Copy-Number Gains of HUWE1 Due to Replication- and Recombination-Based Rearrangements Guy Froyen, Stefanie Belet, Francisco Martinez, Cíntia Barros Santos-Rebouças,

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Copy-Number Gains of HUWE1 Due to Replication- and Recombination-Based Rearrangements Guy Froyen, Stefanie Belet, Francisco Martinez, Cíntia Barros Santos-Rebouças, Matthias Declercq, Jelle Verbeeck, Lene Donckers, Siren Berland, Sonia Mayo, Monica Rosello, Márcia Mattos Gonçalves Pimentel, Natalia Fintelman-Rodrigues, Randi Hovland, Suely Rodrigues dos Santos, F. Lucy Raymond, Tulika Bose, Mark A. Corbett, Leslie Sheffield, Conny M.A. van Ravenswaaij-Arts, Trijnie Dijkhuizen, Charles Coutton, Veronique Satre, Victoria Siu, Peter Marynen The American Journal of Human Genetics Volume 91, Issue 2, Pages 252-264 (August 2012) DOI: 10.1016/j.ajhg.2012.06.010 Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 1 Pedigrees of Families with Xp11.22 Copy-Number Gains (A) Pedigrees of six unreported families with a nonrecurrent microduplication at Xp11.22, including HUWE1. All tested individuals are marked with Nrl if the duplication was not present or Dup if the duplication was found in this individual. X-inactivation ratios in females are provided between brackets. Ni, not informative; dn, de novo event. (B) Pedigrees of the four families with the partial HUWE1 copy-number gain. Segregation of the aberrations was analyzed by qPCR in family members from whom DNA was available. Family members with weak cognitive levels are indicated in gray. The American Journal of Human Genetics 2012 91, 252-264DOI: (10.1016/j.ajhg.2012.06.010) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 2 Overview of the 12 Nonrecurrent and 4 Recurrent Microduplications at Xp11.22 The locations and sizes of each nonrecurrent duplication, as defined by high-resolution oligo array and iterative qPCR mapping, are illustrated by horizontal blue bars. The sizes of each copy-number gain are indicated, as well as the sequence used as microhomology substrates for rearrangement, if defined. Where LCR was involved, the minimal size of the LCR is provided between brackets. The positions of the SNPs and markers that we analyzed are indicated at the top. The genes present within this region are shown at the bottom, in red. The shortest region of overlap is indicated in gray and harbors HUWE1 and the intronically located microRNAs miR-98 and let-7f-2. The recurrent polymorphic duplication identified in the four unrelated families is indicated by the yellow box shown above the genes. Positions are according to UCSC hg18. Nd, not determined due to insufficient DNA, repeat-rich, or nonreference breakpoint regions. The American Journal of Human Genetics 2012 91, 252-264DOI: (10.1016/j.ajhg.2012.06.010) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 3 A Recurrent Partial HUWE1 Copy-Number Gain Is Identified in Four Unrelated Families Mapping of the recurrent copy-number gain was performed by iterative rounds of qPCR, for which each result is indicated as “−” for a normal copy number of 1.0 or “+” when the locus had a copy-number gain. The duplication starts at 53.57 Mb, which is upstream of HUWE1, and ends at 53.63 Mb within intron 28 of this gene. Analysis of both breakpoint regions by RepeatMasker identified the presence of 2.9 and 2.5 kb TcMAR-Tigger DNA elements (indicated as vertical-striped boxes) at the distal (TcMAR-Tigger-Dist) and proximal (TcMAR-Tigger-Prox) side, respectively. The locations of HSD17B10, part of HUWE1, and both microRNAs are at the bottom. Positions (in kb) are according to UCSC hg18. The American Journal of Human Genetics 2012 91, 252-264DOI: (10.1016/j.ajhg.2012.06.010) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 4 HUWE1 but Not HSD17B10 mRNA Expression Is Increased in EX469 The microduplication in EX469 is the only one that does not include HSD17B10, thereby limiting the minimal duplicated region to HUWE1 only. The qPCR data are the mean of four independent experiments. Four controls were used in each experiment. SDs are provided. The American Journal of Human Genetics 2012 91, 252-264DOI: (10.1016/j.ajhg.2012.06.010) Copyright © 2012 The American Society of Human Genetics Terms and Conditions