Maternal origin of a unique extra chromosome,der(9)(pter→q13::q13→q12:) in a girl with typical trisomy 9p syndrome

We report on a girl with the typical trisomy 9p syndrome who had an additional E‐sized metacentric chromosome. On the basis of GTG‐ and CBG‐banding, her karyotype was considered to be 47,XX,+der(9)(pter→q13::q13→q12:) de novo. Results of a fluorescence in situ hybridization study using a chromosome 9‐specific painting probe were compatible with this cytogenetic interpretation. Molecular analyses of six highly polymorphic dinucleotide repeat loci on the short arm and the proximal long arm of chromosome 9 demonstrated that the girl inherited one allele from her father and two identical or different alleles from the mother. We speculated that the extra chromosome may have resulted from either nondisjunction of chromosome 9 followed by a U‐type exchange and a crossing‐over between different sister chromatids during maternal meiosis I and subsequent breakage and malsegregation during meiosis II, or nondisjunction during meiosis II followed by isochromosome formation in one of the two maternal chromosomes 9 and subsequent breakage. © 2001 Wiley‐Liss, Inc.     

Translocation 9q/13q resulting in duplication (trisomy 9pter→9q22) and deficiency (monosomy 13pter→13q12)

A profoundly retarded, 12-year-old female is described. Her phenotype is compatible with the clinical features of the trisomy 9p syndrome. Cytogenetic analyses showed her to be trisomic for 9pter→9q22 and monosomic for 13pter→13q12, as the result of adjacent-2 segregation during meiosis in her mother. The family pedigree shows this (9;13) translocation to be present in at least three generations.     

Molecular cytogenetic studies of duplication 9q32→q34.3 inserted into 9q13

Fluorescence in situ hybridization (FISH) studies using whole chromosome 9 painting probe, classical satellite (9q12-specific) probe and abl cosmid probe (locus: 9q34) were performed on a female infant who was born with multiple congenital anomalies and the karyotype 46,XX, 9q+. The results of FISH confirm the euchromatic nature of the extra material on the long arm of chromosome 9, and provide evidence that it is of chromosome 9 origin. The structural rearrangement has probably resulted from an insertion of a duplicated segment 9q32→q34.3 into band q13, as shown by the abl cosmid probe. The clinical features in this patient are similar to the previously reported cases of partial trisomy 9q3.     

The origin of trisomy 13

Trisomy 13 is one of the most common trisomies in clinically recognized pregnancies and one of the few trisomies identified in liveborns, yet relatively little is known about the errors that lead to trisomy 13. Accordingly, we initiated studies to investigate the origin of the extra chromosome in 78 cases of trisomy 13. Our results indicate that the majority of cases (>91%) are maternal in origin and, similar to other autosomal trisomies, the extra chromosome is typically due to errors in meiosis I. Surprisingly, however, a large number of errors also occur during maternal meiosis II ( approximately 37%), distinguishing trisomy 13 from other acrocentric and most nonacrocentric chromosomes. As with other trisomies, failure to recombine is an important contributor to nondisjunction of chromosome 13.     

Inverted duplications are recurrent rearrangements always associated with a distal deletion: description of a new case involving 2q

We studied the case of a subject with an inverted duplication of 40 cM of 2q33-q37 concurrent with a 10 cM deletion of the distal 2q, the latter not being detectable by cytogenetics. Microsatellite analysis demonstrated the absence of maternal alleles in the deleted region and a double dosage for one of the maternal alleles in the duplication region. We hypothesised that this type of rearrangement occurs at meiosis I, while the two homologues are synapsed for most of their length. The presence of inverted duplicons in the same chromosome arm would favour the partial refolding of one homologue into itself so leading to the intrachromatid synapsis and recombination of the inverted repeats. The arising recombinant chromosome is deleted for the region beyond the most distal repeat and with the chromatids joined together at the level of the region located between the two duplicons. At meiosis II, the two linked chromatids can join the opposite poles provided that a breakage between the two centromeres occurs leading to a duplicated/deleted chromosome and a simply deleted chromosome. This model can be extended to all the so-called inverted duplication cases and to part of the terminal deletions. In fact the finding that, in our invdup(2q), the entire 40 cM duplication region involves only one of the two maternal alleles, indeed indicates that the abnormal crossover occurs between sister chromatids. The phenotype associated with our 2q rearrangement led us to narrow the critical region for the Albright-like syndrome to 10 cM in the subterminal 2q region.     

Multiplex PCR of three dinucleotide repeats in the Prader-Willi/Angelman critical region (15q11-q13): molecular diagnosis and mechanism of uniparental disomy

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are distinctmental retardation disorders caused by a deficiency of paternal(PWS) or maternal (AS) contributions for chromosome 15 by eitherdeletion or uniparental disomy (UPD). To further study the molecularmechanisms involved in these disorders and to improve moleculardiagnostic methods, we have isolated three dinucleotide repeatmarkers in the PWS/AS critical region. An Alu-CA PCR methodwas used to isolate CA-repeat markers directly from yeast artificialchromosome (YAC) clones identified by probes IR4–3R (D15S11),LS6–1 (D15S113), and GABA_A receptor B3 (GABRB3). Threemarkers with 6–11 alleles and 73–83% heterozygositieswere identified and analyzed by multiplex PCR. Gene-centromeremapping was performed on a panel of ovarian teratomas of knownmeiotic origin, and showed the most proximal marker, IR4–3R,to be 13 cM (95% confidence limits: 7–19 cM) from thecentromere of chromosome 15. Molecular diagnostic studies wereperformed on 20 PWS and 9 AS patients. In 17 patients with deletions,the parental origin of deletion was determined. Ten PWS patientswere shown to have maternal heterodisomy. Since these markersare only 13 cM from the centromere, heterodisomy indicates thatmaternal meiosis I nondisjunction is involved in the originof UPD. In contrast, two paternal disomy cases of AS showedisodisomy for all markers tested along the length of chromosome15. This suggests a paternal meiosis II nondisjunction event(without crossing over) or, more likely, monosomic conception(due to maternal nondisjunction) followed by chromosome duplication.This latter mechanism would indicate that UPD in PWS and ASmay initiate as reciprocal products of maternal nondisjunctionevents.     

The association of low socioeconomic status and the risk of having a child with Down syndrome: a report from the National Down Syndrome Project

PurposeAdvanced maternal age and altered recombination are known risk factors for Down syndrome cases due to maternal nondisjunction of chromosome 21, whereas the impact of other environmental and genetic factors is unclear. The aim of this study was to investigate an association between low maternal socioeconomic status and chromosome 21 nondisjunction.MethodsData from 714 case and 977 control families were used to assess chromosome 21 meiosis I and meiosis II nondisjunction errors in the presence of three low socioeconomic status factors: (i) both parents had not completed high school, (ii) both maternal grandparents had not completed high school, and (iii) an annual household income of <$25,000. We applied logistic regression models and adjusted for covariates, including maternal age and race/ethnicity.ResultsAs compared with mothers of controls (n = 977), mothers with meiosis II chromosome 21 nondisjunction (n = 182) were more likely to have a history of one low socioeconomic status factor (odds ratio = 1.81; 95% confidence interval = 1.07–3.05) and ≥2 low socioeconomic status factors (odds ratio = 2.17; 95% confidence interval = 1.02–4.63). This association was driven primarily by having a low household income (odds ratio = 1.79; 95% confidence interval = 1.14–2.73). The same statistically significant association was not detected among maternal meiosis I errors (odds ratio = 1.31; 95% confidence interval = 0.81–2.10), in spite of having a larger sample size (n = 532).ConclusionWe detected a significant association between low maternal socioeconomic status and meiosis II chromosome 21 nondisjunction. Further studies are warranted to explore which aspects of low maternal socioeconomic status, such as environmental exposures or poor nutrition, may account for these results.Genet Med15 9, 698–705.     

Double chromosome anomaly: Interstitial deletion 5q and reciprocal translocation (1;11) (p22;q21)

We describe a girl with multiple congenital abnormalities and developmental delay; her karyotype showed an apparently balanced translocation between the short arm of chromosome 1 and the long arm of chromosome 11, and an interstitial deletion of the long arm of chromosome 5 (q15q31). The clinical findings are compared with those described in other cases of 5q deletion, and the origin of the chromosome rearrangements is briefly discussed.     

Interstitial duplications of chromosome region 15q11q13: Clinical and molecular characterization

Duplications of chromosome region 15q11q13 often occur as a supernumerary chromosome 15. Less frequently they occur as interstitial duplications [dup(15)]. We describe the clinical and molecular characteristics of three patients with de novo dup(15). The patients, two males and one female (ages 3–21 years), had nonspecific findings that included autistic behavior, hypotonia, and variable degrees of mental retardation. The extent, orientation, and parental origin of the duplications were assessed by fluorescent in situ hybridization, microsatellite analyses, and methylation status at D15S63. Two patients had large direct duplications of 15q11q13 [dir dup(15)(q11q13)] that extended through the entire Angelman syndrome/Prader-Willi syndrome (AS/PWS) chromosomal region. Their proximal and distal breaks, at D15S541 or D15S9 and between D15S12 and D15S24, respectively, were comparable to those found in the common AS/PWS deletions. This suggests that duplications and deletions may be the reciprocal product of an unequal recombination event. These two duplications were maternally derived, but the origin of the chromatids involved in the unequal crossing over in meiosis differs. In one patient, the duplication originated from two different maternal chromosomes, while in the other patient it arose from the same maternal chromosome. The third patient had a much smaller duplication that involved only D15S11 and parental origin could not be determined. There was no obvious correlation between phenotype and extent of the duplication in these patients. Am. J. Med. Genet. 79:82–89, 1998. © 1998 Wiley-Liss, Inc.     

Paternal nondisjunction in trisomy 21: excess of male patients

Paternal nondisjunction accounts for approximately 5% of casesof trisomy 21. We have studied 36 cases of free trisomy 21,in which the supernumerary chromosome was of paternal origin,with DNA markers in the pericentromeric region and along thelong arm of chromosome 21. Fifteen of the paternal cases wereconsistent with melosis II errors, 8 with mitotic errors andonly 7 with melosis I nondisjunction. This contrasts markedlywith maternally derived trisomy 21, in which meiosis I errorspredominate. An excess of males was observed in the meloticcases (21 maies:6 females), highly significantly different froma 1.06 ratio. A significant difference in mean maternal agewas found between cases of paternal origin (28.1 years) andthose of maternal origin (31.8 years, n=429). This indicatesthat the maternal age effect is confined to maternal nondisjunction.     

Partial trisomy 13 plus partial trisomy 4q due to unusual segregation of translocation chromosomes

The cytogenetic analysis of a 7-month-old retarded girl with clinical signs compatible with partial trisomy 13 revealed a translocation t(4;13)(q33;ql4) and an additional derivative chromosome 13. This karyotype probably resulted from 3:1 segregation during meiosis of the patient's mother.     

Trisomy 5q12→q13.3 in a patient with add(13q): Characterization of an interchromosomal insertion by forward and reverse chromosome painting

We report on a patient with azoospermia, mild mental retardation, and minor physical anomalies. Chromosome analysis demonstrated the presence of additional material on the long arm of one chromosome 13. Forward chromosome painting using chromosome-specific libraries showed an insertion of material from chromosome 5. Further characterization with flow sorting of the aberrant chromosome and amplification by DOP-PCR followed by reverse chromosome painting showed specific trisomy of 5q12→q13.3. Am. J. Med. Genet. 73:351–355, 1997. © 1997 Wiley-Liss, Inc.     

Low-level complex mosaic with multiple cell lines affecting the 18q21.31q21.32 region in a patient with de novo 18q terminal deletion

We describe a 5-year-old girl who was diagnosed at birth with 18q de novo homogeneous deletion at G-banding karyotype. Her clinical condition, characterized by hypotonia, psychomotor retardation, short stature, deafness secondary to bilateral atresia of the external auditory canals, was in agreement with the 18q deletion syndrome though presence of coloboma of a single eye only suggested a mosaic condition as an unusual sign. By combining multiple technologies including array-CGH, FISH, and WGS, we found that the terminal deletion 18q21.32q23 (21 Mb) was in segmental mosaicism of the proximal region 18q21.31q21.32 (2.7 Mb), which showed a variable number of copies: one, two, or three, in 7, 41 and 55% of the cells respectively. Breakpoint junction analysis demonstrated the presence of an inv-dup del (18q) with a disomic segment of 4.7 kb between the inverted and non-inverted copies of the duplicated region 18q21.31q21.32. From these results, we propose that all three types of abnormal chr18 (the inv-dup del and the two 18q terminal deletions of different sizes) arisen from breaks in a dicentric mirror chromosome 18q, either in more than one embryo cell or from subsequent breaking-fusion-bridge cycles. The duplication region was with identical polymorphisms as in all non-recurrent inv-dup del rearrangements though, in contrast with most of them, the 18q abnormality was of maternal origin. Taking into account that distal 18q deletions are not rarely associated with inv-dup del(18q) cell lines, and that the non-disjunction of chromosome 18 takes place especially at maternal meiosis II rather than meiosis I, multiple rescue events starting from trisomic zygotes could be considered alternative to the postmitotic ones. From the clinical point of view, our case, as well as those of del(18q) in mosaic with the dic(18q), shows that the final phenotype is the sum of the different cell lines that acted on embryonic development with signs typical of both the 18q deletion syndrome and trisomy 18. Asymmetrical malformations, such as coloboma of the iris only in the right eye, confirm the underlying mosaicism regardless of whether it is still detectable in the blood.     

Familial complex chromosome rearrangement giving rise to balanced and unbalanced recombination products

We report on a family ascertained through a 14-month-old girl with a terminal deletion of chromosome 8p23.1. Analysis of the karyotype of other relatives showed that the mother is the carrier of a balanced complex 4-break chromosome rearrangement, which she and her brother inherited from their father following recombination. This complex chromosome rearrangement (CCR) was confirmed by fluorescence in-situ hybridization (FISH) using libraries for chromosomes 1, 8, and 9, and telomeric probes for the long arm of chromosome 9. The karyotype of the maternal grandfather was 46,XY,t(1;8) (p31;q21.1),t(8;9)(p23.1;q34). The karyotype of his daughter is 46,XX,rec(8)t(1;8) (p31;q21.1)t(8;9)(p23.1;q34)pat. The karyotype of the proposita is 46,XX,rec(8)t(8;9) (p23.1;q34)mat, and that of her abnormal elder sister is 46,XX,t(1;8)(p31;q21.1)rec(8) t(8;9)(p23.1;q34)mat,der(9)t(8;9)(p23.1;q34) mat. Unbalanced segregation and/or recombination during maternal meiosis gave rise to the two abnormal sisters, one effectively with 8p trisomy and the other with monosomy for that same 8p segment. To our knowledge, this is the first case of a familial CCR giving rise to unbalanced recombination products. Am. J. Med. Genet. 79:30–34, 1998. © 1998 Wiley-Liss, Inc.     

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.     

Transmission of ring chromosome 13 from a mother to daughter with both having a 46,XX, r(13)(p13q34) karyotype

Ring chromosomes are thought to be the result of breakage in both arms of a chromosome, with fusion of the points of fracture and loss of the distal fragments. Another mechanism of ring formation is believed to be the simple fusion of chromosome ends with preservation of telomeric and subtelomeric sequences. Ring chromosome 13 was first described in 1968 and its incidence estimated at 1 in 58,000 live births. Severe phenotypes associated with large deletions of 13q have been described as "ring chromosome 13 syndrome." Features of the "ring chromosome 13 syndrome" include mental retardation (often severe), growth retardation, microcephaly, facial dysmorphism, and hand, foot or toe abnormalities. We report on a case of a mother and daughter with r(13) and mild phenotypes. Our patient, IA, had chromosome analysis performed at about 4(1/2) years of age due to some developmental delay. This revealed 46,XX, r(13)(p13q34) karyotype with no loss of any chromosomal band. Her mother, EA, was subsequently found to have the same ring 13. IA's maternal grandmother had a normal karyotype while her maternal grandfather was unavailable for testing. Fluorescence in situ hybridization (FISH) analysis showed loss of a specific subtelomeric 13q region in r(13) in the mother. Clinically, IA had macular hyperpigmentation on the chin and mild delay in speech and fine motor skills. EA, 22 years of age, had mild short stature and borderline mental retardation. To our knowledge, this is the first report of a case of familial transmission of r(13). We compare phenotypes of our cases with those from other reported cases of r(13) and discuss the possible mechanism of formation of this ring chromosome.     

Familial translocation t(Y;15)(q12;p11) and de novo deletion of the Prader-Willi syndrome (PWS) critical region on 15q11-q13

We describe a 17-year-old girl with mild Prader-Willi syndrome (PWS) due to 15q11-q13 deletion. The deletion occurred on a paternal chromosome 15 already involved in a translocation, t(Y;15)(q12;p11), the latter being present in five other, phenotypically normal individuals in three generations. This appears to be the first case of PWS in which the causative 15q11-q13 deletion occurred on a chromosome involved in a familial translocation, but with breakpoints considerably distal to those of the familial rearrangement. The translocation could predispose to additional rearrangements occurring during meiosis and/or mitosis or, alternatively, the association of two cytogenetic anomalies on the same chromosome could be fortuitous. Am. J. Med. Genet. 70: 222–228, 1997. © 1997 Wiley-Liss, Inc.     

Auto-immune disorders in a child with PIK3CD variant and 22q13 deletion

22q13 deletion syndrome is a genetic disorder caused by the deletion or disruption of the segment of the long arm of chromosome 22. The characteristic clinical features of this syndrome include delayed expressive speech, autistic behavior and hypotonia, and clinically severe complications associated with autoimmunity are rarely reported. We herein report a girl with 22q13 deletion syndrome complicated with multiple inflammatory and autoimmune diseases during early childhood. We performed whole-exome sequencing to identify the genes responsible for her autoimmune diseases and identified the de novo variant p.R512W in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta (PIK3CD) gene. We suspected it to be the disease-causing variant at the conserved residue in PIK(3)C p110δ. Alternatively, haplo-insufficiency of SHANK3 or other genes by 22q13 deletion and the PIK3CD variant might have synergistically contributed to the onset of the distinctive clinical manifestations in this patient.     

Constitutional heteromorphism of 9q13→q21 in a patient with chronic myelogenous leukemia

An apparently balanced de novo reciprocal translocation t(5;21) (q13;q22) was demonstrated in a girl with acrobrachycephaly, ventriculomegaly, pulmonary stenosis and anal malformation. The possible relationships between her karyotype and malformations are discussed.