Approximately 25-40% of the children that present in the Genetics Clinic with multiple physical anomalies (including structural anomalies, mental and growth retardation) cannot be diagnosed with a specific syndrome. Most of the families have only a single affected member and the disorder is thus considered sporadic and of unknown etiology. We hypothesize that this disorder is at least partially attributable to cytogenetically undetectable alterations in gene dosage resulting from uniparental disomy (UPD) or sub-microscopic chromosomal duplications and deletions. Because the resolution of microscopic cytogenetics is too coarse to detect clinically important structural alterations in chromosomes, we are searching for such alterations using molecular tools. We are defining a group of patients from the NIH Clinical Center genetics clinic and outside institutions with a diagnosis of unknown MCA and are analyzing the inheritance of all 22 autosomes using PCR analysis of microsatellite polymorphic markers positioned near the telomeres. In addition, we have implemented a whole genome STRP screening project that uses markers throughout the genome to search for interstitial aberrations. This project is expected to define a novel etiology for birth defect syndromes and have clinical and research implications. To date we have analyzed nearly 100 subjects and have found submicroscopic deletions and duplications in several subjects. These have included a child with a duplication of 22qter, a child with deletion of 18qter, and a child with an interstitial deletion of 4q.
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