Prader-Willi syndrome resulting from an unbalanced translocation: characterization by array comparative genomic hybridization

Prader-Willi syndrome (PWS) is caused by lack of expression of paternally inherited genes on chromosome 15q11-->15q13. Most cases result from microdeletions in proximal chromosome 15q. The remainder results from maternal uniparental disomy of chromosome 15, imprinting center defects, and rarely from balanced or unbalanced chromosome rearrangements involving chromosome 15. We report a patient with multiple congenital anomalies, including craniofacial dysmorphology, microcephaly, bilateral cryptorchidism, and developmental delay. Cytogenetic analysis showed a de novo 45,XY,der(5)t(5;15)(p15.2;q13), -15 karyotype. In effect, the proband had monosomies of 5p15.2-->pter and 15pter-->15q13. Methylation polymerase chain reaction analysis of the promoter region of the SNRPN gene showed only the maternal allele, consistent with the PWS phenotype. The proband's expanded phenotype was similar to other patients who have PWS as a result of unbalanced translocations and likely reflects the contribution of the associated monosomy. Array comparative genomic hybridization (array CGH) confirmed deletions of both distal 5p and proximal 15q and provided more accurate information as to the size of the deletions and the molecular breakpoints. This case illustrates the utility of array CGH in characterizing complex constitutional structural chromosome abnormalities at the molecular level.     

Cryptic Xp duplication including the SHOX gene in a woman with 46,X, del(X)(q21.31) and premature ovarian failure

BACKGROUND: Premature ovarian failure (POF) is defined as amenorrhoea for >6 months, occurring before the age of 40, with an FSH serum level in the menopausal range. Although Xq deletions have been known for a long time to be associated with POF, the mechanisms involved in X deletions in order to explain ovarian failure remain unknown. In order to look for potentially cryptic chromosomal imbalance, we used high-resolution genomic analysis to characterize X chromosome deletions associated with POF. METHODS: Three patients with POF presenting terminal Xq deletions detected by conventional cytogenetics were included in the study. Genome wide microarray comparative genomic hybridization (CGH) at a resolution of 1 Mb and fluorescence in situ hybridization (FISH) was performed. RESULTS: Microarray CGH and FISH studies characterized the three deletions as del(X)(q21.2), del(X)(q21.31) and del(X)(q22.33). Microarray CGH showed that the del(X)(q21.31) was also associated with a Xpter duplication including the SHOX gene. In these patients with POF, deletions or duplications of autosomes have been excluded. CONCLUSION: This study is the first one using microarray in patients with POF. It demonstrates that putative X chromosome deletions can be associated with other chromosomal imbalances such as duplications, and therefore illustrates the use of microarray CGH to screen chromosomal abnormalities in patients with POF.     

Intellectual disability and epilepsy due to the K/L‐mediated Xq28 duplication: Further evidence of a distinct,dosage‐dependent phenotype

Copy number variants of the X‐chromosome are a common cause of X‐linked intellectual disability in males. Duplication of the Xq28 band has been known for over a decade to be the cause of the Lubs X‐linked Mental Retardation Syndrome (OMIM 300620) in males and this duplication has been narrowed to a critical region containing only the genes MECP2 and IRAK1. In 2009, four families with a distal duplication of Xq28 not including MECP2 and mediated by low‐copy repeats (LCRs) designated “K” and “L” were reported with intellectual disability and epilepsy. Duplication of a second more distal region has been described as the cause of the Int22h‐1/Int22h‐2 Mediated Xq28 Duplication Syndrome, characterized by intellectual disability, psychiatric problems, and recurrent infections. We report two additional families possessing the K/L‐mediated Xq28 duplication with affected males having intellectual disability and epilepsy similar to the previously reported phenotype. To our knowledge, this is the second cohort of individuals to be reported with this duplication and therefore supports K/L‐mediated Xq28 duplications as a distinct syndrome.

     

20‐Mb duplication of chromosome 9p in a girl with minimal physical findings and normal IQ: Narrowing of the 9p duplication critical region to 6 Mb

We studied the case of a girl with a partial 9p duplication, dup(9)(p22.1 → p13.1). Molecular cytogenetics studies defined the chromosome 9 rearrangement as a direct duplication of 20 Mb from D9S1213 to D9S52. Microsatellite analysis demonstrated the presence of a double dosage of the paternal alleles and demonstrated that the duplication occurred between sister chromatids. The patient's phenotype was almost normal, with a few minor anomalies (dolichocephaly, crowded teeth, high arched palate) and normal IQ. The breakpoint's location in this patient and previously reported cases suggest that the critical region for the 9p duplication syndrome lies within a 6‐Mb portion of chromosome 9p22 between markers D9S267 and D9S1213. © 2002 Wiley‐Liss, Inc.     

Reversed clinical phenotype due to a microduplication of Sotos syndrome region detected by array CGH: microcephaly, developmental delay and delayed bone age

Haploinsufficiency of the NSD1 gene due to 5q35 microdeletions or intragenic mutations is the major cause of Sotos syndrome characterized by generalized overgrowth, large hands and feet with advanced bone age, craniofacial dysmorphic features, learning disability, and possible susceptibility to tumors. Here, we report on a 14-month-old boy with a reverse phenotype of Sotos syndrome due to the reciprocal duplication of the 5q35.3 region, including the NSD1 gene, detected by array CGH. The phenotype includes delayed bone age, microcephaly, seizures, and failure to thrive. Our case suggests that the gene dosage effect of the NSD1 gene is the likely cause for the reversed phenotype of Sotos syndrome in this patient.     

Attitudes toward prenatal genetic testing and therapeutic termination of pregnancy among parents of offspring with Prader-Willi syndrome

IntroductionPrenatal diagnosis (PND) raises ethical dilemmas such as the option of termination of pregnancy (TOP) in cases with severe outcome. Prader-Willi Syndrome (PWS), a complex neurogenetic syndrome with high morbidity and mortality throughout life. Recently, a unique prenatal phenotype was reported and TOP becomes a possibility.ObjectiveTo explore factors influencing the attitudes of parents of PWS children toward PND and TOP concerning a hypothetical pregnancy with a PWS fetus.MethodsAll 85 parents of individuals with PWS were interviewed regarding their attitudes towards PND and TOP using semi-structured questionnaire.ResultsFifty-seven parents were supportive of invasive PND and 28 of non-invasive tests only; none opposed PND. Thirty eight favored TOP, additional 31 supported TOP under certain conditions such as spiritual advice, 15 were categorically against TOP. Attitudes correlated with religiosity (p < 0.025), mother's education (p < 0.001), mother's work status (p < 0.001), current age of the child with PWS (p < 0.008). Couples had similar attitudes regarding PND and TOP. No correlation was found with gender, genetic subtype and parental age.ConclusionsMost parents of individuals with PWS support PND, however less than half support TOP. Religiosity was the most influential factor. Familial worldview should be taken into account during prenatal counseling.     

De novo tandem duplication of chromosome segment 22q11-q12: Clinical,cytogenetic, and molecular characterization

We report on a case of duplication of the segment 22q11–q12 due to a de novo duplication. Molecular cytogenetics studies demonstrated this to be a tandem duplication, flanked proximally by the marker D22Z4, a centromeric alpha satellite DNA repeat, and distally by D22S260, an anonymous DNA marker proximal to the Ewing sarcoma breakpoint. The segment includes the regions responsible for the “cat-eye,” Di George, and velo-cardio-facial syndromes and extends distal to the breakpoint cluster region (BCR). The clinical picture is dominated by the cardiac defects and includes findings reminiscent of “cat-eye” syndrome. These findings reinforce the hypothesis that the proximal 22q region contains dosagesensitive genes involved in development. © Wiley-Liss, Inc.     

A new genomic duplication syndrome complementary to the velocardiofacial (22q11 deletion) syndrome

Fluorescence in situ hybridization (FISH) analysis can reveal undetected chromosomal rearrangements. We report a patient with cleft palate, hydronephrosis, and minor dysmorphic features, including low-set posteriorly rotated ears, down-slanting palpebral fissures, mandibular micrognathia, and brachymesophalangia. Routine chromosome analysis identified no abnormality of chromosome 22; FISH analysis with the TUPLE1 probe disclosed an interstitial duplication of 22q11.2. FISH analysis did not reveal the duplication on the initial testing of metaphase chromosomes, although, on review, the area was brighter on one chromosome in each metaphase spread. FISH analysis of interphase cells showed three TUPLE1-probe sites with two chromosome-specific identification probes in each cell. Family history showed two older full siblings, a brother with behavior problems, oppositional defiant disorder, and learning problems and a sister with hydronephrosis and mild delays. The father and both siblings had similar facial features, and all three had the same interstitial duplication of the TUPLE1 probe. This family illustrates the novel complementary duplication syndrome of the velocardiofacial syndrome, which adds it to the expanding list of genomic deletion/duplication syndromes. The laboratory results further show the utility and need for careful analysis of interphase cells even in samples where good quality metaphases are available.     

Prader-Willi syndrome in two siblings: one with normal karyotype, one with a terminal deletion of distal Xq

Two sibs, a 13-year-old girl and an 11-year-old girl, with typical clinical features of the Prader-Willi syndrome (PWS) are reported. High-resolution chromosome analysis showed the normal karyotype in the elder sister, and 46,X,del(X)(pter----q26.1:) in the younger sister. But an interstitial deletion of 15q was not detected in either of the cases. PWS is most probably an etiologically heterogeneous syndrome consisting of two subgroups, with partial deletion and non-deletion of chromosome 15, respectively.     

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.     

The origin of inverted tandem duplications,and phenotypic effects of tandem duplication of the X chromosome long arm

Tandem repeats of chromosome material can arise as inverted or as direct duplications. Such duplications of the X chromosome are instructive regarding X-linked genetic determinants of phenotype. We describe a 40-year-old woman with a direct duplication Xq13.3 to Xq27.2, short stature, gonadal dysgenesis, and secondary amenorrhea. Comparison of her phenotype with that of two other women with a direct duplication of part of Xq confirms the existence of statural determinants within the region X13 to Xq21, determinants of ovarian function within X22 to X27, and the X inactivation center within or proximal to band Xq13.3. In humans, direct duplications are more frequent than inverted, but both forms are rare. The mean age of parents is normal in subjects with direct duplications, but is advanced in subjects with inverted duplications. An inverted duplication can arise from a three-break rearrangement that includes a U-type exchange; a similar origin (two breaks and a U-type exchange) and a parental age association can be postulated for dicentric inverted duplications including dicentric isochromosome X.     

Microduplication of 15q13.3 and Xq21.31 in a family with tourette syndrome and comorbidities

Tourette syndrome (TS) is a childhood onset neurodevelopmental disorder. Although it is widely accepted that genetic factors play a significant role in TS pathogenesis the etiology of this disorder is largely unknown. Identification of rare copy number variations (CNVs) as susceptibility factors in several neuropsychiatric disorders such as attention deficit‐hyperactivity disorder (ADHD), autism and schizophrenia, suggests involvement of these rare structural changes also in TS etiology. In a male patient with TS, ADHD, and OCD (obsessive compulsive disorder) we identified two microduplications (at 15q13.3 and Xq21.31) inherited from a mother with subclinical ADHD. The 15q duplication included the CHRNA7 gene; while two genes, PABPC5 and PCDH11X, were within the Xq duplication. The Xq21.31 duplication was present in three brothers with TS including the proband, but not in an unaffected brother, whereas the 15q duplication was present only in the proband and his mother. The structural variations observed in this family may contribute to the observed symptoms, but further studies are necessary to investigate the possible involvement of the described variations in the TS etiology. © 2013 Wiley Periodicals, Inc.     

Association of the X chromosomal region q11→22 and Klinefelter syndrome

A male patient with typical Klinefelter syndrome features was found to have a 47, XXq-Y chromosome complement. The X chromosome with the deletion was late-replicating. We suggest that the region q11→22 of the extra X chromosome is important for expression of the Klinefelter phenotype.     

47,XX,UPD(7)mat,+r(7)pat/46,XX,UPD(7)mat mosaicism in a girl with Silver-Russell syndrome (SRS): possible exclusion of the putative SRS gene from a 7p13-q11 region

Maternal uniparental disomy for chromosome 7 (UPD7) may present with a characteristic phenotype reminiscent of Silver-Russell syndrome (SRS). Previous studies have suggested that approximately 10% of SRS patients have maternal UPD7. We describe a girl with a mos47,XX,+mar/46,XX karyotype associated with the features of SRS. Chromosome painting using a chromosome 7 specific probe pool showed that the small marker was a ring chromosome 7 (r(7)). PCR based microsatellite marker analysis of the patient detected only one maternal allele at each of 16 telomeric loci examined on chromosome 7, but showed both paternal and maternal alleles at four centromeric loci. Considering her mosaic karyotype composed ofdiploid cells and cells with partial trisomy for 7p13-q11, the allele types obtained at the telomeric loci may reflect the transmission of one maternal allele in duplicate, that is, maternal UPD7 (complete isodisomy or homodisomy 7), whereas those at the centromeric loci were consistent with biparental contribution to the trisomic region. It is most likely that the patient originated in a 46,XX,r(7) zygote, followed by duplication of the maternally derived whole chromosome 7 in an early mitosis, and subsequent loss of the paternally derived ring chromosome 7 in a subset of somatic cells. The cell with 46,XX,r(7) did not survive thereafter because of the monosomy for most of chromosome 7. If the putative SRS gene is imprinted, it can be ruled out from the 7p11-q11 region, because biparental alleles contribute to the region in our patient.     

Diagnosis of chromosome 3 duplication q23→qter,deletion p25→pter in a patient with the C (trigonocephaly) syndrome

The cells of a deceased patient previously reported to have the C (trigonocephaly) syndrome were reinvestigated because his phenotype resembled that of a patient with a duplication-deficiency of chromosome 3. This diagnosis was confirmed using fibroblasts grown from frozen cells, and his mother was shown to carry an inversion of chromosome 3 in her peripheral blood leukocytes. His findings are compared to those of another patient with the C trigonocephaly syndrome with normal chromosomes and to others from the literature. At least one other patient from the literature has a phenotype compatible with “3q duplication syndrome”.     

West syndrome associated with mosaic duplication of FOXG1 in a patient with maternal uniparental disomy of chromosome 14

FOXG1 on chromosome 14 has recently been suggested as a dosage-sensitive gene. Duplication of this gene could cause severe epilepsy and developmental delay, including infantile spasms. Here, we report on a female patient diagnosed with maternal uniparental disomy of chromosome 14 and West syndrome who carried a small supernumerary marker chromosome. A chromosomal analysis revealed mosaicism of 47,XX, + mar[8]/46,XX[18]. Spectral karyotyping multicolor fluorescence in situ hybridization analysis confirmed that the marker chromosome was derived from chromosome 14. A DNA methylation test at MEG3 in 14q32.2 and microsatellite analysis using polymorphic markers on chromosome 14 confirmed that the patient had maternal uniparental disomy 14 as well as a mosaic small marker chromosome of paternal origin containing the proximal long arm of chromosome 14. Microarray-based comparative genomic hybridization analysis conclusively defined the region of the gain of genomic copy numbers at 14q11.2-q12, encompassing FOXG1. The results of the analyses of our patient provide further evidence that not only duplication but also a small increase in the dosage of FOXG1 could cause infantile spasms.     

Dicentric chromosome 9 due to tandem duplication of the 9p11‐q13 region: Unusual chromosome 9 variant

We report on a 31‐year‐old mentally retarded woman with minor facial anomalies and a heteromorphic chromosome 9 with tandem duplication of the 9p11‐q13 pericentromeric region. To the best of our knowledge, this is the first report of tandem duplication of this region. An identical chromosome 9 morphology was found in the healthy and phenotypically normal sister of the proposita. The usefulness of double‐color FISH techniques and the presumed mechanism accounting for the origin of the chromosomal anomaly and for the phenotypic discordance observed between the two sisters are discussed. Am. J. Med. Genet. 93:192–197, 2000. © 2000 Wiley‐Liss, Inc.