We evaluated a mildly retarded pregnant young African American whose family history suggested cultural-familial retardation. Dysmorphic features included a long face, epicanthal folds, and down-turned mouth corners. She had a history of serious behavior problems starting in preschool and had been intermittently drug addicted. A high-resolution karyotype revealed a duplication of 4p at 4p16.3, confirmed by FISH with the D4S96 probe. Amniocentesis utilizing interphase FISH found this duplication in her pregnancy and again in two subsequent pregnancies. The two older children have shown normal developmental milestones with borderline speech delay whereas the third child has significant delays. None have striking dysmorphic features and all are > 75% for growth parameters. In her 4th pregnancy the mother sought prenatal diagnosis at 29 weeks' gestation. Ultrasound revealed ventriculomegaly. Amniocentesis FISH results were equivocal. At birth the female infant was hypotonic and had dysmorphic features similar to her mother's. FISH and array comparative genomic hybridization (array CGH) studies were undertaken to clarify the prenatal studies. CGH confirmed a duplication of 4p and, interestingly, identified a 22q11.2 duplication. FISH with D4S96 and TUPLE1 probes confirmed both duplications. Family studies utilizing FISH determined that the 22q11.2 duplication was de novo in child #4. No well-defined phenotype has been reported in the few published patients with microduplications of 4p16.1. To date, 21 children with a variable phenotype have been reported with microduplications in the 22q11.2 VCFS region (AJMG 2005;137:47). Most have been discovered incidentally in patients referred for 22q11.2 deletion FISH. In addition to its utility in the detection and confirmation of telomeric deletions, array CGH appears to be useful in the detection of small duplications not easily detectable by FISH. Our experience suggests that the combination of FISH and CGH can be a powerful tool in the evaluation of families with apparent cultural-familial mental retardation. A family history of mental retardation might prompt consideration of array CGH when conventional studies are negative.
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