Homozygosity mapping in families with Joubert syndrome identifies a locus on chromosome 9q34.3 and evidence for genetic heterogeneity

Joubert syndrome is a rare developmental defect of the cerebellar vermis, w ith autosomal recessive inheritance, The phenotype is highly variable and m ay include episodic hyperpnea, abnormal eye movements, hypotonia, ataxia, d evelopmental delay, and mental retardation. Even within sibships the phenot ype may vary, making it difficult to establish the exact clinical diagnosti c boundaries of Joubert syndrome, To genetically localize the gene region, we have performed a whole-genome scan in two consanguineous families of Ara bian/Iranian origins, with multiple affected probands. In one family we det ected linkage to the telomeric region of chromosome 9q, close to the marker D9S158, with a multipoint LOD score of Z = +3.7. The second family did not show linkage to this region, giving a first indication of genetic heteroge neity underlying Joubert syndrome. These findings were supported by subsequ ent analysis of two smaller families-one compatible with linkage to 9q; the other, unlinked. We conclude that Joubert syndrome is clinically and genet ically heterogeneous and that one locus maps to chromosome 9q.