CLINICAL CORRELATIONS OF CONTIGUOUS GENE SYNDROMES

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Chromosomal rearrangements in humans are diverse, frequent, and often result in phenotypic abnormalities. Contiguous gene syndromes (CGS) are disorders caused by chromosomal rearrangements, including deletions and duplications, which result in an alteration of normal gene dosage. Clinically, each CGS is characterized by a specific and often complex phenotype, which was recognized in most cases as a genetic syndrome prior to knowledge of the cytogenetic etiology. The responsible chromosomal segment is usually small on a cytogenetic scale (<5 Mb), but encompasses multiple genes, some of which are dosage sensitive and contribute to the phenotype independently. For most autosomal loci, deletion causes a reduction of gene dosage to structural and functional monosomy. Haploinsufficiency for specific genes in the critical interval is implicated for del(17)(p11.2p11.2) in Smith-Magenis syndrome (SMS) and for monosomy 1p-del(1)(p36). The spectrum of clinical findings in SMS includes short stature, ophthalmologic, otolaryngologic, cardiac, and renal anomalies, developmental delay, and neurobehavioral abnormalities including destructive behavior and sleep disturbances. Although the phenotype may vary between SMS patients, the majority (>90%) of persons with SMS harbor the same sized deletion by molecular analysis. The clinical features associated with deletion of the most distal band on the short arm of chromosome 1 have been recently delineated. Patients show a wide range of features including variable degrees of mental retardation, growth delay, seizures and/or abnormal EEGs, hypotonia, developmental delay, early puberty, orofacial clefting or palatal anomalies, enlarged anterior fontanel, dysmorphic features, deafness, and cardiomyopathy. The 1p36 deletions vary in size and ongoing genotype-phenotype correlation will likely elucidate the causative genes in this region. Duplication of chromosomal segments causes increased dosage and gene expression. Duplication of the SMS region (17p11.2) has been molecularly identified in our laboratory as the recombination reciprocal of the SMS deletion. Persons with this cytogenetic abnormality are less severely affected than persons with SMS, do not seem to have major organ system anomalies or sleep disturbance, and can have normal or borderline intelligence. Likewise, persons with duplications of 1p36 have been identified in our laboratory and have different phenotypic anomalies than their deletion counterparts. Rigorous evaluations of patients with SMS have been completed through the General Clinical Research Center (GCRC) at the Texas Children's Hospital (TCH). Further evaluation of individuals with unusual sized SMS deletions will also determine genotype-phenotype correlation. Evaluations of patients with duplication 17p11.2 is necessary to completely characterize this novel molecularly defined syndrome. Persons with deletion of 1p36 have also been studied through the GCRC and duplication of this region has so far only been reported in one patient. As these patients have deletions of various sizes, a greater number must be studied to accurately define the clinical spectrum and genotype-phenotype correlation. Cytogenetic and molecular studies are performed concurrently with these clinical analyses and thus complement this clinical research.