Paternal Uniparental Disomy Of Chromosome Research Articles

Paternal uniparental disomy for chromosome 14: a case report and review.

Uniparental disomy (UPD) for several chromosomes has been associated with disease phenotypes. Maternal UPD for chromosome 14 has been described and has a characteristic abnormal phenotype. Paternal UPD14 is rare and only three previous cases have been reported. We describe a new case of paternal UPD for chromosome 14 in an infant with a 45,XX,der(13q;14q) karyotype, which was confirmed by molecular analysis. The proposita had findings similar to those of the previous cases of patUPD14 and we conclude that there is a characteristic patUPD14 syndrome most likely due to imprinting effects. Couples with Robertsonian translocations involving chromosome 14 should be counseled as to the possibility of UPD14 and the option of prenatal diagnosis when indicated.

Paternal uniparental disomy for chromosome 6 causes transient neonatal diabetes.

We report an infant with intrauterine growth retardation and transient neonatal diabetes who has paternal uniparental disomy for chromosome 6. The infant was not dysmorphic and had no congenital anomalies....

Cortical myoclonus in angelman syndrome

Angelman syndrome (AS) results from lack of genetic contribution from maternal chromosome 15q11-13. This region encompasses three GABAA receptor subunit genes (beta3, alpha5, and gamma3). The characteristic phenotype of AS is severe mental retardation, ataxic gait, tremulousness, and jerky movements. We studied the movement disorder in 11 AS patients, aged 3 to 28 years. Two patients had paternal uniparental disomy for chromosome 15, 8 had a >3 Mb deletion, and 1 had a microdeletion involving loci D15S10, D15S113, and GABRB3. All patients exhibited quasicontinuous rhythmic myoclonus mainly involving hands and face, accompanied by rhythmic 5- to 10-Hz electroencephalographic (EEG) activity. Electromyographic bursts lasted 35 +/- 13 msec and had a frequency of 11 +/- 2.4 Hz. Burst-locked EEG averaging in 5 patients, generated a premyoclonus transient preceding the burst by 19 +/- 5 msec. A cortical spread pattern of myoclonic cortical activity was observed. Seven patients also demonstrated myoclonic seizures. No giant somatosensory evoked potentials or C-reflex were observed. The silent period following motor evoked potentials was shortened by 70%, indicating motor cortex hyperexcitability. Treatment with piracetam in 5 patients significantly improved myoclonus. We conclude that spontaneous, rhythmic, fast-bursting cortical myoclonus is a prominent feature of AS.

Parental Imprinting on Mouse Chromosome 7

Genetic studies have shown that both a maternally and paternally inherited copy of mouse chromosome 7 are essential for normal embryogenesis. When the parental dosage is altered, such as in maternal or paternal uniparental disomy for chromosome 7 (UPD7), the resulting embryos die. This is due to the altered dosage of imprinted genes which are normally expressed only from the paternally or maternally inherited chromosome homologue. Several genes on mouse chromosome 7 are subject to parental imprinting. Mutant phenotypes seen in UPD7 embryos and chimaeras can be explained by the altered dosage of some of these genes.The mechanism(s) that causes genes to be expressed in a parental origin specific manner has not yet been determined but is believed to involve germline specific modifications to DNA and/or chromatin which are acted upon after fertilisation to affect the activity of imprinted genes. Two genes, H19 and Igf2, are located 90kb apart on the distal end of chromosome 7 and are imprinted reciprocally with the maternally inherited allele of HI9 and paternally inherited allele of Igf2 being expressed. We have used UPD7 embryos to identify epigenetic modifications that distinguish the two parental alleles in the H19 and Igf2 domain by comparing DNA and chromatin from normal and maternal UPD cobceptuses. Clear cut differences in DNA methylation and chromatin compaction were observed for the H19 gene with the paternal allele exhibiting promoter methylation and nuclease insensitivity. These were not found in sperm. In addition, no major differences were noted for the Igf2 gene, although subtle parental origin specific modifications were found. These studies suggest that the two genes may share a common regulatory mechanism which controls their reciprocal imprinting.

Angelman syndrome due to paternal uniparental disomy of chromosome 15: A milder phenotype?

The Angelman syndrome (AS) is a neurological disorder characterized by severe mental retardation, absent speech, seizures, gait disturbances, and a typical age-dependent facial phenotype. Most cases are due to an interstitial deletion on the maternally inherited chromosome 15, in the critical region q11-q13. Rare cases also result from paternal uniparental disomy of chromosome 15. In a group of 14 patients with sporadic AS diagnosed in Switzerland, we found 2 unrelated females with paternal isodisomy for the entire chromosome 15. Their phenotypes were milder than usually seen in this syndrome: one girl did not show the typical AS facial changes; both patients had late-onset mild seizures; as they grew older, they had largely undisturbed gross motor functions, in particular no severe ataxia. Both girls were born to older fathers (45 and 43 years old, respectively). The apparent association of a relatively milder phenotype in AS with paternal uniparental disomy will have to be confirmed by detailed clinical descriptions of further patients.

Novel patterns of inheritance of genetic disease are illustrated by the Angelman syndrome.

To characterise the molecular abnormalities present in a cohort of patients with the Angelman syndrome. DNA samples from 10 patients with the Angelman syndrome were investigated with molecular probes. Family studies were performed by means of DNA polymorphism analysis and densitometric estimation of allele copy number to determine the underlying mutation and its parental origin. Nine probands were shown to have molecular (DNA) deletions involving chromosome 15q11-q13. Polymorphism analyses demonstrated that all deletions were maternal in origin. Five of the nine had normal karyotypes, with deletions only detected after DNA study. One patient had inherited both chromosomes 15 from her father. This represented an example of paternal uniparental disomy of chromosome 15. Development of the Angelman syndrome can result from either deletion of the maternally-derived copy of chromosome 15q11-q13 or the presence of two paternally derived copies of chromosome 15, that is, uniparental disomy. DNA testing allows the identification of deletions that are not seen on cytogenetic analysis and can provide additional information regarding the parental origin of the deletion. Uniparental disomy is most readily established by DNA studies.

Paternal uniparental disomy in a child with a balanced 15;15 translocation and Angelman syndrome

Chromosome 15 (15q11-q13) abnormalities cause two distinct conditions, Angelman syndrome (AS) and Prader-Willi syndrome (PWS). We present the first case of a child with a balanced 15;15 translocation and AS in whom molecular studies were crucial in confirming a diagnosis. DNA polymorphisms demonstrated paternal uniparental disomy for chromosome 15, consistent with the diagnosis of AS. The molecular studies also showed the patient to be homozygous at all loci for which the father was heterozygous, suggesting that the structural rearrangement was an isochromosome 15q and not a Robertsonian translocation.