Maternal uniparental disomy for chromosome 14 in a boy with intrauterine growth retardation

Maternal uniparental disomy (UPD) for chromosome 14 [upd(14)mat] may cause a characteristic phenotype with growth and developmental deficiency and precocious puberty. We report the case of a Japanese infant with an isochromosome 14 [i(14q)] and intrauterine growth retardation (IUGR). The infant is one of triplets comprising a boy (the patient) and two karyotypically normal girls. We analyzed parent–child transmission modes of alleles on the i(14q) at 17 CA-repeat marker loci along the entire length of chromosome 14. Genotypes at 4 proximal and 5 distal loci on the i(14q) were consistent with maternal isodisomy, whereas those at an intervening region indicated maternal heterodisomy. Thus, the derivative chromosome 14 had arisen through a translocation between maternal homologous chromosomes 14 [t(14;14)(p10;q10)] after at least two crossing-over events at the first meiosis. This result also suggests that there must be maternally imprinted gene(s) on 14q, and that loss of the functionally active, paternally derived allele in the same locus may lead to IUGR. Alternatively, IUGR may be an autosomal recessive trait. In the latter case, the mother would be a heterozygote and the putative disease locus would be either at the most proximal or most distal region of 14q. Received: December 19, 1997 / Accepted: February 7, 1998     

Maternal disomy and Prader-Willi syndrome consistent with gamete complementation in a case of familial translocation (3;15) (p25;q11.2)

Maternal uniparental disomy (UPD) for chromosome 15 is responsible for an estimated 30% of cases of Prader-Willi syndrome (PWS). We report on an unusual case of maternal disomy 15 in PWS that is most consistent with adjacent-1 segregation of a paternal t(3;15)(p25;q11.2) with simultaneous maternal meiotic nondisjunction for chromosome 15. The patient (J.B.), a 17-year-old white male with PWS, was found to have 47 chromosomes with a supernumerary, paternal der(15) consisting of the short arm and the proximal long arm of chromosome 15, and distal chromosome arm 3p. The t(3;15) was present in the balanced state in the patient's father and a sister. Fluorescent in situ hybridization analysis demonstrated that the PWS critical region resided on the derivative chromosome 3 and that there was no deletion of the PWS region on the normal pair of 15s present in J.B. Methylation analysis at exon alpha of the small nuclear ribonucleoprotein-associated polypeptide N (SNRPN) gene showed a pattern characteristic of only the maternal chromosome 15 in J.B. Maternal disomy was confirmed by polymerase chain reaction analysis of microsatellite repeats at the gamma-aminobutyric acid receptor beta3 subunit (GABRB3) locus. A niece (B.B.) with 45 chromosomes and the derivative 3 but without the der(15) demonstrated a phenotype consistent with that reported for haploinsufficiency of distal 3 p. Uniparental disomy associated with unbalanced segregation of non-Robertsonian translocations has been reported previously but has not, to our knowledge, been observed in a case of PWS. Furthermore, our findings are best interpreted as true gamete complementation resulting in maternal UPD 15 and PWS. Am. J. Med. Genet. 78:134–139, 1998. © 1998 Wiley-Liss, Inc.     

Malformation syndrome of duplication 12q24.1→qter

While duplication and deletion of the short arm of chromosome 12 cause well-recognized syndromes, duplication of the long arm of chromosome 12 is rarely observed. We are reporting a duplication of chromosome 12 distal to band q24.1 in a five-month-old child. His chromosome constitution is 46,XY,-4, + der(4),t(4:12)(p16;q24.1)mat. The balanced translocation is also carried by his maternal grandmother and two of the mother's brothers. The malformation syndrome consisted of unusual facial appearance and anomalies of the musculoskeletal, cardiovascular, genitourinary, and central nervous systems. Four previously reported patients had similar break points on chromosome 12 with similar malformations; therefore, phenotype-karyotype correlation suggests a definitive malformation syndrome associated with duplication of chromosome region 12q24.1→qter.     

Detailed characterization of 12 supernumerary ring chromosomes using micro‐FISH and search for uniparental disomy

Twelve patients with varying degrees of mosaicism for a supernumerary ring chromosome were studied. The ring chromosomes were characterized using microdissection in combination with degenerate nucleotide‐primed polymerase chain reaction (PCR) and reverse painting (micro‐FISH). This method made it possible to determine the chromosomal origin of the ring chromosomes in detail, and thus to compare the phenotypes of similar cases. Eleven of the marker chromosomes were derived from the most proximal part of 1p, 3p, 3q, 5p, 7q, 8p, 8q, 9p, 10p and 20p. One marker chromosome had a complex origin, including the proximal and the most distal part of 20q. Eight of the families were also investigated for uniparental disomy (UPD) using microsatellite analysis. One case with maternal UPD 9 was found in a child with a ring chromosome derived from chromosome 9, r(9)(p10p12). © 2001 Wiley‐Liss. Inc.     

Detailed characterization of 12 supernumerary ring chromosomes using micro-FISH and search for uniparental disomy

Twelve patients with varying degrees of mosaicism for a supernumerary ring chromosome were studied. The ring chromosomes were characterized using microdissection in combination with degenerate nucleotide-primed polymerase chain reaction (PCR) and reverse painting (micro-FISH). This method made it possible to determine the chromosomal origin of the ring chromosomes in detail, and thus to compare the phenotypes of similar cases. Eleven of the marker chromosomes were derived from the most proximal part of 1p, 3p, 3q, 5p, 7q, 8p, 8q, 9p, 10p and 20p. One marker chromosome had a complex origin, including the proximal and the most distal part of 20q. Eight of the families were also investigated for uniparental disomy (UPD) using microsatellite analysis. One case with maternal UPD 9 was found in a child with a ring chromosome derived from chromosome 9, r(9)(p10p12).     

Molecular screening for proximal 15q abnormalities in a mentally retarded population.

Paternal or maternal deletions in the 15q11.2-q13 region are known to result in Prader-Willi syndrome (PWS) or Angelman syndrome (AS), respectively. Maternal duplications in 15q11.2-q13 have been found in patients with autism. A population of adults with moderate to profound mental retardation was studied to examine the usefulness of PCR based molecular methods in screening for proximal chromosome 15 abnormalities. Two hundred and eighty-five subjects were initially screened at five microsatellite markers with average heterozygosity values of 0.74 (range 0.54-0.82). Of these subjects, four had a single allele at all five loci, suggestive of a deletion or uniparental isodisomy. The four samples were further screened with additional markers located within 15q11.2-q13 as well as markers telomeric to this region. One subject had uniparental disomy (UPD) and three subjects had a deletion. To determine the parental origin of the 15q11-q13 region containing the single haplotype, samples were analysed with a newly developed methylation specific PCR technique at the SNRPN locus. Each of the four subjects showed presence of the paternal allele and absence of the maternal allele. All cases had a phenotype consistent with Angelman syndrome as expected for the level of mental retardation, but the subject with UPD was distinct from the other subjects with an absence of a history of seizures and presence of bilateral undescended testes and Parkinsonism. Although Angelman syndrome has an estimated population prevalence of 0.008%, at least 1.4% of the moderately to profoundly mentally retarded subjects screened were found to have Angelman syndrome.     

Genetic events in tumour initiation and progression in multiple endocrine neoplasia type 2

Multiple endocrine neoplasia type 2 (MEN 2) is a familial cancer syndrome arising from mutation at a locus or loci in chromosome region 10p11.2-q11.2. The disease is characterized by medullary thyroid carcinoma (MTC) and pheochromocytoma (Pheo). To assess the genetic events in tumour initiation and progression in this disease, we have compiled an allelotype for MTC and Pheo tumours using polymorphic marker loci from each chromosome arm. Using a panel of 58 tumours, we found frequent allele losses on chromosome arms 1p (42%), 3p (30%), 3q (38%), 11p (11%), 13q (10%), 17p (8%), and 22q (29%). Loss of heterozygosity (LOH) for loci on chromosome 10 was detected in a single tumour where one whole chromosome copy was lost. We used a panel of polymorphic markers for each of chromosomes 1, 3, 11, and 17 to define a shortest region of overlap for these regions. The most frequent allele losses were on chromosome 1, spanning the entire short arm of the chromosome but not loci on 1q. LOH on chromosome 3 encompassed a minimal common region of 3q12-qter. The regions of allelic deletion on chromosome 11(11pter-p13), 17(17pter-p11.2), and 13 (13q) encompass known tumour suppressor loci (WTI, TP53, RBI) which must therefore be candidates for genes contributing to MTC and Pheo development. Our data suggest allele loss on chromosome 11, 13, or 17 occurs predominantly in tumours with losses on chromosome 3, potentially reflecting the accumulation of genetic change in tumour progression. These events may be associated with more advanced disease in MTC. We suggest that at least 7 genes contribute to tumour development in MEN 2, including an initiating locus on chromosome 10 and loci on chromosomes 1, 3, 11, 13, 17, and 22 which have a progressional role in these tumours. © 1993 Wiley-Liss, Inc.     

Case of interstitial 12q deletion in association with Wilms tumor

A 14‐month‐old boy presenting with Wilms tumor (WT) was found to have a small de novo deletion of the long arm of chromosome 12 (12q11‐12q13.11). Microsatellite analysis of this region from constitutional DNA showed that the paternal allele was absent between the markers D12S331 and D12S1713 (inclusive). In the WT there was no evidence of loss of the maternal chromosome. Constitutional chromosome abnormalities can often point to the presence of genes that are important in disease, and the deletion of chromosome 12 in this patient may indicate a gene involved in WT. To determine whether a WT predisposition locus exists at 12q we examined the region in two familial Wilms tumor (FWT) pedigrees unlinked to the known FWT genes on chromosomes 17q (FWT1), 19q (FWT2), and 11p (WT1). In both families WT did not segregate with chromosome 12q markers located within the deletion boundaries. © 2001 Wiley‐Liss, Inc.     

Mirror-symmetric duplicated chromosome 21q with minor proximal deletion, and with neocentromere in a child without the classical Down syndrome phenotype

We report on a mentally retarded child with multiple minor anomalies and an unusually rearranged chromosome 21. This der(21) chromosome has a deletion of 21p and of proximal 21q, whereas the main portion of 21q is duplicated leading to a mirror-symmetric appearance with the mirror axis at the breakpoint. The centromere is only characterized by a secondary constriction (with a centromeric index of a G chromosome) at an unexpected distal position, but fluorescence in situ hybridization (FISH) with either chromosome specific or with all human centromeres alpha satellite DNA shows no cross hybridization. Thus, the marker chromosome represents a further example of an "analphoid marker with neocentromere." Molecular analysis using polymorphic markers on chromosome 21 verified a very small monosomic segment of the proximal long arm of chromosome 21, and additionally trisomy of the remaining distal segment. Although trisomic for almost the entire 21q arm, our patient shows no classical Down syndrome phenotype, but only a few minor anomalies found in trisomy 21 and in monosomy of proximal 21q, respectively.     

Refinement of the commonly deleted segment in myeloid leukemias with a del(20q)

A deletion of the long arm of chromosome 20 [del(20q)] is a recurring abnormality in a wide spectrum of myeloid disorders. Loss of genetic material from 20q may confer a proliferative advantage to myeloid cells, possibly through loss of function of a tumor suppressor gene. Previously, we analyzed leukemia cells from 19 patients with a del(20q) by fluorescence in situ hybridization (FISH) and identified a segment that was deleted in 95% of all patients examined. The deleted interval extended from 20q11.2 to q12, spanned approximately 13 Mb, and was flanked proximally by RPN2 and distally by D20S17. To narrow the commonly deleted segment and facilitate the identification of candidate genes, we have employed molecular approaches in combination with FISH. By using 21 microsatellite markers positioned in a recently generated physical map of 20q, we performed allele loss studies in myeloid leukemia cells from 23 patients with a del(20q). The results of these studies allowed us to delineate a new proximal border, flanked by marker D20S206. By FISH analysis of additional leukemia samples from patients with a del(20q), we have also delineated a new distal boundary between markers D20S119 and UT654. As a result of the redesignation of both the proximal and distal boundaries, we have successfully narrowed the commonly deleted segment within 20q12 to a region spanning approximately 8 Mb. Identification of the smallest deleted segment will facilitate the eventual cloning of a candidate myeloid tumor suppressor gene. Genes Chromosomes Cancer 21:75–81, 1998. © 1998 Wiley-Liss, Inc.     

Maternal uniparental disomy (UPD) for chromosome 2 discovered by exclusion of paternity

Serological and molecular (DNA-STR) analysis of a paternity case demonstrated exclusion of paternity of the presumptive father in two markers (ACP and Apo B, both localized on chromosome 2, region 2p25.2 and 2p23/24, respectively) in a phenotypically normal girl with a normal karyotype 46,XX (by GT-banding). The index of paternity calculated for other serological (seven erythrocyte antigens, six serum protein systems, and seven isozymes, as well as the A- and B-HLA loci) and nine DNA markers, excluding ACP and Apo B, gives a very high (virtually certain) degree of paternity for the presumptive father. Maternal uniparental disomy (UPD) for chromosome 2 was suspected. Evaluation of polymorphic DNA markers (STRs) spanning chromosome 2 of the child, mother, and presumptive father demonstrated that the girl had inherited two maternal chromosome 2 homologues, whereas alleles for markers from other chromosomes were inherited from the father in a Mendelian fashion. The girl was homoallelic for informative markers mapping to the chromosomal regions 2p23-25, but she was heteroallelic for informative markers on the long arm of chromosome 2, establishing that the maternal UPD with partial isodisomy of the short arm was caused by a meiosis I nondisjunction event with genetic recombination (chiasmata in this region 2p23-25) during oogenesis.     

Duplication of distal 17q from a maternal translocation: an additional case with some unique features.

A female with multiple dysmorphic features was found to have an unbalanced karyotype with duplication of the distal long arm of chromosome 17 and deletion of the terminal region of the short arm of chromosome 12. This was derived from a reciprocal translocation in the mother, 46,XX,t(12;17)(p13.3;q23). Clinical findings are presented and comparison with other reported cases of distal 17q duplication shows several unique features in our case.     

Mirror‐symmetric duplicated chromosome 21q with minor proximal deletion,and with neocentromere in a child without the classical Down syndrome phenotype

We report on a mentally retarded child with multiple minor anomalies and an unusually rearranged chromosome 21. This der(21) chromosome has a deletion of 21p and of proximal 21q, whereas the main portion of 21q is duplicated leading to a mirror‐symmetric appearance with the mirror axis at the breakpoint. The centromere is only characterized by a secondary constriction (with a centromeric index of a G chromosome) at an unexpected distal position, but fluorescence in situ hybridization (FISH) with either chromosome specific or with all human centromeres alpha satellite DNA shows no cross hybridization. Thus, the marker chromosome represents a further example of an “analphoid marker with neocentromere.” Molecular analysis using polymorphic markers on chromosome 21 verified a very small monosomic segment of the proximal long arm of chromosome 21, and additionally trisomy of the remaining distal segment. Although trisomic for almost the entire 21q arm, our patient shows no classical Down syndrome phenotype, but only a few minor anomalies found in trisomy 21 and in monosomy of proximal 21q, respectively. Am. J. Med. Genet. 91:116–122, 2000. © 2000 Wiley‐Liss, Inc.     

Search for imprinted regions on chromosome 14: comparison of maternal and paternal UPD cases with cases of chromosome 14 deletion

Over the past few years, regions of genomic imprinting have been identified on a small number of chromosomes through a search for the etiology of various disorders. Distinct phenotypes have been associated with both maternal and paternal uniparental disomy (UPD) for chromosome 14. This observation indicates that there are imprinted genes present on chromosome 14, although none have been identified to date. In order to focus the search for imprinted genes on chromosome 14, we analyzed cases of maternal and paternal UPD 14 and compared them with cases of chromosome 14 deletions. Cases of paternal UPD were compared with maternal deletions and maternal UPD compared with paternal deletions. The paternal UPD anomalies seen in maternal deletion cases allowed us to associate the following features and chromosomal regions: Hirsute forehead: del(14)(q12q13. 3) and del(14)(q32); blepharophimosis: del(14)(q32); small thorax: del(14)(q11.2q13); and joint contractures: del(14)(q11.2q13) and del(14)(q31). Comparison of maternal UPD and paternal deletion cases revealed fleshy nasal tip to be most often associated with del(14)(q32), scoliosis with del(14) (q23q24.2), and del(14)(q32. 11qter) and small size at birth to be associated with del(14)(q11q13) and del(14)(q32). Our study, in conjunction with a prior study of UPD 14 and partial trisomy 14 cases, and what is known of imprinting in regions of mouse chromosomes homologous to human chromosome 14, leads us to conclude that 14q23-q32 is likely an area where imprinted genes may reside.     

Duplication of part of 9q due to maternal 12;9 inverted insertion associated with pyloric stenosis

We report on a 9-month-old boy who had duplication of the long arm of chromosome 9 [46,XY, -12, +der(12) inv ins (12;9)(p13;q32q13)mat.]. The clinical manifestations of the patient were different from those seen in distal 9q duplication. Pyloric stenosis appears to be common in cases with proximal 9q duplications.     

Modification of 15q11 -- q13 DNA methylation imprints in unique Angelman and Prader -- Willi patients

The clearest example of genomic Imprinting in humans comes fromstudies of the Angelman (AS) and Prader—Wil (PWS) syndromes.Although these are clinically distinct disorders, both typicallyresult from a loss of the same chromosomal region, 15q11 - q13.AS usually results from either a maternal deletion of this region,or paternal uniparental disomy (UPD; both chromosomes 15 Inheritedfrom the father). PWS results from paternal deletion of 15q11- q13 or maternal UPD of chromosome 15. We have recently describeda parent-specific DNA methylation imprint in a gene at the D15S9locus (new gene symbol, ZNF 127), within the 15q11 - q13 region,that identifies AS and PWS patients with either a deletion orUPD. Here we describe an AS sibship and three PWS patients inwhich chromosome 15 rearrangements alter the methylation stateat ZNF127, even though this locus is not directly involved inthe rearrangement. Parent-specific DNA methylation imprintsare also altered at ZNF127 and D15S63 (another locus with aparent-specific methylation imprint) in an AS sibship whichhave no detectable deletion or UPD of chromosome 15. These uniquepatients may provide insight into the imprinting process thatoccurs in proximal chromosome 15 in humans.     

An interstitial deletion of chromosome 7 at band q21: a case report and review

We report on a girl with moderate developmental delay and mild dysmorphic features. Cytogenetic investigations revealed a de novo interstitial deletion at the proximal dark band on the long arm of chromosome 7 (7q21.1-q21.3) in all analyzed G-banded metaphases of lymphocytes and fibroblasts. Fluorescence in situ hybridization (FISH) and molecular studies defined the breakpoints at 7q21.11 and 7q21.3 on the paternal chromosome 7, with the proximal deletion breakpoint between the elastin gene (localized at 7q11.23) and D7S2517, and the distal breakpoint between D7S652 and the COL1A2 gene (localized at 7q21.3-q22.1). Deletions of interstitial segments at the proximal long arm of chromosome 7 at q21 are relatively rare. The karyotype-phenotype correlation of these patients is reviewed and discussed. The clinical findings of patients with a deletion at 7q21 significantly overlap with those of patients with maternal uniparental disomy of chromosome 7 (matUPD(7)) and Silver-Russell syndrome (SRS, OMIM 180860). Therefore, 7q21 might be considered a candidate chromosomal region for matUPD(7) and SRS.     

In search of the psychosis gene in people with Prader-Willi syndrome

The two main causes of Prader-Willi syndrome (PWS) are a paternally derived deletion in the maternally imprinted 15q11-q13 region or UPD(15)mat. Both mechanisms result in a loss of the active paternal contribution to the region. The affective psychosis associated with PWS has been found to be mainly confined to the propositi with UPD(15)mat rather than to those with a deletion. This suggests that the psychosis may be related to the presence of two copies rather than a single copy of a gene or genes located in the distal half of the region which is paternally imprinted, but maternally active, and whose loss results in Angelman syndrome (AS). A large population-based study of PWS allowed the identification of 12 people with a 15q11-q13 deletion who had suffered psychotic episodes and four adults with UPD(15)mat who so far had not. When these people were investigated using microsatellite markers, the 12 with a deletion were found to have two maternally derived copies of a narrow region between D15S975 and D15S661 making them effectively disomic for these loci. Thus all of the people with psychosis had two active copies of any imprinted genes in the region while all non-psychotic people (including controls) had only one. Quantitative RT-PCR studies suggest that a lack of expression of FLJ33332, either as a result of or resulting in gene dysregulation, may be associated with psychosis in PWS.     

dup(8p)/del(8q) recombinant chromosome in a girl with hepatic focal nodular hyperplasia

A 15-year-old girl had exertion dyspnea, focal nodular hyperplasia of the liver, portal vein hypoplasia, portopulmonary hypertension, mental retardation, and minor facial abnormalities. Cytogenetic analysis demonstrated an abnormal chromosome 8 with 8p22-pter duplication and 8q24.3-qter deletion, with the duplicated 8p segment attached to band 8q24.3. Her mother had a pericentric inversion of chromosome 8, inv(8)(p22q24.3). Therefore, the girl's abnormal chromosome 8 was a recombinant of maternal inversion chromosome: 46,XX,rec(8)dup(8p)inv(8)(p22q24.3)mat. Further characterization of the recombinant chromosome, using array CGH and regional FISH analyses, defined 15 Mb distal 8p duplication and 0.5 Mb 8q deletion. Possible correlation of the recombinant chromosome and hepatic focal nodular hyperplasia in the patient is discussed.     

An interstitial,apparently-balanced chromosomal insertion in the etiology of Langer–Giedion syndrome in an Asian family

Langer–Giedion syndrome (LGS; MIM 150230), also called trichorhinophalangeal syndrome type II (TRPS2), is a contiguous gene syndrome caused by a one-copy deletion in the chromosome 8q23-q24 region, spanning the genes TRPS1 and EXT1. We identified an LGS family with two affected and two unaffected siblings from unaffected parents. To investigate the etiology of recurrence of LGS in this family, array CGH was performed on all family members. We identified a 7.29 Mb interstitial deletion at chromosome region 8q23-q24 in the two affected siblings, but no such deletion in the unaffected family members. However, the mother and one of the two unaffected siblings carried a 1.29 Mb deletion at chromosome region 8q24.1, sharing the distal breakpoint with the larger deleted segment found in the affected siblings. Another unaffected sibling had a 6.0 Mb duplication, sharing the proximal breakpoint of the deletion in the affected siblings. Karyotypic and FISH analyses in the unaffected mother revealed an insertional translocation of 8q23-q24 genomic material into chromosome 13: 46,XX,ins(13;8)(q33;q23q24). This insertional translocation in the mother results in the recurrence of LGS in this family, highlighting the importance of submicroscopic rearrangements in the genetic counseling for LGS.