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The association of maternal uniparental disomy for chromosome 7 and postnatal growth failure has been reported in four cases and suggests the presence of genomic imprinting of one or more growth related genes on chromosome 7. However, in the reported cases, the possibility of homozygosity for a recessive mutation could not be excluded as the cause...
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Citations
... Chromosome 7 includes the imprinted gene cluster of PEG1/MEST; this cluster is involved in placental and fetal growth and has recently been shown to be variably imprinted in human preimplantation embryos (Huntriss et al., 2013). However, UPD, including UPD7 (Langlois et al., 1995;Kotzot et al., 2000), is often a consequence of trisomy rescue in CPM, which independently can cause FGR (Robinson et al., 1997). Thus, it can be difficult to separate the effects of trisomy on placental function from the effects of UPD alone. ...
Genetic variation shapes placental development and function, which has long been known to impact fetal growth and pregnancy outcomes such as miscarriage or maternal pre-eclampsia. Early epidemiology studies provided evidence of a strong heritable component to these conditions with both maternal and fetal-placental genetic factors contributing. Subsequently, cytogenetic studies of the placenta and the advent of prenatal diagnosis to detect chromosomal abnormalities provided direct evidence of the importance of spontaneously arising genetic variation in the placenta, such as trisomy and uniparental disomy, drawing inferences that remain relevant to this day. Candidate gene approaches highlighted the role of genetic variation in genes influencing immune interactions at the maternal-fetal interface and angiogenic factors. More recently, the emergence of molecular techniques and in particular high-throughput technologies such as Single-Nucleotide Polymorphism (SNP) arrays, has facilitated the discovery of copy number variation and study of SNP associations with conditions related to placental insufficiency. This review integrates past and more recent knowledge to provide important insights into the role of placental function on fetal and perinatal health, as well as into the mechanisms leading to genetic variation during development.
... The origin of cffDNA is mainly derived from the cytotrophoblast but not the fetus. The scenario of confined placental mosaicism (CPM), or abortuses with growth failure [20][21][22] could both contribute to the false positive cases. We also noted that CNVs most frequently observed by eNIPS were on Chr5/Chr4/Chr2/Chr7 (Table 1). ...
Objective
To evaluate the clinical application of expanded noninvasive prenatal screening (eNIPS) for genome-wide large copy number variation (CNV), i.e. chromosomal deletion/duplication >5 Mb, and aneuploidy; also to provide practical information for counseling eNIPS positive cases.
Method
We recruited 34,620 women with singleton pregnancy for genome-wide cell-free plasma DNA sequencing. Screening positive cases were verified by karyotyping and/or SNP array.
Result
A total of 461 (1.33%) positive cases were identified through our cfDNA screening including 209 cases of common trisomies (0.60%), 124 cases of sex chromosomal abnormalities (SCA) (0.36%), 71 cases of other autosomal anueploidies (OAA) (0.21%), and 57 CNVs larger than 5 Mb (0.16%). The predictive positive values (PPV) were 70.06% in general for common trisomies with as high as 91.67% for Trisomy21 (T21), 40.22% in general for SCAs with as high as 100% for Jacob Syndrome (XYY). The PPV for OAAs was 5.45%, and T7/T8/T16/T22 were the most frequent OAAs (n = 15, 9, 9, 8, respectively). The PPV for CNVs larger than 5 Mb was 51.22% (n = 57) with the CNV mostly detected on Chr5/Chr4/Chr2/Chr7 (n = 10, 8, 5, 5, respectively).
Conclusion
The expanded NIPS had shown promising PPVs for CNVs (large than 5 Mb), SCAs and common trisomies, yet this method required higher efficacy in screening for OAAs. The post-test genetic counseling for expanded NIPS should be tailored to the types of positive cases and also address the origin of abnormal signals (fetal vs. maternal).
... In 7% of sporadic cases, maternal uniparentaldisomy of chromosome 7 has been identified. Recent findings suggested that imprinting defects in the region of 11p15 is also pays in SRS [8][9][10][11]. According to pathophysiologically, growth failure is a primary abnormality. Patients typically present with intrauterine growth retardation, difficulty in feeding, failure to thrive, or postnatal growth retardation and also growth hormone insufficiency may be present. ...
... Molecular evaluation of UPD 7 should be considered in patients with unexplained growth retardation or features similar to Russell-Silver syndrome. DNA studies should be considered when prenatal diagnosis indicates trisomy 7 mosaicism [12,13]. Here we want to report a case of trisomy 7 mosaicism and the discrepancy between the triple test and the analysis of fetal karyotype from amniotic fluid. ...
... Molecular evaluation of UPD 7 should be considered in patients with unexplained growth retardation or features similar to Russell-Silver syndrome. DNA studies should be considered when prenatal diagnosis indicates trisomy 7 mosaicism [12,13]. Here we want to report a case of trisomy 7 mosaicism and the discrepancy between the triple test and the analysis of fetal karyotype from amniotic fluid. ...
Trisomy 7 mosaicism is a very rare chromosomal disorder where there is an extra copy of chromosome 7 in some of the body's cells.
Most cases with this chromosomal abnormality have no clinical symptoms. The presence of abnormalities in some cases is dependent on which body cells contain the chromosomal defect. Here we report a case diagnosed incidentally, in which is raised a suspicion of trisomy 21 in fact, based on a biochemical screening test for the second quarter (triple test).
Two contradictions have led us to publish this case: first, the fact that although the triple test raised the suspicion of Down syndrome with a biochemical risk calculated from 1 to 225 with a very low level of free Estriol under 0.45 MoM corrected, it turned out to be about an extremely rare mosaicism.
Secondly the fact that pregnancy has stopped evolving a few days after amniocentesis, although subsequently anatomopathological examination found no fetal or placental abnormalities. We searched in the specialty literature and found very few cases described, usually diagnosed after birth at children with various congenital abnormalities, growth retardation and developmental delay.
Trisomy 7 has variable expression, most common symptoms are: facial asymmetry, hypomelanosis of Ito, kidney abnormalities. In our case we identified only facial dysmorphism and severe ulnar deviation of both hands without any malformations of internal organs. Because we did not anticipate such a genetic defect and considering the fact that the pregnancy has stopped in evolution we have not performed cultures of fibroblasts and we could not determine at what level and how the fetus was genetically affected so it was impossible to speculate how it would have evolved the pregnancy and how it would have been the baby after birth.
... Molecular evaluation of UPD 7 should be considered in patients with unexplained growth retardation or features similar to Russell-Silver syndrome. DNA studies should be considered when prenatal diagnosis indicates trisomy 7 mosaicism [12,13]. Here we want to report a case of trisomy 7 mosaicism and the discrepancy between the triple test and the analysis of fetal karyotype from amniotic fluid. ...
Trisomy 7 mosaicism is a very rare chromosomal disorder where there is an extra copy of chromosome 7 in some of the body's cells. Most cases with this chromosomal abnormality have no clinical symptoms. The presence of abnormalities in some cases is dependent on which body cells contain the chromosomal defect. Here we report a case diagnosed incidentally, in which is raised a suspicion of trisomy 21 in fact, based on a biochemical screening test for the second quarter (triple test). Two contradictions have led us to publish this case: first, the fact that although the triple test raised the suspicion of Down syndrome with a biochemical risk calculated from 1 to 225 with a very low level of free Estriol under 0.45 MoM corrected, it turned out to be about an extremely rare mosaicism. Secondly the fact that pregnancy has stopped evolving a few days after amniocentesis, although subsequently anatomo-pathological examination found no fetal or placental abnormalities. We searched in the specialty literature and found very few cases described, usually diagnosed after birth at children with various congenital abnormalities, growth retardation and developmental delay. Trisomy 7 has variable expression, most common symptoms are: facial asymmetry, hypomelanosis of Ito, kidney abnormalities. In our case we identified only facial dysmorphism and severe ulnar deviation of both hands without any malforma-tions of internal organs. Because we did not anticipate such a genetic defect and considering the fact that the pregnancy has stopped in evolution we have not performed cultures of fibroblasts and we could not determine at what level and how the fetus was genetically affected so it was impossible to speculate how it would have evolved the pregnancy and how it would have been the baby after birth. RÉSUMÉ La trisomie 7 en mesaïque La trisomie 7 en mosaïque est une anomalie chromosomique rare dans laquelle il y a une copie supplémentaire du chromosome 7 dans certaines cellules du corps. Dans la plupart des cas avec cette anomalie chromosomique il n'y a aucun symptôme clinique. La présence d'anomalies dans certains cas dépend de cellules du corps qui contiennent l'anomalie chromosomique. Nous rapportons ici un cas diagnostiqué par hasard qui a soulevé une suspicion de trisomie 21 en effet, sur la base d'un test de dépistage biochimique pour le deuxième trimestre (test triple). Deux contradictions nous ont amené à publier ce cas: d'une part le fait que bien que le triple test ait soulevé la suspicion de syndrome de Down à un risque biochimique calculé de 1 à 225 avec un très faibles niveau d'estriol libre, au-dessuns de 0,45 MoM, il s'est avéré être un cas extrêmement rare de mosaïcisme. Deuxièmement le fait que la grossesse a cessé d'évoluer quelques jours après l'amniocentèse bien que l'examen pathologique n'ait trouvé aucune anomalie foetale ou placentaire. Nous avons cherché dans la littérature de spécialité et nous avons trouvé très peu de cas décrits, généralement diagnostiqués après la naissance à des enfants avec des anomalies congénitales variées, un retard de croissance et un retard du développement. La trisomie 7 a une expression variable, les symp-tômes les plus courants sont: l'asymétrie faciale, la dépigmentation de Ito et les anomalies rénales. Dans notre cas, nous avons identifié seulement la dysmorphie du visage et la déviation ulnaire sévères des mains sans malformations des organes internes. Parce qu'on n'a pas prévu un tel défaut génétique et considérant que la grossesse a cessé d'évoluer, nous n'avons pas effectué de cultures de fibroblastes
... Prenatal diagnosis of trisomy 7 in chorionic villi is most often secondary to confined placental mosaicism (CPM) without consequence on fetal intrauterine growth, as observed in other CPMs, 1,2 except when trisomy rescue leads to maternal uniparental disomy of chromosome 7 [UPD (7)m] in the fetus. 1,3,4 In amniocytes, trisomy 7 is a rare condition that can be associated with pseudomosaicism 5 or true mosaicism with normal fetal outcome in most cases. 6 Phenotypic features of trisomy 7 mosaicism such a blaschkolinear skin pigmentary dysplasia, body asymmetry, enamel dysplasia, and developmental delay were reported in four prenatal cases 7-10 for which UPD(7)m was not investigated. ...
Objectives:
We report here the unusual association of Silver-Russell syndrome (SRS) and cerebellar dysplasia with trisomy 7 mosaicism and maternal uniparental disomy of chromosome 7 [UPD(7)m].
Methods:
Low-level trisomy 7 mosaicism was diagnosed prenatally on amniocytes, and UPD(7)m was confirmed after birth.
Results:
Medical examination at birth showed dysmorphic facial features of SRS. Cytogenetic analysis on several tissues and cells confirmed mosaic trisomy 7. Unusual severe psychomotor retardation, hypotonia, and choreoathetoid movement were noted at 6 months. Brain magnetic resonance imaging showed both cerebellar hypoplasia and dysplasia.
Conclusions:
This unusual association of SRS and dysplasia of the cerebellum might be related to the presence of the trisomy 7 mosaicism on the cerebellum. Our observation strengthens the hypothesis that the phenotype observed in patients with SRS with UPD(7)m might also result from an undetected low level of trisomy 7 mosaicism that could best be revealed by performing cytogenetic investigations.
... affected by pre and postnatal growth retardation but not SRS phenotype with matUPD7 were published [4][5][6] . The incidence of SRS is approximately 1/3000 and more than 60 SRS patients with matUPD7 have been reported till the end of 2002 [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] and matUPD7 has been found in approximately 5-10% of SRS patients with unexplained etiology [17] . ...
... affected by pre and postnatal growth retardation but not SRS phenotype with matUPD7 were published [4][5][6] . The incidence of SRS is approximately 1/3000 and more than 60 SRS patients with matUPD7 have been reported till the end of 2002 [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] and matUPD7 has been found in approximately 5-10% of SRS patients with unexplained etiology [17] . After description of matUPD7 SRS cases, both arms of chromosome 7 were searched for candidate genes. ...
Silver-Russell syndrome (SRS) is a clinically and genetically heterogeneous syndrome which is characterized by severe intrauterine and postnatal growth retardation, and typical characteristic facial dysmorphisms. It has been associated with maternal uniparental disomy (UPD) for chromosome 7 and hypomethylation of imprinting control region 1 (IGF2/H19) in 11p15. UPD refers to the situation in which both copies of a chromosome pair have originated from one parent. UPD can be presented both as partial heterodisomy and isodisomy. The aim of this study was to determine the maternal UPD7 (matUPD7) in 13 Turkish SRS patients.
Genotyping for matUPD7 was performed with microsatellite markers by polymerase chain reaction.
The maternal UPD7 including the entire chromosome was identified in 1/13 (7.6%) of individuals within SRS patients. There were no significant differences between clinical features of matUPD7 case and other SRS cases except congenital heart defects.
It is often difficult to establish diagnosis of a child with intrauterine growth retardation (IUGR), growth failure and dysmorphic features. Thus, screening for matUPD7 in IUGR children with growth failure and mild SRS features might be a valuable diagnostic tool.
... Maternal uniparental disomy of chromosome 7 (mUPD7) was first described in a girl with short stature [Langlois et al., 1995] and later was reported in 7-10% of RSS and RSS-like individuals [Eggermann et al., 1997;Preece et al., 1997;Nakabayashi et al., 2002]. ...
Over a 10-year period blood samples were collected from 57 individuals with growth restriction and RSS-like features. Our goal was to identify epigenetic abnormalities in this cohort, including uniparental disomy of chromosome 7 (UPD7), methylation changes at chromosome 11p15, as well as new epigenomic alterations. We evaluated the methylation status of 7 imprinting control regions on chromosomes 7, 11, 14, and 15. UPD7 and chromosome 7 structural abnormalities had been previously identified in five patients. Epigenetic alterations on chromosome 11p15 were identified in 11 patients. Of interest, in 3 of these 11 patients, the epigenetic alterations were limited to the H19 promoter and the distal region of its associated imprinting center, ICR1. In addition, in one patient, we detected methylation changes consistent with maternal UPD at all tested imprinted regions. This patient series suggests that epimutations on chromosome 11p15 can be most efficiently detected in RSS patients by screening for DNA methylation defects at the H19 promoter or the distal region of ICR.
... Three cases of maternal uniparental isodisomy 7 with a CFTR gene mutation (13,15,16) have been associated with CF and unusual severe IUGR. All the matUPD7 cases reported in children without CF presented severe IUGR and PNGR (9,10,(29)(30)(31)(32)(33)(34). ...
Uniparental disomy (UPD) for several human chromosomes is associated with clinical abnormalities. We report the case of a 2-year-old boy with severe intrauterine and post-natal growth retardation (IUGR/PNGR) and highly variable sweat chloride concentrations. The patient was identified as heterozygous for the F508del mutation of the CFTR (cystic fibrosis transmembrane conductance regulator) gene. Unexpectedly, the signal corresponding to the maternally inherited F508del allele appeared much more intense than the paternally derived wild allele. Molecular analysis including polymorphic marker studies, microsatellites and single-nucleotide polymorphisms subsequently showed that the boy was a carrier of a de novo mosaic maternal isodisomy of a chromosome 7 segment while there was a biparental inheritance of the rest of the chromosome. This is the first report of a mosaic partial UPD7. The matUPD7 segment at 7q21-qter extends for 72.7 Mb. The karyotype (550 bands) of our patient was normal, and fluorescence in situ hybridization with probes mapping around the CFTR gene allowed us to rule out a partial duplication. The detection of this chromosomal rearrangement confirms the hypothesis that the 7q31-qter segment is a candidate for the localization of human imprinted genes involved in the control of IUGR and PNGR. It also emphasizes the importance of searching for UPD7 in severe, isolated and unexplained IUGR and PNGR.
