Origin of uniparental disomy 6: presentation of a new case and review on the literature

doi:10.1016/S0003-3995(01)01035-8

Annales de Génétique

Volume 44, Issue 1, January–March 2001, Pages 41-45

https://doi.org/10.1016/S0003-3995(01)01035-8 Get rights and content

Abstract

Paternal uniparental disomy (UPD) of chromosome 6 has been reported several times in patients with (transient) neonatal diabetes mellitus ((T)NDM). Here we present our short tandem repeat typing results in a new patient with NDM, revealing a paternal isodisomy (UPiD). Summarising these data with those published previously on complete paternal (n=13) and maternal (n=2) UPD6, all cases show isodisomy. In general, several modes of UPD formation have been suggested: While a meiotic origin of UPD mainly results in a uniparental heterodisomy (UPhD), UPiD is probably the result of a post-zygotic mitotic error. This mode of formation consists of a mitotic nondisjunction in a disomic zygote, followed by either a trisomic rescue or a reduplication. Endoduplication in a monosomic zygote is another possible but less probable mechanism, taking into consideration that monosomic zygotes are not viable. The exclusive finding of isodisomy in case of chromosome 6 therefore gives strong evidence that segregational errors of this chromosome are mainly influenced by postzygotic factors. This hypothesis is supported by the observation of two cases with partial paternal UPiD6 originating from mitotic recombination events. The influence of mitotic segregational errors in UPD6 formation is in agreement with the results in trisomy/UPD of other chromosomes of the C group (7 and 8), and is in remarkable contrast to the findings in studies on the origin of the frequent aneuploidies. Multiple factors ensure normal segregation and we speculate that they vary in importance for each chromosome.

Introduction

Uniparental Disomy (UPD) is the inheritance of two homologous chromosomes from one parent in an euploid offspring 〚10〛. Two types of UPD can be distinguished: uniparental heterodisomy (UPhD), e.g. both homologous chromosomes are transmitted from the same parent, and uniparental isodisomy (UPiD) with two copies of the same parental chromosome being present. Depending on their maternal or paternal origin, distinct and recurrent phenotypes are well known for some chromosomes (for review: 〚18〛, 〚19〛). These include Prader–Willi syndrome (maternal UPD15), Angelman syndrome (paternal UPD15), Beckwith–Wiedemann syndrome (paternal UPD11) and Silver–Russell syndrome (maternal UPD7). Paternal UPD6 has been described 12 times in patients with (transient) neonatal diabetes mellitus ((T)NDM)〚1〛, 〚6〛, 〚7〛, 〚8〛, 〚11〛, 〚14〛, 〚15〛, 〚21〛, 〚23〛, 〚27〛, 〚29〛 and in 3 further patients not suffering from NDM 〚4〛, 〚20〛, 〚28〛. Two of these patients showed a segmental paternal UPD6 with biparental disomy of terminal 6q 〚20〛 and 6p 〚8〛, respectively. Conversely, maternal UPD6 is not associated with a specific phenotype except intrauterine growth retardation 〚3〛, 〚26〛. The pattern of inheritance of (T)NDM and its association with UPD6 is consistent with the presence of an imprinted gene(s) on chromosome 6. Systematic screening for chromosome 6 abnormalities in (T)NDM patients allowed to delineate the region suspected of harbouring the gene(s) of interest to be 6q24; an imprinted locus associated with TNDM was identified by Gardner and coworkers 〚12〛.

Studies on the formation of UPDs allow to get insights in nondisjunction mechanisms of the respective chromosomes, since UPDs are the products of meiotic or mitotic segregation errors. Similar studies have recently been reported for UPD and trisomy of chromosomes 7 and 15 〚22〛, 〚24〛. Trisomy 6 is a relatively rare condition in spontaneous abortions with a frequency of 0.3 % 〚16〛. With the exception of hematologic disorders, non-mosaic or mosaic trisomy of the complete chromosome 6 has neither been described in stillbirths nor in livebirths. This observation may be explained by the lethality of trisomy 6.

To estimate the contribution of mitotic and meiotic nondisjunction to the formation of UPD6, we analysed an own case with paternal UPD6 as well as the cases published in the literature. We then draw conclusions with respect to trisomy 6 origin.

Section snippets

Patient

The female newborn presented with low birth weight, macroglossia and NDM. At the age of two months, the girl was still under insulin therapy. Molecular genetic studies were performed at the age of 1 month. Cytogenetic analysis showed a normal karyotype in the patient (46,XX). Maternal and paternal age at birth were 23 and 40 years, respectively.

Material and methods

DNA from the patient and her parents was extracted from peripheral blood lymphocytes by a simple salting-out procedure. Uniparental disomy of chromosome 6 was determined by short tandem repeat typing (STR) (table I). Data and PCR conditions can be obtained from Genome Database. Following electrophoresis on a denaturing sequencing gel, the alleles were visualized by silver-staining. Typing of three different markers on chromosomes other than 6 was carried out to confirm normal maternal and

Results and discussion

The results of STR analysis in our NDM patient are presented in table I. The girl showed inheritance of a single paternal allele at 6 informative loci (figure 1), STR D6S295 was not informative. Thus, the child inherited two identical copies of the same chromosome 6 from the father indicating a complete isodisomy. Complete isodisomy has been described for all the 12 paternal UPD6 patients published so far 〚1〛, 〚4〛, 〚6〛, 〚7〛, 〚11〛, 〚14〛, 〚15〛, 〚21〛, 〚23〛, 〚28〛, 〚29〛. A further TNDM patient was

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Original articleOrigin of uniparental disomy 6: presentation of a new case and review on the literature

Abstract

Introduction

Section snippets

Patient

Material and methods

Results and discussion

Hum. Immun.

J. Pediatr.

Am. J. Hum. Genet.

Ann. Génét.

Isodisomy of chromosome 6 in a newborn with methylmalonic acidemia and agenesis of pancreatic beta cells causing diabetes mellitus

J. Clin. Invest.

Mitotic errors in somatic cells cause trisomy 21 in about 4.5 % of cases and are not associated with advanced maternal age

Nat. Genet.

Fortuitous detection of uniparental isodisomy of chromosome 6

J. Med. Genet.

Non-disjunction of chromosome 18

Hum. Mol. Genet.

Refinement of the 6q chromosomal region implicated in transient neonatal diabetes

Diabetes

Trisomy of human chromosome 18: molecular studies on parental origin and cell stage of nondisjunction

Hum. Genet.

A new genetic concept: uniparental disomy and its potential effect, isodisomy

Am. J. Med. Genet.

Paternal uniparental disomy of chromosome 6 and transient neonatal diabetes mellitus

Clin. Genet.

An imprinted locus associated with transient neonatal diabetes mellitus

Hum. Mol. Genet.

The 1993–94 Généthon human genetic linkage map

Nat. Genet.

Paternal uniparental isodisomy of chromosome 6 in transient neonatal diabetes mellitus

Eur. J. Pediatr.

Original article
Origin of uniparental disomy 6: presentation of a new case and review on the literature