HEREDITY DISORDERS OF CONNECTIVE TISSUE--CLINICAL AND MOLECULAR STUDIES

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A total of 145 patients with Marfan syndrome and related conditions (MASS phenotype, mitral valve prolapse syndrome, familial aortic dissection) have been seen in the NHGRI Genetics Clinic. Clinical data collected included detailed information on skeletal, ocular and cardiovascular manifestations in each patient. Eventually, the plan is to correlate clinical observations with specific mutations in the fibrillin-1 (FBN1) gene. Additionally, clinical data will be analyzed to assess the validity of proposed new diagnostic criteria for Marfan syndrome. Long-term clinical follow-up is planned for patients not fulfilling the diagnostic criteria, to determine the natural history of these patients and also the optimal management scheme for them. A total of 30 new families (8 sporadic cases, 22 multigenerational) with Nail-Patella syndrome were recruited and molecular studies initiated. Novel recombination events further refined the gentic interval. Physical mapping studies have been initiated and the entire NPS interval is defined in a series of overlapping YAC clones. In a subset of families, open angle glaucoma is linked to NPS. Whether glaucoma represents a previously unrecognized aspect of the syndrome or results from mutation(s) in a linked gene, is under investigation. Linkage of glaucoma to chromosome 9 has not been reported previously. In an effort to clarify the relationship between the Stickler syndrome phenotype and underlying gene mutations, we have initiated the study of 26 Stickler syndrome families by clinical and molecular means. Recently it has been proposed that two subtypes of Stickler syndrome can be defined based on the severity of ocular findings. In seven of the families we studied, the Stickler phenotype was not linked to COL2A1. Our data demonstrate that not all families with "classical" Stickler syndrome have mutations in the COL2A1 gene. We suggest that until sufficient families with identified molecular defects are studied, Stickler syndrome subtypes be based on clinical phenotype alone and not defined by the locus carrying the mutation.