When a known microimbalance affecting multiple genes is detected in a patient 
with syndromic intellectual disability, it is usually presumed causative for all 
observed features. Whole exome sequencing (WES) allows questioning this 
assumption. In this study of three families with children affected by 
unexplained syndromic intellectual disability, genome-wide copy number and 
subsequent analyses revealed a de novo maternal 1.1 Mb microdeletion in the 
14q32 imprinted region causing a paternal UPD(14)-like phenotype, and two 
inherited 22q11.21 microduplications of 2.5 or 2.8 Mb. In patient 1 carrying the 
14q32 microdeletion, tall stature and renal malformation were unexplained by 
paternal UPD(14), and there was no altered DLK1 expression or unexpected 
methylation status. By WES and filtering with a mining tool, a novel FBN1 
missense variant was found in patient 1 and his mother, who both showed clinical 
features of Marfan syndrome by thorough anthropometric assessment, and a novel 
EYA1 missense variant as a probable cause of the renal malformation in the 
patient. In patient 2 with the 22q11.21 microduplication syndrome, skin hypo- 
and hyperpigmentation and two malignancies were only partially explained. By 
WES, compound heterozygous BLM stop founder mutations were detected causing 
Bloom syndrome. In male patient 3 carrying a 22q11.21 microduplication inherited 
from his unaffected father, WES identified a novel missense variant in the OPHN1 
X-linked intellectual disability gene inherited from the unaffected mother as a 
possible additional cause for developmental delay. Thus, WES seems warranted in 
patients carrying microdeletions or microduplications, who have unexplained 
clinical features or microimbalances inherited from an unaffected parent.