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PubMed2001

Maternal uniparental heterodisomy for chromosome 2: detection through 'atypical' maternal AFP/hCG levels, with an update on a previous case.

We report a case of maternal uniparental disomy 2, detected through routine screening of placental karyotypes following the finding of 'atypical' AFP/hCG levels in the second trimester, with intrauterine growth retardation (IUGR) but otherwise normal outcome at term. Although the child remained small, subsequent early physical and mental development has also been normal. Additionally, we report long-term follow-up of an earlier case, again with relatively normal physical and mental development. The significance of atypical AFP/hCG results and the predictive value of prenatal testing for UPD2 in trisomy 2 confined placental mosaicism (CPM) cases are discussed.

Adult↗
PubMed2005

Maladaptive behaviors and risk factors among the genetic subtypes of Prader-Willi syndrome.

Maladaptive behaviors among 65 people with Prader-Willi syndrome were assessed using the Reiss Screen for maladaptive behaviors. Young adults in their twenties were more likely to display aggressive behavior than adolescents and older adults. Differences in maladaptive behaviors between the typical deletion and uniparental disomy (UPD) subtypes were evaluated. The typical deletion subtype had higher self-injury and stealing scores than the UPD subtype. Subject characteristics were differentially related to maladaptive behavior among the typical deletion and UPD subtypes. Differences in maladaptive behavior were also examined between the typical deletion type I and type II subtypes. The type I deletion subtype had greater physical depression scores than the type II deletion subtype. The Reiss Screen cut-off scores were used to determine whether differences occurred between the subtypes at a clinically significant level. These findings offer insight into the health care needs of people with PWS.

Adaptation, Psychological↗
PubMed2004

Congenital afibrinogenaemia caused by uniparental isodisomy of chromosome 4 containing a novel 15-kb deletion involving fibrinogen Aalpha-chain gene.

Among rare inherited deficiencies of coagulation factors, congenital afibrinogenaemia is characterised by the lack of fibrinogen in plasma. In the last few years, several genetic defects underlying afibrinogenaemia (mostly point mutations) have been described in the fibrinogen gene cluster. In this study, the molecular basis responsible for afibrinogenaemia in a Thai proband was defined. Point mutation screening was accomplished by directly sequencing the three fibrinogen genes. The impossibility to amplify fibrinogen Aalpha-chain gene (FGA) exons 5 and 6 suggested the presence of a homozygous deletion. A specific long-range PCR assay enabled the identification of a novel 15-kb deletion, representing the largest afibrinogenaemia-causing deletion described so far. Direct sequencing of the deletion junction allowed mapping of the breakpoints in FGA intron 4 and in the intergenic region between Aalpha- and Bbeta-chain genes. Since the mutation was inherited only from the mother and nonpaternity was ruled out, a maternal uniparental disomy (UPD) was hypothesised. UPD test, carried out with markers covering the whole chromosome 4, revealed that maternal isodisomy was responsible for homozygosity of the 15-kb deletion in the proband. The apparently normal phenotype of the proband, except for afibrinogenaemia, suggests that UPD for chromosome 4 is clinically silent. This represents the first case of a documented complete isodisomy of chromosome 4 causing the phenotypic expression of a recessive disorder. In silico analyses of the regions surrounding the breakpoints suggested that the 15-kb deletion might have originated from an inappropriate repair of a double-strand break by the nonhomologous end joining mechanism.

Afibrinogenemia↗
PubMed2006

CD36 expression and its relationship with obesity in blood cells from people with and without Prader-Willi syndrome.

Although Prader-Willi syndrome (PWS) has been linked to the loss of function of imprinted genes in 15q11q13, very little is known about the pathogenesis. Using quantitative real-time PCR, we have confirmed the previous observation of an abnormality of CD36 expression in cells with maternal uniparental disomy 15, obtained from a proband with mosaicism for PWS, by demonstrating reduced expression levels in blood cells from a series of non-mosaic probands with PWS. Furthermore, we have extended these observations to show that CD36 expression in a non-PWS population is inversely correlated with body mass index but that this correlation does not hold in PWS. CD36 which maps to 7q11.2 is the first gene outside the 15q11q13 region whose level of expression appears to be reduced in people with PWS. Low CD36 expression levels in PWS point to an abnormal control of lipid and glucose homeostasis which may explain the insatiable hunger in these patients.

Adult↗
PubMed2004

QF-PCR-based prenatal detection of aneuploidy in a southeast Asian population.

OBJECTIVES: We have investigated the efficacy of using quantitative fluorescent polymerase chain reaction (QF-PCR) for the prenatal recognition of aneuploidy in chromosomes 13, 18, 21, X and Y. A total of 1115 samples, from mainly southeast Asian patients, were analysed and compared in a blind trial to the results previously obtained cytogenetically. METHODS: A multiplex PCR involving 15 short tandem repeat (STR) sequences was used. The probability of two or more of these markers being informative was calculated, and this required the multiplex PCR to be modified. RESULTS: The QF-PCR and previous cytogenetic results concurred, except for two products of conception (POC). One of these may be a case of complete uniparental disomy that was not recognized cytogenetically. The other was tetraploid, and as such appeared normal using QF-PCR. A mosaic trisomy 18 was correctly identified. The population sample was of a mainly Chinese, ethnic origin, and the allele frequency, size and heterozygosity appeared more restricted than the population groups analysed hitherto. CONCLUSION: The QF-PCR methodology is an efficient cost-effective method of screening for major chromosome aneuploidy, and, for certain referral categories, could be used alone. It also appears to be applicable to patients of different ethnic origins.

Alleles↗
PubMed2001

Identification of a small supernumerary marker chromosome, r(2)(p10q11.2), and the problem of determining prognosis.

The identification of small supernumerary marker chromosomes (SMCs) and the elucidation of their clinical significance remain two of the problems in classical human cytogenetics. We observed a small supernumerary ring in amniotic fluid cell cultures and identified its origin as r(2)(p10q11.2) and its extent by means of fluorescent in situ hybridisation (FISH). Uniparental disomy (UPD) was excluded by microsatellite analysis using polymorphic markers localised in the same region. On the basis of normal ultrasonographic checks, the patient decided to continue the pregnancy. A normal female was delivered at term and subsequent neonatal follow-ups confirmed the normal phenotype and development. In the present case, genetic counselling was not helpful because of the absence of reference cases. Detailed characterisation made it possible to correlate the normal baby phenotype with the trisomic 2p10-2q11.2 genomic region. Further molecular cytogenetic investigations of SMCs classified by DNA content and pregnancy outcome data should improve genetic counselling and risk evaluation.

Adult↗
PubMed2026

Prader-Willi syndrome as a neurogenetic model for psychosis and obsessive-compulsive disorder: A review of clinical, behavioral, and biological insights.

Prader-Willi syndrome (PWS) is a complex neurodevelopmental disorder classically defined by hyperphagia and obesity. However, its profound psychiatric phenotype offers a unique genetic framework for understanding major mental illnesses. This review positions PWS as a potentially informative biological model for psychosis and obsessive-compulsive disorder (OCD), bridging the gap between 15q11-q13 imprinting defects and neural circuit dysfunction. We synthesize evidence demonstrating that psychosis in PWS is not a uniform trait but is disproportionately linked to the maternal uniparental disomy (mUPD) subtype. This genotype-phenotype correlation suggests that overexpression of maternally imprinted genes and loss of paternal expression disrupt cortical excitatory-inhibitory balance, resembling the "schizophrenia-bipolar" genomic architecture. Furthermore, synthesized evidence characterizes the repetitive, ritualistic behaviors in PWS not merely as behavioral challenges, but as a developmentally arrested OCD-spectrum phenotype driven by distinct serotonergic-oxytocinergic imbalances and hypothalamic-limbic dysconnectivity. Mechanistic insights from preclinical models of MAGEL2, SNORD116, and NDN deficiency are integrated with clinical findings to highlight shared neurobiological substrates. Finally, we outline a roadmap for precision psychiatry in PWS, emphasizing the necessity of pharmacogenomics in antipsychotic management and the potential of targeted circuit-based therapeutics. By deconstructing the psychiatric comorbidities of PWS, we provide a framework for translating genomic architecture into mechanistic understanding and targeted treatment for complex neuropsychiatric disorders.

15q11-q13↗
PubMed2001

Silver-Russell syndrome: a dissection of the genetic aetiology and candidate chromosomal regions.

The main features of Silver-Russell syndrome (SRS) are pre- and postnatal growth restriction and a characteristic small, triangular face. SRS is also accompanied by other dysmorphic features including fifth finger clinodactyly and skeletal asymmetry. The disorder is clinically and genetically heterogeneous, and various modes of inheritance and abnormalities involving chromosomes 7, 8, 15, 17, and 18 have been associated with SRS and SRS-like cases. However, only chromosomes 7 and 17 have been consistently implicated in patients with a strict clinical diagnosis of SRS. Two cases of balanced translocations with breakpoints in 17q23.3-q25 and two cases with a hemizygous deletion of the chorionic somatomammatropin gene (CSH1) on 17q24.1 have been associated with SRS, strongly implicating this region. Maternal uniparental disomy for chromosome 7 (mUPD(7)) occurs in up to 10% of SRS patients, with disruption of genomic imprinting underlying the disease status in these cases. Recently, two SRS patients with a maternal duplication of 7p11.2-p13, and a single proband with segmental mUPD for the region 7q31-qter, were described. These key patients define two separate candidate regions for SRS on both the p and q arms of chromosome 7. Both the 7p11.2-p13 and 7q31-qter regions are subject to genomic imprinting and the homologous regions in the mouse are associated with imprinted growth phenotypes. This review provides an overview of the genetics of SRS, and focuses on the newly defined candidate regions on chromosome 7. The analyses of imprinted candidate genes within 7p11.2-p13 and 7q31-qter, and gene candidates on distal 17q, are discussed.

Abnormalities, Multiple↗
PubMed2004

Sleep disturbances in Angelman syndrome: a questionnaire study.

Only few studies are available on sleep disorders in Angelman syndrome (AS), a neurodevelopmental disorder with several behavior disturbances. The aim of this study was to determine the prevalence of sleep disorders in a relatively large group of AS subjects, compared to that of age-matched controls. Forty-nine consecutive parents of patients with AS (26 males and 23 females aged 2.3-26.2 years) were interviewed and filled out a comprehensive sleep questionnaire. Based on their genetic etiology, four groups were defined: deletion of chromosome 15q11-13 (25 subjects); methylation imprinting mutation (six subjects), UBE3A mutations (seven subjects) and paternal uniparental disomy (five subjects). In the remaining cases genetic testings were negative. A significantly high frequency of disorders of initiating and maintaining sleep, prolonged sleep latency, prolonged wakefulness after sleep onset, high number of night awakenings and reduced total sleep time were found in our AS patients, as compared to age-matched controls. We also found other types of sleep disorders, never reported before, such as enuresis, bruxism, sleep terrors, somnambulism, nocturnal hyperkinesia, and snoring. No differences were found between the four genetic aetiology groups. Moreover, we did not find important improvement of sleep disturbances from pre-pubertal to post-pubertal ages. Our data confirm the significant presence of sleep/wake rhythms fragmentation, peculiar of AS, and also demonstrate the presence of several other types of sleep disturbances in this syndrome.

Adolescent↗
PubMed2004

Polar overdominant inheritance of a DLK1 polymorphism is associated with growth and fatness in pigs.

The polar overdominance model of inheritance was proposed to explain the non-Mendelian expression of callipyge muscular hypertrophy in sheep. The callipyge locus (CLPG) maps to the distal portion of ovine Chromosome 18 within the DLK1- GTL2 region and corresponds to human Chromosome 14q32, where uniparental disomy (UPD) of the region is associated with multiple congenital anomalies, including growth retardation and obesity. We investigated the porcine DLK1- GTL2 region in a cross of two pig breeds to determine if the callipyge polar overdominance is present in another species. Analyses of the parental origin of DLK1 polymorphism in the F2 offspring found that paternal inheritance of DLK1 allele 2 and maternal inheritance of the allele 1 was significantly associated with decreased fat deposition and increased lean muscle mass, while the opposite parental inheritance of these alleles was associated with slower prenatal and postnatal growth. These results suggest that the polar overdominance mode of inheritance is present in the pig chromosomal region that is homologous to the CLPG locus in sheep. Further study in pigs can provide important insights into understanding the molecular regulation of imprinted genes that are associated with human UPD14 and sheep callipyge phenotypes.

Alleles↗
PubMed2005

Effectiveness of multiplex ligation-dependent probe amplification assay used for detecting deletion of Prader-Willi syndrome.

OBJECTIVE: Prader-Willi syndrome (PWS) is characterized by severe hypotonia and feeding difficulties in early infancy, followed by excessive eating and gradual development of morbid obesity in later infancy or early childhood. Patients with PWS are often too young to manifest sufficient features or have atypical findings, making genetic testing important to confirm the diagnosis of PWS. Approximately 99% of patients with PWS have a diagnostic abnormality in the parent-specific methylation imprint within the Prader-Willi critical region (PWCR) at chromosome 15q11.2-q12. Of them, 70% have a paternal deletion; 25% have a maternal uniparental disomy (UPD); and <5% have a mutation in the imprinting center. METHODS: Current techniques can identify a diagnostic abnormality, such as paternal deletion or maternal UPD for most of patients with PWS, but they are labor-intensive and cost-expensive. Multiplex ligation-dependent probe amplification (MLPA) is a novel, simple, and cost-effective technique for analysis of relative quantification in a single assay, which has recently been applied for the detection of genomic deletions, duplications, and amplifications in a variety of genes. RESULTS: Six out of 20 patients referred for genetic diagnosis of PWS were found to have a deletion by MLPA, confirmed by FISH and DNA methylation analysis with 100% concordance. CONCLUSION: MLPA's high sensitivity and specificity for deletion detection is the same as FISH or Southern blot based analysis. Additional collaborative effort for developing and validating the complete MLPA-PWS assay, for not only detecting deletion but also identifying methylation abnormality, is on going.

Child↗
PubMed2002

Maternal isodisomy for 14q21-q24 in a man with diabetes mellitus.

We report a 20-year-old man with maternal uniparental disomy for chromosome 14 (UPD14) and maturity-onset diabetes mellitus (DM). He had pre- and postnatal growth retardation, developed DM at age 20 years without any autoimmune antibodies, and had a mosaic 45,XY,der(14;14)(q10;q10)[129]/46,XY,+14,der(14;14)(q10;q10)[1] karyotype. Allelotyping using microsatellite markers covering the entire 14q indicated segmental maternal isodisomy for 14q21-q24 and maternal heterodisomy of the remaining regions of the chromosome. It is thus tempting to speculate that the segmental isodisomy led to reduction to homozygosity for a mutant gene and thus caused his DM, although the possibility of coincidental occurrence of the two events cannot totally be ruled out. Fluorescence in situ hybridization (FISH) analysis using BAC clone probes revealed that the isodisomic segment did not overlap any known IDDM or NIDDM susceptibility loci on chromosome 14, suggesting a novel locus for a subset of DM at the isodisomic segment.

Adult↗
PubMed2004

Severe hemihypotrophy in a female infant with mosaic Turner syndrome: a variant of Russell-Silver syndrome?

Russell-Silver syndrome is a genetically heterogeneous condition. For most affected individuals, it represents a phenotype rather than a specific disorder. Although chromosomal anomalies, imprinting disorder, maternal uniparental disomy 7 as well as familial autosomal dominant and X-linked forms have been reported, the diagnosis remains determined on clinical grounds. Russell-Silver syndrome is characterized by asymmetric intrauterine growth retardation, postnatal failure to thrive, distinct facial features, limb asymmetry, excessive sweating and minor skin lesions. We report here a female infant who had a karyotype of 45,X on prenatal amniocytes. After delivery she was noted to have features not explainable on the basis of Turner syndrome. Her phenotype actually was quite consistent with Russell-Silver syndrome. She had a triangular face with prominent forehead, large eyes, a thin nose, malar hypoplasia, thin upper lip with down-turned corner of the mouth and a pointed chin. Marked body asymmetry was evident at birth, with the left side significantly smaller than the right side. She has a diphalangeal left fifth finger. Skin fibroblast culture and analysis showed a karyotype of 45,X on the right side and 45,X/46,XX on the left side. The case is another illustration of the genetic heterogeneity of Russell-Silver phenotype.

Female↗
PubMed2007

The course and outcome of psychiatric illness in people with Prader-Willi syndrome: implications for management and treatment.

BACKGROUND: This study is part of a larger UK-wide study investigating psychiatric illness in people with Prader-Willi syndrome (PWS), and describes the longitudinal aspect of psychiatric illness, in particular psychotic illness, and examines the use and role of psychotropic medication. METHOD: A total of 119 individuals with genetically confirmed PWS were included in the study. An informant-based questionnaire was administered for each participant to screen for a history of psychopathology. Those who screened positive were visited at their homes to obtain further information. This assessment included a full psychiatric history and mental state examination using the Psychiatric Assessment Schedule for Adults with Developmental Disability and the Operational Criteria Checklist for psychotic and affective illness to collect information regarding phenomenology and course of illness, and a modified life events questionnaire. At the end of the study period, informant-based telephone interviews were again carried out, up to 2.5 years after the initial screening. Information regarding medication usage was collected. RESULTS: The results confirm previous findings that psychiatric illness in people with PWS resembles an affective disorder. Individuals with the maternal uniparental disomy genetic subtype had a more severe course of illness than those with the deletion genetic subtype in terms of a greater risk of recurrence, more episodes, higher incidence and a possibly poorer response to medication with more side-effects. Individuals with a recurrent episode during the follow-up period had a poorer course of illness. Selective serotonin reuptake inhibitor medication is frequently used, and beneficial effects may reflect fundamental pathological processes in PWS. Mood-stabilizing medication was found to be of little benefit and reasons for this are examined. CONCLUSION: The longitudinal course of psychiatric illness and response to medication in people with PWS is fully described. Further research is needed regarding the effect of psychotropic medications, particularly mood-stabilizing medication. These data will enable informed decisions to be made regarding management options and provide information on the possible long-term outcome of illness.

Adolescent↗
PubMed2004

Maternal UPD(14) in the patient with a normal karyotype: clinical report and a systematic search for cases in samples sent for testing for Prader-Willi syndrome.

Maternal uniparental disomy for chromosome 14 causes a recognizable phenotype that has a number of consistent features, irrespective of the underlying chromosome abnormality. To illustrate this, we describe a patient with a 46,XX karyotype whose short stature, hypotonia, feeding problems, truncal obesity, early puberty, learning difficulties, and craniofacial characteristics led to a diagnosis of maternal (mat) UPD(14). No evidence is available to indicate how common mat UPD(14) in patients with a normal karyotype might be. Because of the similarity between Prader-Willi syndrome (PWS) and the mat UPD(14) phenotype in childhood, we systematically tested samples from 35 patients with normal karyotypes and an unexplained PWS-like phenotype referred to the Wessex Genetics Service. We sought to address the practical question should laboratories carry out tests for mat UPD(14) on all samples received for PWS testing when PWS testing gives negative results? None of the samples tested showed evidence of mat UPD(14). Routine screening of DNA from patients with possible PWS cannot be recommended on this basis.

Adolescent↗
PubMed2006

Integration of global SNP-based mapping and expression arrays reveals key regions, mechanisms, and genes important in the pathogenesis of multiple myeloma.

Multiple myeloma is characterized by genomic alterations frequently involving gains and losses of chromosomes. Single nucleotide polymorphism (SNP)-based mapping arrays allow the identification of copy number changes at the sub-megabase level and the identification of loss of heterozygosity (LOH) due to monosomy and uniparental disomy (UPD). We have found that SNP-based mapping array data and fluorescence in situ hybridization (FISH) copy number data correlated well, making the technique robust as a tool to investigate myeloma genomics. The most frequently identified alterations are located at 1p, 1q, 6q, 8p, 13, and 16q. LOH is found in these large regions and also in smaller regions throughout the genome with a median size of 1 Mb. We have identified that UPD is prevalent in myeloma and occurs through a number of mechanisms including mitotic nondisjunction and mitotic recombination. For the first time in myeloma, integration of mapping and expression data has allowed us to reduce the complexity of standard gene expression data and identify candidate genes important in both the transition from normal to monoclonal gammopathy of unknown significance (MGUS) to myeloma and in different subgroups within myeloma. We have documented these genes, providing a focus for further studies to identify and characterize those that are key in the pathogenesis of myeloma.

Bone Marrow↗
PubMed2001

Low incidence of UPD in spontaneous abortions beyond the 5th gestational week.

Approximately 15-20% of all clinically recognised pregnancies abort, most commonly between 8-12 gestational weeks. While the majority of early pregnancy losses is attributed to cytogenetic abnormalities, the aetiology of approximately 40% of early abortions remains unclear. To determine additional factors causing spontaneous abortions we retrospectively searched for uniparental disomies (UPD) in 77 cytogenetically normal diploid spontaneous abortions. In all cases an unbalanced chromosome anomaly was ruled out by cytogenetic investigation of chorionic/amniotic membranes and/or chorionic villi. For UPD screening microsatellite analyses were performed on DNA of abortion specimens and parental blood using highly polymorphic markers showing UPD in two cases. The distribution of markers analysed indicated maternal heterodisomy for chromosome 9 (UPhD(9)mat) in case 1 and paternal isodisomy for chromosome 21 (UPiD(21)pat) in case 2. The originating mechanism suggested was monosomy complementation in UPiD(21)pat and trisomy rescue in UPhD(9)mat. In the case of UPhD(9)mat purulent chorioamnionitis was noted and a distinctly growth retarded embryo of 3 cm crown-rump length showing no gross external malformations. Histological analysis in the case of UPiD(21)pat suggested a primary anlage defect. Our results indicate that less than 3% of genetically unexplained pregnancy wastage is associated with total chromosome UPD. UPD may contribute to anlage defects of human conception. Chromosome aneuploidy correction can occur in very early cleavage stages. More research, however, ought to be performed into placental mosaicism to further clarify timing and mechanisms involved in foetal UPD.

Abortion, Spontaneous↗
PubMed2002

Mice lacking paternally expressed Pref-1/Dlk1 display growth retardation and accelerated adiposity.

Preadipocyte factor 1 (Pref-1/Dlk1) inhibits in vitro adipocyte differentiation and has been recently reported to be a paternally expressed imprinted gene at human chromosome 14q32. Studies on human chromosome 14 deletions and maternal uniparental disomy (mUPD) 14 suggest that misexpression of a yet-to-be-identified imprinted gene or genes present on chromosome 14 causes congenital disorders. We generated Pref-1 knockout mice to assess the role of Pref-1 in growth and in vivo adipogenesis and to determine the contribution of Pref-1 in mUPD. Pref-1-null mice display growth retardation, obesity, blepharophimosis, skeletal malformation, and increased serum lipid metabolites. Furthermore, the phenotypes observed in Pref-1-null mice are present in heterozygotes that harbor a paternally inherited, but not in those with a maternally inherited pref-1-null allele. Our results demonstrate that Pref-1 is indeed paternally expressed and is important for normal development and for homeostasis of adipose tissue mass. We also suggest that Pref-1 is responsible for most of the symptoms observed in mouse mUPD12 and human mUPD14. Pref-1-null mice may be a model for obesity and other pathologies of human mUPD14.

Abnormalities, Multiple↗