57 - Characterization of a Complex Derivative Chromosome 18

Abstract

We present an unbalanced potential recombinant chromosome 18 [46,XY,der(18)(qter->q22.3::p11.22->qter::?p11.2->pter)] that likely originated from multiple crossing over events during meiosis I from an ancestral balanced pericentric inversion of chromosome 18(p11.22q22.3). Cytogenetic analysis suggests that the distal short arm is retained at the 18q inversion break site along with the duplicated 18q22.2->qter region. The chromosome was detected in a fetus referred for prenatal diagnosis with abnormal ultrasound findings including lower urinary tract obstruction, oligohydramnios, and hypoplastic cerebellum. The derivative 18 chromosome was maternally inherited from a patient with learning disabilities, recurrent hiccups, partial hearing loss and aortic valve insufficiency. Maternal and prenatal microarray analysis detected an 8.64 Mb terminal duplication of 18q22.3->qter and an additional presumably unrelated 3.17 Mb microduplication at 22q11.21. The 18q duplication interval includes numerous OMIM genes. Although patients with intellectual disability carrying similar 18q duplications have been reported, the clinical phenotypes associated with terminal 18q duplications have not been well characterized in the literature. The 22q duplication is the meiotic reciprocal of the DiGeorge/VCF syndrome microdeletion region with phenotypes ranging from normal to affected with intellectual disability, developmental delay, and hypotonia . The combined clinical effects of these two duplications may be associated with a more severe variably expressed phenotype. The unusual structure of the derivative chromosome 18 may result in meiotic pairing problems beyond what is normally seen in pericentric inversion carriers. Inversion unbalanced recombinant risk increases with the distance between the breakpoints, and in this family there may be carriers of a presumed original inversion, as well as family members with this derivative chromosome 18 or more typical unbalanced recombinant chromosomes. FISH studies are in progress and a more detailed family history is being acquired to better characterize this chromosome.