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