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1.  Molecular Testing for Fragile X: Analysis of 5062 Tests from 1105 Fragile X Families—Performed in 12 Clinical Laboratories in Spain 
BioMed Research International  2014;2014:195793.
Fragile X syndrome is the most common inherited form of intellectual disability. Here we report on a study based on a collaborative registry, involving 12 Spanish centres, of molecular diagnostic tests in 1105 fragile X families comprising 5062 individuals, of whom, 1655 carried a full mutation or were mosaic, three cases had deletions, 1840 had a premutation, and 102 had intermediate alleles. Two patients with the full mutation also had Klinefelter syndrome. We have used this registry to assess the risk of expansion from parents to children. From mothers with premutation, the overall rate of allele expansion to full mutation is 52.5%, and we found that this rate is higher for male than female offspring (63.6% versus 45.6%; P < 0.001). Furthermore, in mothers with intermediate alleles (45–54 repeats), there were 10 cases of expansion to a premutation allele, and for the smallest premutation alleles (55–59 repeats), there was a 6.4% risk of expansion to a full mutation, with 56 repeats being the smallest allele that expanded to a full mutation allele in a single meiosis. Hence, in our series the risk for alleles of <59 repeats is somewhat higher than in other published series. These findings are important for genetic counselling.
PMCID: PMC4058505  PMID: 24987673
2.  3p14 De Novo Interstitial Microdeletion in a Patient with Intellectual Disability and Autistic Features with Language Impairment: A Comparison with Similar Cases 
Case Reports in Genetics  2015;2015:876348.
To date, few cases of 3p proximal interstitial deletions have been reported and the phenotype and genotype correlation is not well understood. Here, we report a new case of a 3p proximal interstitial deletion. The patient is an 11-year-old female with speech and social interaction difficulties, learning disability, and slight facial dysmorphism, but no other major malformations. An 8 Mb de novo interstitial deletion at 3p14.2-p14.1, from position 60.461.316 to 68.515.453, was revealed by means of array comparative genomic hybridization and confirmed using quantitative reverse-transcription polymerase chain reaction assays. This region includes six genes: FEZF2, CADPS, SYNPR, ATXN7, PRICKLE, and MAGI1, that are known to have a role in neurodevelopment. These genes are located on the proximal side of the deletion. We compare our case with previously well-defined patients reported in the literature and databases.
PMCID: PMC4446465  PMID: 26075115
3.  Analysis of PALB2 Gene in BRCA1/BRCA2 Negative Spanish Hereditary Breast/Ovarian Cancer Families with Pancreatic Cancer Cases 
PLoS ONE  2013;8(7):e67538.
The PALB2 gene, also known as FANCN, forms a bond and co-localizes with BRCA2 in DNA repair. Germline mutations in PALB2 have been identified in approximately 1% of familial breast cancer and 3–4% of familial pancreatic cancer. The goal of this study was to determine the prevalence of PALB2 mutations in a population of BRCA1/BRCA2 negative breast cancer patients selected from either a personal or family history of pancreatic cancer.
132 non-BRCA1/BRCA2 breast/ovarian cancer families with at least one pancreatic cancer case were included in the study. PALB2 mutational analysis was performed by direct sequencing of all coding exons and intron/exon boundaries, as well as multiplex ligation-dependent probe amplification.
Two PALB2 truncating mutations, the c.1653T>A (p.Tyr551Stop) previously reported, and c.3362del (p.Gly1121ValfsX3) which is a novel frameshift mutation, were identified. Moreover, several PALB2 variants were detected; some of them were predicted as pathological by bioinformatic analysis. Considering truncating mutations, the prevalence rate of our population of BRCA1/2-negative breast cancer patients with pancreatic cancer is 1.5%.
The prevalence rate of PALB2 mutations in non-BRCA1/BRCA2 breast/ovarian cancer families, selected from either a personal or family pancreatic cancer history, is similar to that previously described for unselected breast/ovarian cancer families. Future research directed towards identifying other gene(s) involved in the development of breast/pancreatic cancer families is required.
PMCID: PMC3720732  PMID: 23935836
4.  Common variants at the 19p13.1 and ZNF365 loci are associated with ER subtypes of breast cancer and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers 
Couch, Fergus J. | Gaudet, Mia M. | Antoniou, Antonis C. | Ramus, Susan J. | Kuchenbaecker, Karoline B. | Soucy, Penny | Beesley, Jonathan | Chen, Xiaoqing | Wang, Xianshu | Kirchhoff, Tomas | McGuffog, Lesley | Barrowdale, Daniel | Lee, Andrew | Healey, Sue | Sinilnikova, Olga M. | Andrulis, Irene L. | Ozcelik, Hilmi | Mulligan, Anna Marie | Thomassen, Mads | Gerdes, Anne-Marie | Jensen, Uffe Birk | Skytte, Anne-Bine | Kruse, Torben A. | Caligo, Maria A. | von Wachenfeldt, Anna | Barbany-Bustinza, Gisela | Loman, Niklas | Soller, Maria | Ehrencrona, Hans | Karlsson, Per | Nathanson, Katherine L. | Rebbeck, Timothy R. | Domchek, Susan M. | Jakubowska, Ania | Lubinski, Jan | Jaworska, Katarzyna | Durda, Katarzyna | Złowocka, Elżbieta | Huzarski, Tomasz | Byrski, Tomasz | Gronwald, Jacek | Cybulski, Cezary | Górski, Bohdan | Osorio, Ana | Durán, Mercedes | Tejada, María Isabel | Benitez, Javier | Hamann, Ute | Hogervorst, Frans B.L. | van Os, Theo A. | van Leeuwen, Flora E. | Meijers-Heijboer, Hanne E.J. | Wijnen, Juul | Blok, Marinus J. | Kets, Marleen | Hooning, Maartje J. | Oldenburg, Rogier A. | Ausems, Margreet G.E.M. | Peock, Susan | Frost, Debra | Ellis, Steve D. | Platte, Radka | Fineberg, Elena | Evans, D. Gareth | Jacobs, Chris | Eeles, Rosalind A. | Adlard, Julian | Davidson, Rosemarie | Eccles, Diana M. | Cole, Trevor | Cook, Jackie | Paterson, Joan | Brewer, Carole | Douglas, Fiona | Hodgson, Shirley V. | Morrison, Patrick J. | Walker, Lisa | Porteous, Mary E. | Kennedy, M. John | Side, Lucy E. | Bove, Betsy | Godwin, Andrew K. | Stoppa-Lyonnet, Dominique | Fassy-Colcombet, Marion | Castera, Laurent | Cornelis, François | Mazoyer, Sylvie | Léoné, Mélanie | Boutry-Kryza, Nadia | Bressac-de Paillerets, Brigitte | Caron, Olivier | Pujol, Pascal | Coupier, Isabelle | Delnatte, Capucine | Akloul, Linda | Lynch, Henry T. | Snyder, Carrie L. | Buys, Saundra S. | Daly, Mary B. | Terry, MaryBeth | Chung, Wendy K. | John, Esther M. | Miron, Alexander | Southey, Melissa C. | Hopper, John L. | Goldgar, David E. | Singer, Christian F. | Rappaport, Christine | Tea, Muy-Kheng M. | Fink-Retter, Anneliese | Hansen, Thomas V. O. | Nielsen, Finn C. | Arason, Aðalgeir | Vijai, Joseph | Shah, Sohela | Sarrel, Kara | Robson, Mark E. | Piedmonte, Marion | Phillips, Kelly | Basil, Jack | Rubinstein, Wendy S. | Boggess, John | Wakeley, Katie | Ewart-Toland, Amanda | Montagna, Marco | Agata, Simona | Imyanitov, Evgeny N. | Isaacs, Claudine | Janavicius, Ramunas | Lazaro, Conxi | Blanco, Ignacio | Feliubadalo, Lidia | Brunet, Joan | Gayther, Simon A | Pharoah, Paul PD | Odunsi, Kunle O. | Karlan, Beth Y. | Walsh, Christine S. | Olah, Edith | Teo, Soo Hwang | Ganz, Patricia A. | Beattie, Mary S. | van Rensburg, Elizabeth J. | Dorfling, Cecelia M. | Diez, Orland | Kwong, Ava | Schmutzler, Rita K. | Wappenschmidt, Barbara | Engel, Christoph | Meindl, Alfons | Ditsch, Nina | Arnold, Norbert | Heidemann, Simone | Niederacher, Dieter | Preisler-Adams, Sabine | Gadzicki, Dorothea | Varon-Mateeva, Raymonda | Deissler, Helmut | Gehrig, Andrea | Sutter, Christian | Kast, Karin | Fiebig, Britta | Heinritz, Wolfram | Caldes, Trinidad | de la Hoya, Miguel | Muranen, Taru A. | Nevanlinna, Heli | Tischkowitz, Marc D. | Spurdle, Amanda B. | Neuhausen, Susan L. | Ding, Yuan Chun | Lindor, Noralane M. | Fredericksen, Zachary | Pankratz, V. Shane | Peterlongo, Paolo | Manoukian, Siranoush | Peissel, Bernard | Zaffaroni, Daniela | Barile, Monica | Bernard, Loris | Viel, Alessandra | Giannini, Giuseppe | Varesco, Liliana | Radice, Paolo | Greene, Mark H. | Mai, Phuong L. | Easton, Douglas F. | Chenevix-Trench, Georgia | Offit, Kenneth | Simard, Jacques
Genome-wide association studies (GWAS) identified variants at 19p13.1 and ZNF365 (10q21.2) as risk factors for breast cancer among BRCA1 and BRCA2 mutation carriers, respectively. We explored associations with ovarian cancer and with breast cancer by tumor histopathology for these variants in mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).
Genotyping data for 12,599 BRCA1 and 7,132 BRCA2 mutation carriers from 40 studies were combined.
We confirmed associations between rs8170 at 19p13.1 and breast cancer risk for BRCA1 mutation carriers (hazard ratio (HR)=1.17; 95%CI 1.07–1.27; p=7.42×10−4) and between rs16917302 at ZNF365 (HR=0.84; 95%CI 0.73–0.97; p=0.017) but not rs311499 at 20q13.3 (HR=1.11; 95%CI 0.94–1.31; p=0.22) and breast cancer risk for BRCA2 mutation carriers. Analyses based on tumor histopathology showed that 19p13 variants were predominantly associated with estrogen receptor (ER)-negative breast cancer for both BRCA1 and BRCA2 mutation carriers, whereas rs16917302 at ZNF365 was mainly associated with ER-positive breast cancer for both BRCA1 and BRCA2 mutation carriers. We also found for the first time that rs67397200 at 19p13.1 was associated with an increased risk of ovarian cancer for BRCA1 (HR=1.16; 95%CI 1.05–1.29; p=3.8×10−4) and BRCA2 mutation carriers (HR=1.30; 95%CI 1.10–1.52; p=1.8×10−3).
19p13.1 and ZNF365 are susceptibility loci for ovarian cancer and ER subtypes of breast cancer among BRCA1 and BRCA2 mutation carriers.
These findings can lead to an improved understanding of tumor development and may prove useful for breast and ovarian cancer risk prediction for BRCA1 and BRCA2 mutation carriers.
PMCID: PMC3319317  PMID: 22351618
BRCA1; BRCA2; breast cancer risk; ovarian cancer risk; 19p13.1; ZNF365
5.  CDKL5 gene status in female patients with epilepsy and Rett-like features: two new mutations in the catalytic domain 
BMC Medical Genetics  2012;13:68.
Mutations in the cyclin-dependent kinase-like 5 gene (CDKL5) located in the Xp22 region have been shown to cause a subset of atypical Rett syndrome with infantile spasms or early seizures starting in the first postnatal months.
We performed mutation screening of CDKL5 in 60 female patients who had been identified as negative for the methyl CpG-binding protein 2 gene (MECP2) mutations, but who had current or past epilepsy, regardless of the age of onset, type, and severity. All the exons in the CDKL5 gene and their neighbouring sequences were examined, and CDKL5 rearrangements were studied by multiplex ligation-dependent probe amplification (MLPA).
Six previously unidentified DNA changes were detected, two of which were disease-causing mutations in the catalytic domain: a frameshift mutation (c.509_510insGT; p.Glu170GlyfsX36) and a complete deletion of exon 10. Both were found in patients with seizures that started in the first month of life.
This study demonstrated the importance of CDKL5 mutations as etiological factors in neurodevelopmental disorders, and indicated that a thorough analysis of the CDKL5 gene sequence and its rearrangements should be considered in females with Rett syndrome-like phenotypes, severe encephalopathy and epilepsy with onset before 5 months of age. This study also confirmed the usefulness of MLPA as a diagnostic screening method for use in clinical practice.
PMCID: PMC3489578  PMID: 22867051
CDKL5; Epilepsy; MECP2; MLPA; Rett syndrome

Results 1-5 (5)