Síndromes clíniques de microdeleció i microduplicació · fenotip genotip ....
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Curs de Formació Continuada 2015-2016 Síndromes clíniques de microdeleció i microduplicació Dr. Ignacio Blanco Coordinador, Programa d’Assessorament i Genètica Clínica Hospital Germans Trias i Pujol
Transcript of Síndromes clíniques de microdeleció i microduplicació · fenotip genotip ....
Curs de Formació Continuada 2015-2016
Síndromes clíniques de microdeleció i
microduplicació
Dr. Ignacio Blanco Coordinador,
Programa d’Assessorament i Genètica Clínica
Hospital Germans Trias i Pujol
Donat el caràcter i la finalitat exclusivament docent i eminentment
il·lustrativa de les explicacions a classe d'aquesta presentació, l’autor
s’acull a l’article 32 de la Llei de propietat intel·lectual vigent respecte de
l'ús parcial d'obres alienes com ara imatges, gràfics o altre material
contingudes en les diferents diapositives
Totes les imatges presentades s’inclouen com a cites necessàries per il·lustrar les explicacions d’aquesta classe
Microdelecions i Microduplicacions
Una microdeleció es defineix com una deleció submicroscòpica que condueix a la monosomia d'un segment cromosòmic massa petit per ser detectat per citogenètica convencional, típicament menys de 5 megabases de tamany.
Una microduplicació es defineix com una duplicació submicroscòpica que condueix a la trisomia d'un segment cromosòmic massa petit per ser detectat per citogenètica convencional, típicament menys de 5 megabases de tamany.
Síndrome
La taxa de prevalença de defectes congènits (detectats prenatalment o en els primers dies de vida) de la població se situa en un 3,6% del total de naixements.
Els defectes congènits poden ser causats per una anomalia cromosòmica o per una anomalia monogènica.
Hi ha un petit grup de defectes congènits causats per causes ambientals, no genètiques.
La majoria de malformacions físiques són d’origen multifactorial, es a dir, hi intervenen factors ambientals i genètics.
Microdelecions i Microduplicacions
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Tjio & Levan (1956)
Els Cromosomes
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Avantatges:
Estudi cromosòmic
complert (nombre i
estructura)
Limitacions:
Resolució (5-10 Mb)
Cariotip convencional
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http://www.thelancet.com/cms/attachment/2000990403/2003650026/gr1.jpg
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DiGeorge 22q11 Deletion 3.5 Mb
Miller Dieker 17p13.3 deletion 4.6 Mb
Prader Willi 15q11-13 deletion 4 Mb
Smith Magenis 17p11.2 deletion 5 Mb
Wolf Hirschhorn 4p16.3 deletion 1.9 Mb
Williams-Beuren 7q11.23Deletion 1.5 Mb
Microdelecions i Microduplicacions
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Growing numbers of publication per year found by searching for the terms
microdeletion syndrome new and microduplication syndrome new in Pub
Med (http://www.ncbi.nlm.nih.gov/pubmed).
Anja Weise et al. J Histochem Cytochem 2012;60:346-358
Copyright © by The Histochemical Society
Anàlisi Cromosòmic
Cariotip Alta Resolució -- Array CGH / array SNPs Resolució (0,1-0,5 Mb)
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Chromosomal microdeletions and microduplications make up a fraction of
copy-number variants (CNVs).
CNVs are defined as either the gain or loss of a stretch of DNA as
compared with the reference human genome; they may range in size
from a kilobase to several megabases or even an entire chromosome
(trisomies and monosomies).
CNVs can involve multiple, one, or no genes, and although some CNVs
cause disease, many others remain benign variants within the population.
There are two major classes of CNVs: recurrent and nonrecurrent.
Recurrent CNVs generally arise by nonallelic homologous recombination
(NAHR) during meiosis, with breakpoints in the large duplicated blocks
of sequence flanking the CNV event.
Copy-Number Variants. Microdeletions and Microduplications
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Copy-Number Variants. Microdeletions and Microduplications
nonallelic homologous recombination (NAHR)
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nonallelic homologous recombination (NAHR)
Hereditary neuropathy with liability to pressure palsies (HNPP) Charcot–Marie–Tooth disease type 1A
17p12
The size of CNV detected by chromosome microarray technologies depends
largely on the probe density.
Whole genome sequencing using MPS or NGS has the potential to provide a
truly unbiased assay that can identify CNVs ranging in size from a single base
pair to entire chromosomes, simultaneously with a complete assessment of
single-nucleotide sequence changes.
More than 8,000 segmental duplications (SDs) have been described. Analysis
of this SD map identified 169 regions of the human genome that were
predicted to be potential rearrangement hot spots because of the presence
of large blocks of SDs with >95% sequence similarity that were separated by
50 kb–10 Mb of intervening sequence. Interestingly, 24 of these regions had
already been linked to recurrent genetic diseases
Copy-Number Variants. Microdeletions and Microduplications
Defining pathogenicity of Copy-Number Variants.
Many criteria can be used to help interpret the clinical relevance of a CNV,
including inheritance, size, gene content, and type.
De novo CNVs are more likely than inherited CNVs to be pathogenic.
Large CNVs are more likely than small CNVs to cause disease.
CNVs that contain many genes or known disease genes are more
likely to be pathogenic than those that contain few genes or genes of
uncertain function.
Deletions result in haploinsufficiency, the consequences of which are
known for some genes. Duplications are more difficult to interpret.
All of these criteria are probabilistic in nature.
Growing numbers of publication per year found by searching for the terms
microdeletion syndrome new and microduplication syndrome new in Pub
Med (http://www.ncbi.nlm.nih.gov/pubmed).
Copyright © by The Histochemical Society
In general, pathogenic duplications are less prevalent than deletions in clinically ascertained samples (except for the X chromosome);
Theoretically, for every microdeletion syndrome there should be a
reciprocal microduplication syndrome.
However, there are at present 211 microdeletion syndromes versus
only 79 microduplication syndromes reported.
This is a 2.5:1 ratio for a total of 267 different genomic loci with
MMSs.
Only for 56 of these, loci are reported as reciprocal/colocalizing
MMSs, that is, 21%.
In general, pathogenic duplications are less prevalent than deletions in clinically ascertained samples (except for the X chromosome);
they usually confer milder phenotypes than the reciprocal deletions, most are inherited from one parent, and the vast majority are tandem (head-to-tail) in orientation.
The relatively milder phenotype conveyed and transmitted to the next generation are both consistent with less detrimental effects for the organism.
Comparison of CNV findings across studies reveals several recurrent
rearrangements that are associated with a wide range and severity of
phenotypes.
Severity of each phenotype associated with these rearrangements can
vary significantly.
The factors underlying such extreme clinical variability are still poorly
understood.
Differences in genetic background
Epigenetic differences and imprinting.
Interaction with environmental or sporadic effects.
Sequence variants in candidate genes within the deleted region.
Incomplete Penetrance and Variable Expressivity of MM Syndromes
The complete phenotypic characterization of these syndromes is still in progress.
Incomplete penetrance of genomic duplications and variable expression of
phenotypes observed in these disorders are of considerable importance in the
context of prenatal diagnosis, where families may be faced with difficult
decisions regarding the management of a pregnancy without having a solid
information base upon which to make those decisions.
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Incomplete penetrance of genomic duplications and variable expression of
phenotypes observed in these disorders are of considerable importance in the
context of prenatal diagnosis, where families may be faced with difficult
decisions regarding the management of a pregnancy without having a solid
information base upon which to make those decisions.
