Microduplication 22q11.2: a benign polymorphism or a syndrome with a very large clinical variability and reduced penetrance?--Report of two families.

We report on two unrelated families where the probands presented with learning difficulties and a microduplication 22q11.2. In the first family the proband was a 7-year-old boy who was referred because of psychomotor retardation, behavioral problems, large weight and height, and mild dysmorphism. His father and one brother also had mental retardation and behavioral anomalies, and presented the same microduplication. In the second family only the proband had mild learning difficulties, but the same microduplication 22q11.2 was discovered in her sister, her asymptomatic mother and grandfather. No distinctly recognizable phenotype has been observed in the individuals from our two families diagnosed with microduplication 22q11.2. The marked clinical variability both inter- and intrafamilial, including the presence of a complete normal phenotype and the presence of high intellectual possibilities in two individuals with this microduplication 22q11.2 is remarkable. So far, 63 patients, corresponding to 35 families, with microduplication 22q11.2 have been described. The fact that microduplication 22q11.2 can be seen in individuals with a normal/near normal phenotype has been previously reported as well. We postulate that the clinical findings described so far could be due to ascertainment bias, since the most common reason for performing FISH 22 analyses is to exclude microdeletion. Future reports are needed to answer the question whether microduplication could be a non-pathogenic polymorphism or whether it is a real syndrome with a very large clinical variability and reduced penetrance.