A novel case of global developmental delay syndrome with microdeletion at 10p14-p15.3 and microduplication at 18p11.31-p11.32

Abstract

To characterize the etiology underlying a novel case of global developmental delay syndrome (GDDS) identified in a female child, aged 3 years old. This syndrome is a common pediatric presentation estimated to affect 3.65% of children aged 3 to 17 years. The proband's detailed family history was used to infer a likely mode of inheritance for the GDDS. Genomic DNA samples collected from the proband and her parents were evaluated using conventional karyotyping, multiplex ligation-dependent probe amplification (MLPA), comparative genomic hybridization microarray (aCGH), and fluorescent in situ hybridization (FISH) analysis techniques. An analysis of the proband's family history suggested that she inherited the GDDS from her father. The conducted conventional karyotyping and MLPA methods failed to identify a causative defect for the GDDS; however, the aCGH analysis revealed both a 6.6-Mb deletion at p14-p15.3 of chromosome 10 (arr[hg19]; 100,026-6,710,183), and a 6.3-Mb duplication at p11.31-p11.32 of chromosome 18 (arr[hg19]; 136,226-6,406,733) in the proband. The conducted FISH analysis subsequently determined that these mutations resulted from a balanced translocation t(10;18)(p15.3; p11.32) carried by the proband's father. Finally, a bioinformatic analysis of the proband's mutations revealed ZMYND11 as a promising candidate causative gene for this case of GDDS. The present study demonstrates that the aCGH method can be used to effectively identify the location and approximate size of microdeletions and/or microduplications, but not balanced reciprocal translocations. The nonconventional analysis methods used in the present study may be applicable to other GDDS cases with elusive etiology, and likewise, ZMYND11 should be considered as a potential causative gene during the investigation of future GDDS cases. Abbreviations: ACGH = comparative genomic hybridization, CMA = chromosomal microarray analysis, CNVs = copy number variations, DD = developmental delay, FISH = fluorescent in situ hybridization, GDDS = global developmental delay syndrome, MLPA = multiplex ligation-dependent probe amplification, MR = mental retardation, OMIM = Online Mendelian Inheritance in Man.