THE RING 14 SYNDROME: CLINICAL AND MOLECULAR DEFINITION OF A RARE CONDITION Giovanni Neri, MD 1,...
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THE RING 14 SYNDROME: CLINICAL AND MOLECULAR THE RING 14 SYNDROME: CLINICAL AND MOLECULAR DEFINITION OF A RARE CONDITION DEFINITION OF A RARE CONDITION Giovanni Neri, MD 1 , Laura Seminara, PhD 1 , Daniela Orteschi, PhD 1 , Giuseppe Gobbi, MD 2 , Simona Giovannini, MD 2 , Elvio Della Giustina, MD 3 , Angela Scarano, MD 3 , Marcella Zollino, MD 1 1 Istituto di Genetica Medica, Università Cattolica del Sacro Cuore, Roma; 2 Neuropsichiatria Infantile, Ospedale Maggiore, Bologna; 3 Neuropsichiatria Infantile, Arcispedale S. Maria Nuova, Reggio Emilia, Italy Introduction Materials and methods Results Subjects: 30 • 20 ring 14 11 males/9 females Aged: 3-36 years • 9 linear deletions 4 males/5 females Aged: 1-33 years • 1 t(10;14)(q25.3;q12) balanced translocation Genetic Tests 1. RBG-banded chromosomes (100 cells) 2. Locus-specific FISH with probes (total 62) spanning the entire chromosome 14q 3. Array-CGH - BAC array-CGH, 1Mb : 8 patients - oligonucleotide array-CGH (Agilent) 4x44B, 75Kb: 4 patients 4. Microsatellite segregation analysis 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: perinatal period 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: facial characteristics Major malformations absent Minor skeletal anomalies (scoliosis) Café-au-lait spots Retinal anomalies Acquired microcephaly Ring 14 : Physical anomalies Hypotonia Seizures Mental retardation Good natured behavior, with hyperactivity and occasional aggressiveness Ring 14 : Neuropsychology and behavior • EPILEPSY • Mental retardation • Susceptibility to infections • RETINAL ANOMALIES • Behavior disorders Ring 14 : relevant clinical signs FISH Deletion size (Mb) 14q32.3 RP11-73M18 RP11-435F10 RP11-815P21 14qter (telomere) (3 Mb) Distance from 14 q tel (1.5 Mb) (1.2 Mb) 2,5 Present Deleted p11.2q32.3 73 M18: +/+ 435F10: +/- Extent and mapping of different deletions Ring 14 Linear 14q deletions Proximal Distal Seizures ++ + MR ++ + + Visual impairment + + Susceptibilty to infections + + Behavior disorders + + Scoliosis + + Acquired microcephaly + + Ring 14 Syndrome is a rare genetic condition, with clinical signs including - Psychomotor delay - Seizures - Hypotonia - Microcephaly - Retinitis pigmentosa - Characteristic face Visual impairment Epilepsy Microcephaly MR (+/-) Brain abnormalities Infections susceptibility MR (+) Behavior disorders Scoliosis Genes IGH 14q11.2q 12 14q32 Phenotypic map NRL RPGRIP1 FOXG1 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 Ring 14 : Genetics - Ring complete 6/20 30 % - Ring with deletions 14/20 70 % - Mosaicism with monosomy 14 CGH Ring with deletion + duplication 1/12 8 % UPD (14) Absent Parental origin Maternal 30% Paternal 70% 6 2.3 1.5 1 0.5 6 3.4 1 No of pat 4 1 6 1 1 15 1 11 * 1 Breakpoint in t(10;14) 3 0.65 3.8 1 2 4.8 1 7.2 5 4.3 1 1 20 1 8 1 Deletions within rings Duplication within rings Linear deletions 2.5
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Transcript of THE RING 14 SYNDROME: CLINICAL AND MOLECULAR DEFINITION OF A RARE CONDITION Giovanni Neri, MD 1,...
THE RING 14 SYNDROME: CLINICAL AND THE RING 14 SYNDROME: CLINICAL AND MOLECULAR DEFINITION OF A RARE CONDITIONMOLECULAR 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
Introduction Materials and methods
Results
Subjects: 30
• 20 ring 14
11 males/9 females Aged: 3-36 years
• 9 linear deletions
4 males/5 females Aged: 1-33 years
• 1 t(10;14)(q25.3;q12) balanced translocation
Genetic Tests
1. RBG-banded chromosomes (100 cells)
2. Locus-specific FISH with probes (total 62) spanning the entire chromosome 14q
3. Array-CGH- BAC array-CGH, 1Mb : 8 patients- oligonucleotide array-CGH (Agilent)
4x44B, 75Kb: 4 patients
4. Microsatellite segregation analysis
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: perinatal period
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: facial characteristics
Major malformations absent Minor skeletal anomalies (scoliosis) Café-au-lait spots Retinal anomalies Acquired microcephaly
Ring 14 : Physical anomalies
Hypotonia
Seizures
Mental retardation
Good natured behavior, with hyperactivity and occasional aggressiveness
Ring 14 : Neuropsychology and behavior
• EPILEPSY
• Mental retardation • Susceptibility to infections • RETINAL ANOMALIES
• Behavior disorders
Ring 14 : relevant clinical signsFISHDeletion size
(Mb)
14q
32.3
RP11-73M18
RP11-435F10
RP11-815P21
14qter (telomere)
(3 Mb)
Distance from 14 q tel
(1.5 Mb)
(1.2 Mb)
2,5
Present
Deleted
p11.2q32.3
73 M18: +/+
435F10: +/-
Extent and mapping of different deletions
Ring 14 Linear 14q deletions
Proximal Distal
Seizures ++ +
MR ++ + +
Visual impairment + +
Susceptibilty to infections + +
Behavior disorders + +
Scoliosis + +
Acquired microcephaly + +
Ring 14 Syndrome is a rare genetic condition, with clinical signs including
- Psychomotor delay - Seizures - Hypotonia - Microcephaly - Retinitis pigmentosa - Characteristic face
Visual impairmentEpilepsyMicrocephalyMR (+/-)Brain abnormalities
Infections susceptibilityMR (+)Behavior disordersScoliosis
Genes
IGH
14q11.2q12
14q32
Phenotypic map
NRLRPGRIP1FOXG1
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
Ring 14 : Genetics
- Ring complete 6/20 30 % - Ring with deletions 14/20 70 % - Mosaicism with monosomy 14
CGH Ring with deletion + duplication 1/12 8 % UPD (14) Absent
Parental origin Maternal 30% Paternal 70%
6
2.3 1.5
1
0.5
6
3.4
1No of pat
4
1
6
1
1
15
1
11
*
1
Breakpoint in t(10;14)
3
0.65
3.8
1 2
4.8
1
7.2
5 4.3
1 1
20
1
8
1
Deletions within rings
Duplication within rings
Linear deletions
2.5
