Genome-wide analysis for micro-aberrations in familial exstrophy of the bladder using array-based comparative genomic hybridization

OBJECTIVE: Exstrophy of the bladder (EB) is part of the bladder-exstrophy-epispadias complex (BEEC). Because familial occurrence of BEEC is rare, exogenous factors are thought to play a major role in the etiology of most BEEC cases. We aimed to investigate a possible genetic basis of BEEC in a consanguineous kindred of Moroccan origin with three members showing the same phenotypic expression of BEEC. PATIENTS AND METHODS: The three affected males (two cousins and their maternal uncle) all presenting with nonsyndromic classic EB, were born in Morocco or The Netherlands. One Moroccan patient had an open bladder surface for 22 years due to late surgical reconstruction, avoided upright posture and developed severe lumbar scoliosis. Because three maternally related males from a consanguineous family living in different environments are affected, a genetic basis for EB is likely in this family. To screen for chromosomal aberrations and micro-aberrations in the two patients who were still alive, conventional karyotyping and array-based comparative genomic hybridization (array-CGH) were used on DNA-microarrays with a genome-wide average resolution of <0.5 Mb. RESULTS: Chromosome banding revealed normal karyotypes. By array-CGH, one of 8000 clones was aberrant in both affected cousins. This clone from 1p21.1 contained the AMY1B, AMY2B, AMY2A genes coding for salivary and pancreatic amylases. CONCLUSION: The aberration detected by array-CGH in both affected cousins is a known copy-number variant and most likely unrelated to the EB-phenotype. Nevertheless, in this family the nonsyndromic EB could be a monogenic disorder inherited in an autosomal-recessive or X-linked fashion.

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