THE RING 14 SYNDROME: CLINICAL AND MOLECULAR DEFINITION OF A RARE CONDITION Giovanni Neri, MD1, Laura Seminara, PhD1, Daniela Orteschi, PhD1, Giuseppe Gobbi, MD2, Simona Giovannini, MD2, Elvio Della Giustina, MD3, Angela Scarano, MD3, Marcella Zollino, MD1 1Istituto di Genetica Medica, Università Cattolica del Sacro Cuore, Roma; 2Neuropsichiatria Infantile, Ospedale Maggiore, Bologna; 3Neuropsichiatria Infantile, Arcispedale S. Maria Nuova, Reggio Emilia, Italy Materials and methods Introduction Subjects: 30 Ring 14 Syndrome is a rare genetic condition, with clinical signs including - Genetic Tests • 20 ring 14 1. RBG-banded chromosomes (100 cells) 11 males/9 females Aged: 3-36 years Psychomotor delay Seizures Hypotonia Microcephaly Retinitis pigmentosa Characteristic face 2. Locus-specific FISH with probes (total 62) spanning the entire chromosome 14q • 9 linear deletions 3. Array-CGH - BAC array-CGH, 1Mb : 8 patients - oligonucleotide array-CGH (Agilent) 4x44B, 75Kb: 4 patients 4 males/5 females Aged: 1-33 years • 1 t(10;14)(q25.3;q12) balanced translocation 4. Microsatellite segregation analysis Results Ring 14: perinatal period Ring 14: facial characteristics Pregnancy - uneventful IUGR uncommon Delivery - at term - normal caesarean section uncommon Birth - normal weight low BW in large 14q deletions - normal length - head circumference: normal, microcephaly possible Ring 14 : Physical anomalies Major malformations absent Minor skeletal anomalies (scoliosis) Café-au-lait spots Retinal anomalies Acquired microcephaly High forehead Linear eyebrows Hypolastic sopraorbital ridges Deep set eyes Short palpebral fissures/ hypotelorism High nasal bridge Long/asymmetric face Full cheeks Small downturned mouth corners Ear anomalies Ring 14 : Neuropsychology and behavior Hypotonia Seizures Mental retardation Good natured behavior, with hyperactivity and occasional aggressiveness Ring 14 : relevant clinical signs Distance from 14 q tel Deletion size (Mb) Ring 14 : Genetics FISH - Ring complete 6/20 73 M18: +/+ RP11-73M18 (3 Mb) - Ring with deletions 14/20 - Mosaicism with monosomy 14 EPILEPSY • 14q32.3 • Mental retardation • Susceptibility to infections p11.2q32.3 • RETINAL ANOMALIES RP11-435F10 (1.5 Mb) CGH Ring with deletion + duplication 1/12 2,5 435F10: +/- UPD (14) Absent RP11-815P21 (1.2 Mb) • Behavior disorders Parental origin Maternal 30% Paternal 70% Present 14qter (telomere) Deleted Extent and mapping of different deletions Phenotypic map Ring 14 1 6 7.2 1 Breakpoint in t(10;14) 1 1 20 15 2.3 1.5 0.5 0.65 No of pat 6 1 6 3 3.8 2.5 4.3 5 Linear 14q deletions Proximal * 4 11 8 4.8 Distal Seizures ++ + MR ++ + Visual impairment + + Susceptibilty to infections + + Behavior disorders + + Scoliosis + + Acquired microcephaly + + + 3.4 1 1 Deletions within rings 1 1 1 1 1 1 30 % 70 % 2 Linear deletions Duplication within rings ACKNOWLEDGEMENTS We gratefully acknowledge the financial support of the “Associazione Ring 14” We also thank the patients with the families for participating in this study Genes Visual impairment Epilepsy Microcephaly MR (+/-) Brain abnormalities Infections susceptibility MR (+) Behavior disorders Scoliosis 14q11.2q12 14q32 NRL RPGRIP1 FOXG1 IGH 8 %