Parental origin of the supernumerary chromosome in trisomy 18

Ya-gang X, Robinson WP, Spiegel R, Binkert F, Ruefenacht U, Schinzel AA. Parental origin of the supernumerary chromosome in trisomy 18. Clin Genet 1993: 44: 57–61. Munksgaard, 1993
The parental origin of an extra chromosome in Edwards syndrome has been investigated in 23 families by the combination of the VNTR probe pERT25, two microsatellite polymorphisms for D18S34 and D18S40, and several two-allele polymorphisms. Of the 23 cases, 22 were informative, with 17 (77%) being maternal and 5 (23%) paternal in origin. These results support the previous investigations, suggesting that trisomy 18 is predominantly of maternal origin, although a higher rate of paternally derived cases was observed than previously reported. A significant increase in maternal age was found to be associated with meiotic nondisjunction. Parental age was increased in both the maternally and paternally derived cases, but the size of the latter class was small and did not reach statistical significance.     

Myelodysplastic syndrome and trisomy 14q.

Trisomy 14 as a sole karyotypic abnormality in neoplasia is extremely rare. In hematologic disorders, 18 cases have been reported so far, 17 of which involved disorders of the myeloid lineage. Five were cases of myelodysplastic syndrome (MDS), and a further four involved Philadelphia-negative atypical chronic myeloid leukemia. The case presented here is the second case of trisomy 14q in MDS involving the chronic myelomonocytic leukemia subtype. There were certain features in common with some of the previously reported cases. We raise the possibility that this represents a specific entity.     

Parental sex effect in spina bifida: a role for genomic imprinting?

Fifty families (491 individuals in 137 sibships) with more than one living case of isolated, nonsyndromic spina bifida (SB) were analyzed genetically. There were twice as many gene-carrier females (56) as gene-carrier males (28) (P < 0.005). This was not an artifact of ascertainment bias because the sex ratio of gene-carriers was the same whether the pedigree was obtained through the proband's father or mother. Also, this effect was not observed in other disorders analyzed by the same method. Neither was the effect due to differential fertility because the number and sex of affected and unaffected children per gene-carrier parent were not different for male or female gene-carrier parents. There was no evidence that the missing male gene-carriers were lost by selective spontaneous abortion. There was no deficit of male-to-male or male-to-female transmission, excluding simple X-linked or simple mitochondrial inheritance. If genomic imprinting plays a role in the unequal female and male carrier frequencies in SB, penetrance should differ with parental sex. Penetrance was higher for offspring of female parents than of male parents, but the difference was not statistically significant. In addition, both male and female gene-carriers were frequently found in the same pedigree. Thus, the present data suggest a possible role for imprinting in SB.     

A gene subject to genomic imprinting and responsible for hereditary paragangliomas maps to chromosome 11q23-qter.

Paragangliomas of the head and neck are slow growing tumors which rarely show malignant progression. Familial transmission has been described consistent with an autosomal dominant mode of inheritance. Clinical manifestations of hereditary paragangliomas are determined by the sex of the transmitting parent. All affected individuals have inherited the disease gene from their father, expression of the phenotype is not observed in the offspring of an affected female until subsequent transmittance of the gene through a male carrier. This finding strongly suggests that genomic imprinting is involved. We report the results of a linkage study on a large Dutch pedigree with hereditary paragangliomas. Highly significant evidence for genetic linkage to chromosome 11q23-qter with the anonymous DNA marker D11S147 was detected with a peak lod score of 6.0 at a recombination fraction theta = 0.0. Likelihood calculations yielded an odds ratio of 2.7 x 10(6) in favor of genomic imprinting versus the absence of genomic imprinting.     

Linkage analysis with chromosome 15q11-13 markers shows genomic imprinting in familial Angelman syndrome.

Angelman syndrome (AS) and Prader-Willi syndrome (PWS) have become the classical examples of genomic imprinting in man, as completely different phenotypes are generated by the absence of maternal (AS) or paternal (PWS) contributions to the q11-13 region of chromosome 15 as a result of deletion or uniparental disomy. Apparently, most patients are sporadic cases. The genetic mechanism underlying familial AS has remained enigmatic for a long time. Recently, evidence has been emerging suggesting autosomal dominant inheritance of a detectable or undetectable defect in a gene or genes at 15q11-13, subject to genomic imprinting. The present report describes an unusually large pedigree with segregation of AS through maternal inheritance and apparent asymptomatic transmission through several male ancestors. Deletion and paternal disomy at 15q11-13 were excluded. However, the genetic defect is still located in this region, as we obtained a maximum lod score of 5.40 for linkage to the GABA receptor locus GABRB3 and the anonymous DNA marker D15S10, which have been mapped within or adjacent to the AS critical region at 15q11-13. The size of the pedigree allowed calculation of an odds ratio in favour of genomic imprinting of 9.25 x 10(5). This family illustrates the necessity of extensive pedigree analysis when considering recurrence risks for relatives of AS patients, those without detectable deletion or disomy in particular.     

Maternal origin of 15q11-13 deletions in Angelman syndrome suggests a role for genomic imprinting

Six persons with the classical Angelman syndrome (AS) phenotype and de novo deletions of chromosome 15q11-q13 were studied to determine the parental origin of the chromosome deletion. Four of the 6 patients had informative cytogenetic studies and all demonstrated maternal inheritance of the deletion. These findings, together with other reported cases of the origin of the chromosome 15 deletion in AS, suggest that deletion of the maternally contributed chromosome leads to the AS phenotype. This contrasts with the Prader-Willi syndrome (PWS) in which a similar deletion of the paternally contributed chromosome 15 is observed. In deletion cases, a parental gamete effect such as genomic imprinting may be the best model to explain why apparently identical 15q11-q13 deletions may develop the different phenotypes of AS or PWS.     

Partial trisomy 14q24 leads to qter.

A newborn male with partial trisomy for the distal part of the long arm of chromosome 14 (14q24 leads to qter) is described. The anomaly arose as an adjacent 1 meiotic segregation product from a balanced translocation t(11;14) (q25;q24) in the mother (figure). To our knowledge only one previous case involving the same segment has been reported. The karyotype was confirmed as 46,XY,der(11),t(11;14)(q25;q24) mat.     

Genomic imprinting: implications for human disease

Genomic imprinting refers to an epigenetic marking of genes that results in monoallelic expression. This parent-of-origin dependent phenomenon is a notable exception to the laws of Mendelian genetics. Imprinted genes are intricately involved in fetal and behavioral development. Consequently, abnormal expression of these genes results in numerous human genetic disorders including carcinogenesis. This paper reviews genomic imprinting and its role in human disease. Additional information about imprinted genes can be found on the Genomic Imprinting Website at http://www.geneimprint.com.     

Maternal origin of 15q11–13 deletions in Angelman syndrome suggests a role for genomic imprinting

Six persons with the classical Angelman syndrome (AS) phenotype and de novo deletions of chromosome 15q11-q13 were studied to determine the parental origin of the chromosome deletion. Four of the 6 patients had informative cytogenetic studies and all demonstrated maternal inheritance of the deletion. These findings, together with other reported cases of the origin of the chromosome 15 deletion in AS, suggest that deletion of the maternally contributed chromosome leads to the AS phenotype. This contrasts with the Prader-Willi syndrome (PWS) in which a similar deletion of the paternally contributed chromosome 15 is observed. In deletion cases, a parental gamete effect such as genomic imprinting may be the best model to explain why apparently identical 15q11-q13 deletions may develop the different phenotypes of AS or PWS.     

Partial trisomy 14q -- and parental translocation of No. 14 chromosome. Report of a case and review of the literature.

A case of partial trisomy 14 (47, + 14q-) is presented. The proband's mother had a balanced translocation of 14q with the long arm of a No. 3 chromosome. Clinical and cytogenetic findings of this case are compared with 5 other cases of 47, + 14q-, in which one parent had a balanced translocation of the distal part of the No. 14 long arm to another chromosome. It appears that this chromosomal aneuploidy produces a fairly typical clinical picture.     

Parental origin of the extra chromosome in trisomy 21 as indicated by analysis of DNA polymorphisms. Down Syndrome Collaborative Group.

BACKGROUND. Over the past 20 years, the parental origin of the extra chromosome in children with trisomy 21 has been investigated with cytogenetic methods of identifying morphologic variations in chromosome 21. These studies have concluded that the origin of the extra chromosome 21 was maternal in approximately 80 percent of cases and paternal in about 20 percent. METHODS. We studied 200 families, each with a single child with trisomy 21, using DNA polymorphisms as markers to determine the parental origin of the nondisjunction causing the extra chromosome 21. These polymorphisms spanned a region of about 120 centimorgans on the long arm of chromosome 21, from the D21S13 locus (the most centromeric) to the COL6A1 gene (the most telomeric). RESULTS. The parental origin of nondisjunction could be determined for all but 7 of the 200 children. It was maternal in 184 children (proportion [+/- SE], 95.3 +/- 1.5 percent) and paternal in 9 (4.7 +/- 1.5 percent). In a subgroup of 31 families, we compared the results of DNA analysis with those of traditional cytogenetic analysis. According to the cytogenetic analyses, nondisjunction originated in the mother in 26 cases (84 percent) and in the father in 5 (16 percent). DNA analysis demonstrated the origin as maternal in 29 (94 percent) and paternal in 2 (6 percent). With the cytogenetic analyses, there were three false determinations of paternal origin. CONCLUSIONS. In trisomy 21 the extra chromosome 21 is maternal in origin in about 95 percent of the cases, and paternal in only about 5 percent--considerably less than has been reported with cytogenetic methods. DNA polymorphic analysis is now the method of choice for establishing the parental origin of nondisjunction.     

Parental origin of triploidy and D and G trisomy in spontaneous abortions.

A cytogenetic study of 15 triploid spontaneous abortuses, 12 trisomic abortuses, and their parents was carried out using the Q-banding technique. Polymorphic regions in abortus chromosomes were compared to corresponding regions of parental chromosomes to determine the origin of the extra chromosomes. Using marker chromosomes it was found that 7 triploids and only one trisomy were informative. Three triploids arose by failure to shed the second polar body during oogenesis. One triploid arose by dispermy. The other three triploids inherited an extra haploid set of chromosomes from the father, either by dispermy or by failure of the second meiotic division during spermatogenesis. The only informative trisomy, a trisomy 22, inherited the extra 22 from the mother. Chromosome polymorphisms are useful in determining the parental origin of extra chromosomes in certain cases.     

Identification of the chromosome 14 origin of a C-negative marker associated with a 14q32 deletion by chromosome painting

A constitutional chromosome 14 rearrangement was observed in a female with a psychodevelopmental disorder. Karyotype analysis using a variety of chromosome techniques, QFQ, GTG, CBG, Ag-NOR and DA-DAPI, showed a deletion of chromosome 14q32.1-qter region in association with a supernumerary marker chromosome. The marker, resembling a submetacentric, approximately half the size of a G group chromosome is C band and Ag-NOR negative. The heteromorphism of the satellites showed that the deleted chromosome 14 is paternal in origin. Chromosome painting using an Alu-PCR probe specific for the human chromosome 14 and fluorescent in situ hybridization (FISH) showed that the marker contains chromosome 14q32 sequences. It is likely that the marker was generated from the deleted chromosome 14 region through a complex rearrangement.     

Partial trisomy 12q: a clinically recognisable syndrome. Genetic risks associated with translocations of chromosome 12q.

A newborn child with an unusual facial appearance and multiple abnormalities was found to be trisomic for a large part of 12q as a result of adjacent 1 segregation of a familial translocation, t(9;12) (p24;q21.2). A combination of cytogenetic analysis, clinical features, and enzyme marker studies allows an accurate assessment of the breakpoints. Although trisomic for a considerably larger area of 12q than other reported cases, there are many similar features suggesting that trisomy 12q is a clinically recognisable syndrome. The frequency and mode of segregation of 12q translocations and their implications for genetic counselling are discussed.     

Reproductive possibilities for balanced translocation (14) carriers in families with partial trisomy of proximal 14q.

Two cases of 14q proximal partial trisomy in sisters from the same family are reported. Clinical features included craniofacial dysmorphism, skin depigmentation, slight anomalies of the limbs, muscular hypertonia, and physical and mental retardation. The third sister had an abnormal phenotype, different from that of her sibs, and proved to be a carrier of a balanced translocation (2;14)(q36;q21) inherited from their phenotypically normal mother.