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Monozygotic twins with chromosome 22q11 deletion and discordant phenotypes: updates with an epigenetic hypothesis
  1. S M Singh,
  2. B Murphy,
  3. R O’Reilly
  1. Molecular Genetics Unit, Department of Biology, Division of Medical Genetics and Department of Psychiatry, The University of Western Ontario, London, Ontario, Canada N6A 5B7
  1. Correspondence to:
 Dr S Singh, Molecular Genetics Unit, Department of Biology and Division of Medical Genetics, The University of Western Ontario, London, Ontario, Canada N6A 5B7;

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The completion of the human genome sequence affords novel approaches to studies on contiguous gene deletion syndromes. These syndromes are caused by a deletion and loss of one copy of a set of contiguous genes on a given chromosome. Here, the syndromic phenotypes are often attributed to haploinsufficiency of a number of deleted genes. One such syndrome deals with deletion of 22q11.2. It is the most common microdeletion syndrome with a frequency of 1:4000 live births.1 This high frequency has been attributed to low copy repeats (LCR) on chromosome 22,2 with most cases (85-90%) representing de novo mutations. Also, the critical common region is relatively large (>1.5-3.0 Mb), may involve >30 genes, and there is no evidence of any correlation between the size of the deletion and the observed syndromic phenotypes.3 In fact, the clinical phenotype of the 22q11 deletion syndrome is characterised by extensive variability.4 It includes velocardiofacial syndrome (VCFS), DiGeorge syndrome (DGS), and associated physical, developmental, neurological, and neuropsychiatric phenotypes. This phenotypic variability associated with the 22q11 deletion is an exception to all the other contiguous gene syndromes. More puzzling are recent reports that monozygotic twins (p>0.99) with 22q11 deletions have discordant phenotypes. In this discussion we will review all published cases of monozygotic twins concordant for del 22q11 and assess phenotypic discordance/concordance between them. More important, we will discuss an epigenetic explanation for their discordance that is compatible with modern molecular understanding of the human genome, the sequence features of this region of chromosome 22, and the “second hit” hypothesis involving genetic and/or epigenetic somatic events.


Twin pair 1

Twin pair 15 was born to a 32 year old mother of European ancestry, at a gestational age of 38 weeks, weighing 2200 g (twin 1) and 2800 g (twin 2), apparently from a single placenta. …

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