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Cytogenetic and molecular characterization of a recombinant X chromosome in a family with a severe neurologic phenotype and macular degeneration.

Magini P, Poscente M, Ferrari S, Vargiolu M, Bacchelli E, Graziano C, Wischmeijer A, Turchetti D, Malaspina E, Marchiani V, Cordelli DM, Franzoni E, Romeo G, Seri M - Mol Cytogenet (2015)

Bottom Line: Our report describes the identification of the actual genetic cause underlying a severe syndrome that previous preliminary analyses erroneously associated to a terminal Xp22.33 region.In the present family as well as in previously reported patients with similar rearrangements, the observed neurologic phenotype is ascribable to MECP2 duplication, with an undefined contribution of the other involved genes.Maculopathy, presented by affected males reported here, could be a novel clinical feature associated to Xq28 disomy due to recombinant X chromosomes, but at present the underlying pathogenetic mechanism is unknown and this potential clinical correlation should be confirmed through the collection of additional patients.

View Article: PubMed Central - PubMed

Affiliation: U.O. Genetica Medica, Policlinico Sant'Orsola-Malpighi, DIMEC, Università di Bologna, via Massarenti, 9, Bologna, 40138 Italy.

ABSTRACT

Background: Duplications of MECP2 gene in males cause a syndrome characterized by distinctive clinical features, including severe to profound mental retardation, infantile hypotonia, mild dysmorphic features, poor speech development, autistic features, seizures, progressive spasticity and recurrent infections. Patients with complex chromosome rearrangements, leading to Xq28 duplication, share most of the clinical features of individuals with tandem duplications, in particular neurologic problems, suggesting a major pathogenetic role of MECP2 overexpression.

Results: We performed cytogenetic and molecular cytogenetic studies in a previously described family with affected males showing congenital ataxia, late-onset progressive myoclonic encephalopathy and selective macular degeneration. Microsatellite, FISH and array-CGH analyses identified a recombinant X chromosome with a deletion of the PAR1 region, encompassing SHOX, replaced by a duplicated segment of the Xq28 terminal portion, including MECP2.

Conclusions: Our report describes the identification of the actual genetic cause underlying a severe syndrome that previous preliminary analyses erroneously associated to a terminal Xp22.33 region. In the present family as well as in previously reported patients with similar rearrangements, the observed neurologic phenotype is ascribable to MECP2 duplication, with an undefined contribution of the other involved genes. Maculopathy, presented by affected males reported here, could be a novel clinical feature associated to Xq28 disomy due to recombinant X chromosomes, but at present the underlying pathogenetic mechanism is unknown and this potential clinical correlation should be confirmed through the collection of additional patients.

No MeSH data available.


Related in: MedlinePlus

Xq28 duplication identified by array-CGH analysis. The duplicated region is circled on the X chromosome ideogram and the RefSeq genes involved are reported under the array-CGH profile
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Fig3: Xq28 duplication identified by array-CGH analysis. The duplicated region is circled on the X chromosome ideogram and the RefSeq genes involved are reported under the array-CGH profile

Mentions: FISH analysis with XpYp subtelomere specific probes confirmed the microdeletion in the tip of chromosome X short arm (Fig. 2a) in all studied samples (III1, III3, III7, III10, IV2 and IV15). As the loss of PAR1 did not explain the neurologic phenotype observed in males, the DNA of carrier female IV2 was analysed by array-CGH to evaluate the presence of additional cryptic imbalances involving different genomic regions. Since both PAR regions were not covered by oligonucleotides in the microarray platform used, we were not able to see the deletion in Xp, but a terminal duplication in Xq28 was detected, encompassing nearly 3.3 Mb (chrX:151,532,990–154,841,455) and 130 genes, including MECP2 (Fig. 3).Fig. 2


Cytogenetic and molecular characterization of a recombinant X chromosome in a family with a severe neurologic phenotype and macular degeneration.

Magini P, Poscente M, Ferrari S, Vargiolu M, Bacchelli E, Graziano C, Wischmeijer A, Turchetti D, Malaspina E, Marchiani V, Cordelli DM, Franzoni E, Romeo G, Seri M - Mol Cytogenet (2015)

Xq28 duplication identified by array-CGH analysis. The duplicated region is circled on the X chromosome ideogram and the RefSeq genes involved are reported under the array-CGH profile
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4522089&req=5

Fig3: Xq28 duplication identified by array-CGH analysis. The duplicated region is circled on the X chromosome ideogram and the RefSeq genes involved are reported under the array-CGH profile
Mentions: FISH analysis with XpYp subtelomere specific probes confirmed the microdeletion in the tip of chromosome X short arm (Fig. 2a) in all studied samples (III1, III3, III7, III10, IV2 and IV15). As the loss of PAR1 did not explain the neurologic phenotype observed in males, the DNA of carrier female IV2 was analysed by array-CGH to evaluate the presence of additional cryptic imbalances involving different genomic regions. Since both PAR regions were not covered by oligonucleotides in the microarray platform used, we were not able to see the deletion in Xp, but a terminal duplication in Xq28 was detected, encompassing nearly 3.3 Mb (chrX:151,532,990–154,841,455) and 130 genes, including MECP2 (Fig. 3).Fig. 2

Bottom Line: Our report describes the identification of the actual genetic cause underlying a severe syndrome that previous preliminary analyses erroneously associated to a terminal Xp22.33 region.In the present family as well as in previously reported patients with similar rearrangements, the observed neurologic phenotype is ascribable to MECP2 duplication, with an undefined contribution of the other involved genes.Maculopathy, presented by affected males reported here, could be a novel clinical feature associated to Xq28 disomy due to recombinant X chromosomes, but at present the underlying pathogenetic mechanism is unknown and this potential clinical correlation should be confirmed through the collection of additional patients.

View Article: PubMed Central - PubMed

Affiliation: U.O. Genetica Medica, Policlinico Sant'Orsola-Malpighi, DIMEC, Università di Bologna, via Massarenti, 9, Bologna, 40138 Italy.

ABSTRACT

Background: Duplications of MECP2 gene in males cause a syndrome characterized by distinctive clinical features, including severe to profound mental retardation, infantile hypotonia, mild dysmorphic features, poor speech development, autistic features, seizures, progressive spasticity and recurrent infections. Patients with complex chromosome rearrangements, leading to Xq28 duplication, share most of the clinical features of individuals with tandem duplications, in particular neurologic problems, suggesting a major pathogenetic role of MECP2 overexpression.

Results: We performed cytogenetic and molecular cytogenetic studies in a previously described family with affected males showing congenital ataxia, late-onset progressive myoclonic encephalopathy and selective macular degeneration. Microsatellite, FISH and array-CGH analyses identified a recombinant X chromosome with a deletion of the PAR1 region, encompassing SHOX, replaced by a duplicated segment of the Xq28 terminal portion, including MECP2.

Conclusions: Our report describes the identification of the actual genetic cause underlying a severe syndrome that previous preliminary analyses erroneously associated to a terminal Xp22.33 region. In the present family as well as in previously reported patients with similar rearrangements, the observed neurologic phenotype is ascribable to MECP2 duplication, with an undefined contribution of the other involved genes. Maculopathy, presented by affected males reported here, could be a novel clinical feature associated to Xq28 disomy due to recombinant X chromosomes, but at present the underlying pathogenetic mechanism is unknown and this potential clinical correlation should be confirmed through the collection of additional patients.

No MeSH data available.


Related in: MedlinePlus