Approximately 25-40% of the children that present in the Genetics Clinic with multiple physical anomalies (including structural anomalies, mental and growth retaradation) 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 course 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. This project is expected to define a novel etiology for birth defect syndromes and have clinical and research implications. To date we have analyzed 50 subject and have found submicroscopic deletions and duplications in 5 subjects.
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