MOLECULAR AND CLINICAL-STUDY OF 183 PATIENTS WITH CONOTRUNCAL ANOMALYFACE SYNDROME

To investigate molecular and clinical aspects of conotruncal anomaly f ace (CAF), we studied the correlation between deletion size and phenot ype and the mode of inheritance in 183 conotruncal anomaly face syndro me (CAFS) patients. Hemizygosity for a region of 22q 11.2 was found in 180 (98%) of the patients with CAFS by fluorescence in situ hybridiza tion (FISH) using the N25(D22S75) DiGeorge critical region (DGCR) prob e. No hemizygosity was found in three (2%) of the patients with CAFS b y FISH using nine DiGeorge critical region probes and a SD10P1 probe ( DGA II locus). None of these three patients had mental retardation and just one had nasal intonation, which was observed in almost all of th e 180 CAFS patients who carried deletions (mental retardation, 92%; na sal voice, 88%). Nineteen of 143 families (13%) had familial CAFS and 16 affected parents (84%) were mothers. Although only two of the affec ted parents had cardiovascular anomalies, the deletion size in the 16 affected parents and their affected family members, who were studied b y FISH analysis. was the same. It indicates that extragenic factors ma y play a role in the genesis of phenotypic variability, especially in patients with cardiovascular anomalies. No familial cases were found a mong CAFS patients with absent thymus/DiGeorge anomaly (DGA). Also, in all 18 CAFS patients with completely absent thymus/DGA and all CAFS p atients with schizophrenia, it was revealed that the deletion was long er distally. A study of the origin of the deletion using microsatellit e analyses in 48 de novo patients showed that in 65% of CAFS patients it was maternal: while in 64% of DGA patients it was paternal. The fin dings of this study indicated that CAF was almost always associated wi th the deletion of 22q11.2. As well as the major features of the syndr ome, other notable extracardiac anomalies were found to be susceptibil ity to infection, schizophrenia, atrophy or dysmorphism of the brain, thrombocytopenia, short stature, facial palsy, anal atresia, and mild limb abnormalities.