Implementation of a complex genome profiling diagnostic algorithm for patients with congenital and developmental abnormalities (CONGEN)

Acronym: CONGEN
Principal investigator: Carmen Cristina Diaconu PhD

(2014–2017; PN-II-PT-PCCA-2013-4-2240) – Principal investigator: Carmen Cristina Diaconu PhD

Program: PN-II-PT-PCCA-2013-4
Project code (agreement): 133/2014
Funds: UEFISCDI (http://uefiscdi.gov.ro)
Project’s length: 24 months (July 2014 – June 2016)
Total buget: 1.457.200,00 lei

Partners

Coordinator institution (CO): Stefan S. Nicolau Institute of Virology, Bucharest
www.virology.ro
Address: 285 Mihai Bravu Ave., Bucharest 3, Romania; tel/fax: 021 3242590
Project director: Dr. Carmen Cristina Diaconu, CS I
e-mail: ccdiaconu@yahoo.com; carmen.diaconu@virology.ro

Partner 1 (P1) Alessandrescu – Rusescu INSMC (old name: Alfred Rusescu IOMC) Bucharest
www.iomc.ro
P1 team leader: Dr. Plăiașu Vasilica, CS
Address: B-dul Lacul Tei no.120, Bucharest 2, Romania
vasilica.plaiasu@gmail.com

Partner 2 (P2) Grigore T. Popa UMF Iaşi
www.umfiasi.ro
P2 team leader: Dr. Gorduza Eusebiu Vlad
Address: 16 Universitatii street- Iasi, Romania
vgord@mail.com

 Partner 3 (P3) Personal Genetics Ltd., Bucharest
www.personalgenetics.ro
P3 team leader: Dr. Stoian Monica
4,Frumoasa st, Bucharest, Romania
monica.stoian@personalgenetics.ro

Summary of the project

The proposed project will set up a consortium in genomics, aiming at the implementation of new investigation methods in clinical practice that could contribute to the elucidation of the molecular mechanisms of congenital and developmental abnormalities with a final practical goal in prophylaxis and better clinical management of patients. The project corresponds to the direction 4 – HEALTH and its objectives refer to the national implementation of new prevention and intervention methods in accordance with European standards (4.1.6). The major objectives of the project are:

 1) Investigation of genetic abnormalities in Romanian patients with congenital/developmental disorders aiming to identify possible new genomic variants;

 2) Integration in the international endeavor of identifying and confirming new genomic variants for these rare disorders through active participation and inclusion of the Romanian data in the multi-center international consortia.

 3) Implementation of a complex genome profiling diagnostic algorithm for patients with congenital and developmental abnormalities and use the integrated results for improving diagnostic yield, genetic counseling and clinical management.

The partnership consists of Stefan S. Nicolau IVN Bucharest, that will set-up the cells/DNA/RNA sample bank and perform PCR, MS-MLPA, sequencing analysis; Alfred Rusescu IOMC Bucharest and Grigore T. Popa UMF Iaşi that will recruit the patients, perform the phenotype/formal-genetic analysis and clinical management of the patients, and Personal Genetics Ltd. which will perform aCGH and next generation sequencing, will integrate the results of the analysis and will apply the resulting algorithm, firstly in their practice, and next will disseminate it to a clearly defined target market. The consortium represents a specialized and complementary team, capable to advancing the knowledge on clinical management, prevention, and eventually, therapy of congenital and developmental abnormalities, and to join international research effort in this direction.

Working plan

Work package
No[1]		Work package titleWork package leader[2]Start
month[3]		End
month[4]
1Establishing the conceptual model for Romanian sample recruitment, defining experimental protocols and enrollment of the first patientsCOMonth 1Month 7
2Romanian sample expansion, experimental analysis and integration of the data in international repositoriesP1/P2Month 8Month 17
3Molecular and clinical data analysis and integration of the results in clinical practice (I)P3Month 25Month 36
4Molecular and clinical data analysis and integration of the results in clinical practice (II)P3/COMonth 36Month 48
 TOTAL Month 1Month 48

[1] Work package number: WP 1 – WP n.

[2] Number of the partner leading the work in the WP

[3] Relative start date for the work in the specific work packages, month 1 marking the start date of the project, and all other start dates being relative to this start date.

[4] Relative end date, month 1 marking the start date of the project, and all end dates being relative to this start date.

Results

WP1: Establishing the conceptual model for Romanian sample recruitment, defining experimental protocols and enrollment of the first patients – 2014

Articles (Accepted/E-pub ahead of print/published in 2014):
  1. A concise review of Hox genes: the molecular bridges between developmental anomalies and cancer, Rom Biotech Letters; 


Oral presentations:
Dysmorphology and radiology of Inborn Errors of Metabolism, 16-17 October 2014, Manchester, United Kingdom
  1. Case presentation, Vasilica Plaiasu

IOMC “Prof. dr. Alfred Rusescu” Days, 27-29 November 2014, Bucuresti
  1. Anomaliile cromozomiale in practica medicala, Vasilica Plaiasu, Ochiana Diana, Motei Gabriela, , Abstract publicat in Revista Romana de Pediatrie, supliment abstracte Zilele Institutului pentru Ocrotirea Mamei si Copilului “Prof. dr. Alfred Rusescu”.

WP2: Romanian sample expansion, experimental analysis and integration of the data in international repositories – 2015

Articles (Accepted/E-pub ahead of print/published in 2015):
  1. A concise review of Hox genes: the molecular bridges between developmental anomalies and cancer, Rom Biotech Letters; 2015, 20(3), 10504- 10511, IF 0,404; 

  2. Epigenetics in gastric carcinogenesis: TET genes as important players. Laura Georgiana Necula, Cristina Mambet, Radu Albulescu, Carmen C. Diaconu. Journal of Immunoassay and Immunochemistry 2015; 36(5): 445-455.
  3. Comparative molecular approaches in Prader-Willi syndrome diagnosis. Botezatu A, Puiu M, Cucu N, Diaconu CC, Badiu C, Arsene C, Iancu IV, Plesa A, Anton G., Gene. 2016 Jan 10;575(2P1):353-358. doi: 10.1016/j.gene.2015.08.058. Epub 2015 Sep 1, IF 2,235; 

  4.  Neonatal Graves-Basedow disease due to long-standing Trab persistence following total thyroidectomy, Emiliana Teodora Dragomir-Ananie, Camelia Procopiuc, Florea Caliopsia, Maricica Gusa, Carmen Cristina Diaconu, Journal of Translational Medicine and Research, 20(3) 168-171, Oct 2015.
International and national conferences:
European Human Genetics Conference, 6 – 9 June 2015, Glasgow
  1. Cytogenetic approach of girls with short stature: unrelated 6 cases with structural X chromosome abnormalities, Plaiasu V., Ochiana D., Motei G., Brezan F., Anca I., Abstract in European Journal of Human Genetics, vol. 23, Supplement 1, June 2015, IF 4.580
  2. Trisomy of the short arm of chromosome 10: description of three new cases, Diana Ochiana, Gabriela Motei, Vasilica Plaiasu, Florin Brezan, Ioana Anca, Abstract in European Journal of Human Genetics, vol. 23, Supplement 1, June 2015, IF 4.580

The 10th European Cytogenetics Conference, 4 – 7 July 2015, Strasbourg
  1. Marker chromosome analysis in two patients with Turner syndrome variant resembling Kabuki phenotype, Plaiasu Vasilica, Ochiana Diana, Motei Gabriela, Anca Ioana. Abstract in Chromosome Research, vol.23, Supplement 1, July 2015

SSIEM (Society for the Study of Inborn Errors of Metabolism) 2015 Annual Symposium, 1 – 4 September 2015, Lyon
  1. X-linked dominant condrodysplasia punctata: clinical phenotype in an affected female, V. Plaiasu, D. Ochiana, G. Motei, A. Coltoiu, SSIEM 2015 Annual Symposium, 1 – 4 Septembrie 2015, Lyon. Abstract in Vol.38, Suppl.1, Sept.2015, Journal of Inherited Metabolic Disease.

A VIII-a Conferinta Nationala de Genetica Medicala, 7-9 October 2015, Orastie, Romania
  1. Sexual aneuploidy associated with a rare subtelomeric deletion – case report, Gabriela Motei, Diana Ochiana, Vasilica Plaiasu, Mirela Covacescu, Florin Brezan, Ioana Anca, Abstract in Romanian Journal of Rare Diseases, Supplement 1/2015
  2. Cytogenetic and clinical assessment of a family with a rare recurrent translocation: coexistence of 10p trisomy and 2p25.1 monosomy, Diana Ochiana, Gabriela Motei, Vasilica Plaiasu, Florin Brezan, Ioana Anca. Abstract in Romanian Journal of Rare Diseases, Supplement 1/2015

Simpozion “Bolile rare: solidaritate medic-pacient-familie-asociatii de pacienti”, 25 February 2015, Bucuresti
  1. Living with a rare disease – Day-by-day, hand-in-hand, Plaiasu Vasilica
  2. Dificultati de diagnostic intr-un caz de tulburare de sexualizare, Gherghina Ioan. Cochino Alexis, Plaiasu Vasilica
  3. Boala Hirschprung sindromatica cu transmitere familiala, Dobre Adelina, Dumitru Cristina, Paraschivescu Ana Maria, Ivan Adina, Tanasie Maria, Bar Gabriela, Craiu Mihai, Cretu Rodica, Brezan Florin, Ghita Lucica, Plaiasu Vasilica, Ioana Anca
  4. Diagnostic de boala rara la un sugar cu anomalii congenitale multiple, Farcas Oana, Covacescu Mirela, Plaiasu Vasilica, Dragostin Octavia, Ghita Lucica
  5. Abordare complexa a unui caz de varsta pediatrica cu anomalie cromozomiala, Dumitru Cristina, Paraschivescu Ana Maria, Ivan Adina, Dobre Adelina, Tanasie Maria, Bar Gabriela, Cretu Rodica, Brezan Florin, Ghita Lucica, Nedea Catalin, Plaiasu Vasilica, Ochiana Diana, Motei Gabriela, Ioana Anca

11th Balkan Congress of Human Genetics, 16-21 September 2015, Belgrad
  1. Implementation of a complex genome profiling diagnostic algorithm for patients with congenital and developmental abnormalities, Cristina Rusu, Mihaela Grămescu, Lavinia Caba, Monica Pânzaru, Lăcrămioara Butnariu, Elena Braha, Roxana Popescu, Setalia Popa, Vasilica Plăiaşu, Carmen Diaconu, Monica Stoian, Eusebiu Vlad Gorduza – oral presentation

SYNEVO CLINICAL RESEARCH SYMPOSIUM XIV Ed, 13 November 2015, Bucuresti
  1. Molecularly targeted therapy – translation of genomics and cell biology data to rational therapeutic approaches for complex disorders, Carmen Diaconu

“Zilele Institutului pentru Ocrotirea Mamei si Copilului” 10 -12 December 2015, Bucuresti
  1. Anomalii cromozomiale rare – diagnostic si management, Plaiasu Vasilica, Ochiana Diana, Motei Gabriela

WP3: Molecular and clinical data analysis and integration of the results in clinical practice (I) – 2016

Articles (Accepted/E-pub ahead of print/published in 2016):
  1. Comparative molecular approaches in Prader-Willi syndrome diagnosis, Botezatu A, Puiu M, Cucu N, Diaconu CC, Badiu C, Arsene C, Iancu IV, Plesa A, Anton G. Gene 575(2P1): 353-358, 2016, ISSN: 0378-1119, IF 2,235. 

  2. A link between the driver mutations and dysregulated apoptosis in BCR-ABL1 negative myeloproliferative neoplasms, Mambet C, Matei L, Necula LG, Diaconu CC. J Immunoassay Immunochem. 2016;37 (4):331-45.
  3. Delivering the “Blueprints” or “DNA Repairing Kits” Instead of Drugs in the Treatment of Congenital Hemoglobinopathies, Diana Chiru, Cristina Mambet, Lilia Matei, Coralia Bleotu, Simona Ruta, Carmen C Diaconu, Current Organic Chemistry (e-pub ahead of print), 20, DOI: 10.2174/1385272820666160511122404,  2016; FI: 1,949.
  4.  A phenotypic screen for small-molecule inhibitors of constitutively active mutant thrombopoietin receptor implicated in myeloproliferative neoplasms, Anna Ngo, Ann Zhufang Koay, Christian Pecquet, Carmen C. Diaconu, Yasmine Ould-Amer, Qiwei Huang, Congbao Kang, Anders Poulsen, David Jenkins, Andrew Shiau, Stefan N Constantinescu, Meng Ling Choong, Combinatorial Chemistry & High Throughput Screening, 19, 2016 Oct 10. [Epub ahead of print] FI 1.041.
  5. TP53 somatic mutations and LOH profile in colorectal cancer in Romania, Daniela Murarasu, Liliana Puiu, Ioana Madalina Aldea Pitica, Cristina Mambet, Corina Elena Mihalcea, Augustin Marian Marincas, Sabin Cinca, Lorelei Brasoveanu, Carmen Cristina Diaconu, Romanian Biotechnological Letters (accepted). FI 0,412
Oral presentations at international and national conferences:
Simpozionul Academician Nicolae Cajal Ed. 11, București, martie 2016
  1. Profiluri de fosforilare proteică în neoplasmele mieloproliferative BCR-ABL1 negative, Cristina Mambet, Laura G. Necula, Coralia Bleotu, Ioana M Aldea-Pitica, Ana I. Neagu, Lilia Matei, Denisa Dragu, Mihaela Chivu-Economescu, Carmen C. Diaconu, Stefan N Constantinescu. 

“Personalized Medicine” 1-2 June 2016, Bruxelles
  1. Prezentarea profilului si proiectelor de medicina personalizata ale Institutului de Virusologie, Carmen C. Diaconu, Coralia Bleotu

A IX a Conferință de Genetică Medicală cu Participare Internaţională, 22-24 septembrie 2016, Alba Iulia
  1. Better diagnostics by current genomic technology, Plaiasu Vasilica, Ozunu Diana, Motei Gabriela, Zeleniuc Monica, Cardos Georgeta, Gurban Petruta, Dinulescu Gabriel, Neagu Ana, Necula Laura, Mambet Cristina, Aldea Pitica Ioana, Matei Lilia, Diaconu Carmen. Abstract in Romanian Journal of Rare Diseases Supplement 1/2016
  2. ArrayCGH – a valuable instrument in clarifying chromosomal abberation identified by conventional karyotype in postnatal diagnosis, Monica Zeleniuc, Vasilica Plaiasu, Vlad Gorduza, Diana Ozunu, Motei Gabriela, Carmen C.Diaconu, Petruta Gurban, Gabriel Dinulescu, Georgeta Cardos. Abstract in Romanian Journal of Rare Diseases Supplement 1/2016

Zilele INSMC „Interdisciplinaritatea in practica clinica” 9-10 decembrie 2016, Bucuresti
  1. Rolul investigatiei citogenetice in diagnosticul bolilor genetice rare, Plaiasu Vasilica, Ozunu Diana, Motei Gabriela

Posters presented at international conferences (abstract published in ISI journals):
Conferinta Europeana de Genetica Umana, 21-24 mai 2016, Barcelona
  1. Rare plurimalformative syndrome marked by dermatological phenotype associated with unbalanced chromosomal anomaly, V. Plaiasu, D. Ozunu, G. Motei, A. Coltoiu, M. Stoian, P. Gurban, G. Dinulescu, C. Diaconu. Abstract in European Journal of Human Genetics, vol. 24E, Supplement 1, May 2016, ISI, IF 4,580. 
  2. Distal 14q trisomy – cytogenetic and clinical assessment of a family with a recurrent t(14;15)(q31.1;q26), D. A. Ozunu, M. Gabriela, V. Plaiasu, M. Stoian, P. Gurban, G. Dinulescu, C. Diaconu. Abstract in European Journal of Human Genetics, vol. 24E, Supplement 1, May 2016, ISI, IF 4,580.
  3. Distal 4q partial trisomy vs. distal 10q monosomy – report of a family with a t(4;10)(q31.3;q24), G. Motei, D. Ozunu, V. Plaiasu. Abstract in European Journal of Human Genetics, vol. 24E, Supplement 1, May 2016, ISI, IF 4,580
  4. A new case of campomelic dysplasia with dextrocardia and without sex-reversal, Augustin I., Pavaloaia O., Pânzaru M., Martiniuc V., Gramescu M., Paduraru L., Stamatin M., Târnovan M., Onofriescu M., Gorduza E.V. Abstract in European Journal of Human Genetics, vol. 24E, Supplement 1, May 2016, ISI, IF 4,580.
  5. The use of different types of chromosomal analyses in clarification of aetiology of a plurimalfromative syndrome, Gramescu M., Caba L., Pânzaru M., Butnariu L., Braha E., Popescu R., Rusu C., Plaiasu V., Martiniuc V., Paduraru L., Stamatin M., Gorduza E.V. Abstract in European Journal of Human Genetics, vol. 24E, Supplement 1, May 2016, ISI, IF 4,580.
  6. Unusual structural abnormalities of small acrocentric chromosomes – difficulties of genetic counseling, Popa S., Popescu R., Braha E., Gramescu M., Graur E., Martiniuc V., Gorduza E.V. Abstract in European Journal of Human Genetics, vol. 24E, Supplement 1, May 2016, ISI, IF 4,580.

Posters presented at international meetings (abstract published in national journals – IDB):
A IX a Conferință de Genetică Medicală cu Participare Internaţională, 22-24 septembrie 2016, Alba Iulia
  1. Rare chromosomal inversions with phenotypic abnormalities – two unrelated cases, Ozunu Diana, Plaiasu Vasilica, Motei Gabriela, Zeleniuc Monica, Cardos Georgeta, Gurban Petruta, Dinulescu Gabriel, Neagu Ana, Necula Laura, Mambet Cristina, Aldea Pitica Ioana, Matei Lilia, Diaconu Carmen. Abstract in Romanian Journal of Rare Diseases Supplement 1/2016
  2. Complex cytogenetic assesment of a case with marker chromosome, Motei Gabriela, Ozunu Diana, Plaiasu Vasilica, Zeleniuc Monica, Cardos Georgeta, Gurban Petruta, Dinulescu Gabriel, Neagu Ana, Necula Laura, Mambet Cristina, Aldea Pitica Ioana, Matei Lilia, Diaconu Carmen. Abstract in Romanian Journal of Rare Diseases Supplement 1/2016
  3. ArrayCGH approach for investigating a case of der(8)dn chromosome, Petruta Gurban, Monica Zeleniuc, Vasilica Plaiasu, Diana Ozunu, Motei Gabriela, Carmen C.Diaconu, Laura Necula, Gabriel Dinulescu, Georgeta Cardos. Abstract in Romanian Journal of Rare Diseases Supplement 1/2016
  4. ArrayCGH analysis of two genomic imbalances on chromosome 8, Gabriel Dinulescu, Monica Zeleniuc, Vasilica Plaiasu, Diana Ozunu, Motei Gabriela, Carmen C.Diaconu, Ana Neagu, Petruta Gurban, Georgeta Cardos. Abstract in Romanian Journal of Rare Diseases Supplement 1/2016

WP4: Molecular and clinical data analysis and integration of the results in clinical practice (II) – 2017

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