15q11-13 region. These cases have been re-evaluated with the probe PW71 (D15S63), which detects parent-of-origin-specific alleles after digestion with a methylation-sensitive restriction enzyme (HpaII). Application of PW71 to DNA samples isolated from leucocytes, confirmed the deletions and uniparental disomies detected earlier by marker analysis, and resolved 50% of the previously uninformative (n = 18) cases. PW71 and restriction fragment length polymorphism analysis indicated that, in all resolved cases, disomies of the 15q11-13 region were present. The use of PW71 increased the percentage of disomies detected in our PWS and AS patient groups. Almost 50% of our PWS patients and 17% of the AS patients showed a disomy of maternal or paternal origin, respectively. DNA of first trimester chorionic villi and of fibroblast cultures was not suitable for analysis with PW71 because of different methylation patterns. The application of PW71 is recommended for the diagnosis of the PWS and AS, with respect to DNA samples from blood.

Alleles↗

PubMed1992

Females with a disorder phenotypically identical to X-linked agammaglobulinemia.

Clinical and laboratory findings in two girls with a disorder phenotypically indistinguishable from typical X-linked agammaglobulinemia (XLA) are described. To examine the possibility that subtle defects in the X chromosome might explain the findings, detailed genetic studies were performed on one of these patients. Cytogenetic studies showed a normal 46XX karyotype. Southern blot analysis of her DNA showed that she had inherited a maternal and a paternal allele at sites flanking the locus for typical XLA at Xq22, making a microdeletion or uniparental disomy unlikely. To determine whether both of her X chromosomes could function as the active X, somatic-cell hybrids that selectively retained the active X were produced from her activated T cells. A normal random pattern of X inactivation was seen. Of 21 T-cell hybrids, 3 retained both X chromosomes, 7 had one X as the active X, and 11 had the other X as the active X. We have interpreted these studies as indicating that there is an autosomal recessive disorder that is phenotypically identical to XLA.

Agammaglobulinemia↗