Clinical and molecular characterization of five new individuals with WAC ‐related intellectual disability: Evidence of pathogenicity for a novel splicing variant

Jose Andres Morales ◽  
Irene Valenzuela ◽  
Ivon Cuscó ◽  
Benjamin Cogné ◽  
Bertrand Isidor ◽  
2021 ◽  
Vol 14 (1) ◽  
Eleonora Marchina ◽  
Michela Forti ◽  
Mariella Tonelli ◽  
Stefania Maccarini ◽  
Francesca Malvestiti ◽  

Abstract Background Small supernumerary marker chromosomes (sSMC) are a heterogeneous group of structurally abnormal chromosomes, with an incidence of 0,044% in newborns that increases up to almost 7 times in developmentally retarded patients. sSMC from all 24 chromosome have been described, most of them originate from the group of the acrocentric, with around half deriving from the chromosome 15. Non-acrocentric sSMC are less common and, in the 30 percent of the cases, are associated with phenotypic effect. Complex sSMC consist of chromosomal material derived from more than one chromosome. Genotype–phenotype correlations in patients with sSMC are difficult to assess. Clinical features depend on factors such as its size, genetic content, the involvement of imprinted genes which may be influenced by uniparental disomy and the level of mosaicism. Trisomy of the short arm of chromosome 18 (18p) is an infrequent finding and does not appear to be associated with a specific syndrome. However, mild intellectual disability with or without other anomalies is reported in almost one-third of the patients. Case presentation Here we present clinical and molecular characterization of a new case of de novo complex sSMC consisting of the entire short arm of chromosome 18p associated with a centromere of either chromosome 13 or 21, evidenced in a 5-year-old boy during diagnostic workup for moderate intellectual disability and dysmorphisms. To date, only seven cases of isolated trisomy 18p due to a sSMC have been reported, three of which have been characterized by array CGH. In two of them the breakpoints and the size of the duplication have been described. In the manuscript we also reviewed cases reported in the DECIPHER database carrying similar duplication and also considered smaller duplications within the region of interest, in order to evaluate the presence of critical regions implicated in the pathological phenotype. Conclusions Our case provides additional information about phenotypic effects of pure trisomy 18p, confirms chromosomal microarray analysis as gold standard to characterize complex sSMC, and supplies additional elements for genetic counselling.

2012 ◽  
Vol 158A (7) ◽  
pp. 1633-1640 ◽  
Gaelle Thierry ◽  
Claire Bénéteau ◽  
Olivier Pichon ◽  
Elisabeth Flori ◽  
Bertrand Isidor ◽  

2017 ◽  
Vol 8 (3) ◽  
pp. 155-160 ◽  
Gustavo R. Nascimento ◽  
Irene P. Pinto ◽  
Aldaires V. de Melo ◽  
Damiana M. da Cruz ◽  
Cristiano L. Ribeiro ◽  

2006 ◽  
Vol 175 (4S) ◽  
pp. 467-467
Victor K. Lin ◽  
Shih-Ya Wang ◽  
Claus G. Roehrbom

2012 ◽  
Vol 224 (03) ◽  
A Streltsov ◽  
S Emmrich ◽  
F Engeland ◽  
JH Klusmann

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