@article {10769, title = {De novo unbalanced translocations have a complex history/aetiology.}, journal = {Hum Genet}, volume = {137}, year = {2018}, month = {2018 Oct}, pages = {817-829}, abstract = {

We investigated 52 cases of de novo unbalanced translocations, consisting in a terminally deleted or inverted-duplicated deleted (inv-dup del) 46th chromosome to which the distal portion of another chromosome or its opposite end was transposed. Array CGH, whole-genome sequencing, qPCR, FISH, and trio genotyping were applied. A biparental origin of the deletion and duplication was detected in 6 cases, whereas in 46, both imbalances have the same parental origin. Moreover, the duplicated region was of maternal origin in more than half of the cases, with 25\% of them showing two maternal and one paternal haplotype. In all these cases, maternal age was increased. These findings indicate that the primary driver for the occurrence of the de novo unbalanced translocations is a maternal meiotic non-disjunction, followed by partial trisomy rescue of the supernumerary chromosome present in the trisomic zygote. In contrast, asymmetric breakage of a dicentric chromosome, originated either at the meiosis or postzygotically, in which the two resulting chromosomes, one being deleted and the other one inv-dup del, are repaired by telomere capture, appears at the basis of all inv-dup del translocations. Notably, this mechanism also fits with the origin of some simple translocations in which the duplicated region was of paternal origin. In all cases, the signature at the translocation junctions was that of non-homologous end joining (NHEJ) rather than non-allelic homologous recombination (NAHR). Our data imply that there is no risk of recurrence in the following pregnancies for any of the de novo unbalanced translocations we discuss here.

}, keywords = {DNA End-Joining Repair, Female, Humans, Male, Meiosis, Recombinational DNA Repair, Translocation, Genetic}, issn = {1432-1203}, doi = {10.1007/s00439-018-1941-9}, author = {Bonaglia, Maria Clara and Kurtas, Nehir Edibe and Errichiello, Edoardo and Bertuzzo, Sara and Beri, Silvana and Mehrjouy, Mana M and Provenzano, Aldesia and Vergani, Debora and Pecile, Vanna and Novara, Francesca and Reho, Paolo and Di Giacomo, Marilena Carmela and Discepoli, Giancarlo and Giorda, Roberto and Aldred, Micheala A and Santos-Rebou{\c c}as, C{\'\i}ntia Barros and Goncalves, Andressa Pereira and Abuelo, Diane N and Giglio, Sabrina and Ricca, Ivana and Franchi, Fabrizia and Patsalis, Philippos and Sismani, Carolina and Mor{\'\i}, Mar{\'\i}a Angeles and Nevado, Juli{\'a}n and Tommerup, Niels and Zuffardi, Orsetta} } @article {10845, title = {Rothmund-Thomson Syndrome: Insights from New Patients on the Genetic Variability Underpinning Clinical Presentation and Cancer Outcome.}, journal = {Int J Mol Sci}, volume = {19}, year = {2018}, month = {2018 Apr 06}, abstract = {

Biallelic mutations in gene, a caretaker of the genome, cause Rothmund-Thomson type-II syndrome (RTS-II) and confer increased cancer risk if they damage the helicase domain. We describe five families exemplifying clinical and allelic heterogeneity of RTS-II, and report the effect of pathogenic variants by predictions and transcripts analyses. Complete phenotype of patients $\#$39 and $\#$42 whose affected siblings developed osteosarcoma correlates with their c.[1048_1049del], c.[1878+32_1878+55del] and c.[1568G>C;1573delT], c.[3021_3022del] variants which damage the helicase domain. Literature survey highlights enrichment of these variants affecting the helicase domain in patients with cancer outcome raising the issue of strict oncological surveillance. Conversely, patients $\#$29 and $\#$19 have a mild phenotype and carry, respectively, the unreported homozygous c.3265G>T and c.3054A>G variants, both sparing the helicase domain. Finally, despite matching several criteria for RTS clinical diagnosis, patient $\#$38 is heterozygous for c.2412_2414del; no pathogenic CNVs out of those evidenced by high-resolution CGH-array, emerged as contributors to her phenotype.

}, keywords = {Adolescent, Adult, Cell Line, Tumor, Child, Female, Homozygote, Humans, Male, Mutation, Pedigree, Phenotype, RecQ Helicases, Rothmund-Thomson Syndrome}, issn = {1422-0067}, doi = {10.3390/ijms19041103}, author = {Colombo, Elisa A and Locatelli, Andrea and Cubells S{\'a}nchez, Laura and Romeo, Sara and Elcioglu, Nursel H and Maystadt, Isabelle and Esteve Mart{\'\i}nez, Altea and Sironi, Alessandra and Fontana, Laura and Finelli, Palma and Gervasini, Cristina and Pecile, Vanna and Larizza, Lidia} } @article {10500, title = {Phenotypic expression of 19q13.32 microdeletions: Report of a new patient and review of the literature.}, journal = {Am J Med Genet A}, year = {2017}, month = {2017 Apr 14}, abstract = {

The phenotypic manifestations of microdeletions in the 19q13.32 region are still poorly known. In this paper we report a patient who presented with hypotonia, developmental delay, facial dysmorphism, micrognathia, kyphoscoliosis, and buried penis. Chromosomal microarray revealed an interstitial 327 kb de novo microdeletion in the 19q13.32 region comprising eight genes (ARGHAP35, NPAS1, TMEM160, ZC3H4, SAE1, BBC3, MIR3190, and MIR3191). Previously reported cases of microdeletions in the 19q13.32 region were reviewed and compared to our patient, highlighting the common features of a possible 19q13.32 microdeletion syndrome.

}, issn = {1552-4833}, doi = {10.1002/ajmg.a.38256}, author = {Travan, Laura and Naviglio, Samuele and De Cunto, Angela and Pellegrin, Andrea and Pecile, Vanna and Spinelli, Alessandro Mauro and Cappellani, Stefania and Faletra, Flavio} } @article {8482, title = {A Case of Prenatal Neurocytoma Associated With ATR-16 Syndrome.}, journal = {J Ultrasound Med}, volume = {35}, year = {2016}, month = {2016 Jun}, pages = {1359-61}, issn = {1550-9613}, doi = {10.7863/ultra.15.07045}, author = {Quadrifoglio, Mariachiara and Faletra, Flavio and Bussani, Rossana and Pecile, Vanna and Zennaro, Floriana and Grasso, Alessandra and Zandon{\`a}, Lorenzo and Alberico, Salvatore and Stampalija, Tamara} } @article {8316, title = {A multi-method approach to the molecular diagnosis of overt and borderline 11p15.5 defects underlying Silver-Russell and Beckwith-Wiedemann syndromes.}, journal = {Clin Epigenetics}, volume = {8}, year = {2016}, month = {2016}, pages = {23}, abstract = {

BACKGROUND: Multiple (epi)genetic defects affecting the expression of the imprinted genes within the 11p15.5 chromosomal region underlie Silver-Russell (SRS) and Beckwith-Wiedemann (BWS) syndromes. The molecular diagnosis of these opposite growth disorders requires a multi-approach flowchart to disclose known primary and secondary (epi)genetic alterations; however, up to 20 and 30~\% of clinically diagnosed BWS and SRS cases remain without molecular diagnosis. The complex structure of the 11p15 region with variable CpG methylation and low-rate mosaicism may account for missed diagnoses. Here, we demonstrate the relevance of complementary techniques for the assessment of different CpGs and the importance of testing multiple tissues to increase the SRS and BWS detection rate.

RESULTS: Molecular testing of 147 and 450 clinically diagnosed SRS and BWS cases provided diagnosis in 34 SRS and 185 BWS patients, with 9 SRS and 21 BWS cases remaining undiagnosed and herein referred to as "borderline." A flowchart including complementary techniques and, when applicable, the analysis of buccal swabs, allowed confirmation of the molecular diagnosis in all borderline cases. Comparison of methylation levels by methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) in borderline and control cases defined an interval of H19/IGF2:IG-DMR loss of methylation that was distinct between "easy to diagnose" and "borderline" cases, which were characterized by values <=mean -3 standard deviations (SDs) compared to controls. Values >=mean +1 SD at H19/IGF2: IG-DMR were assigned to borderline hypermethylated BWS cases and those <=mean -2 SD at KCNQ1OT1: TSS-DMR to hypomethylated BWS cases; these were supported by quantitative pyrosequencing or Southern blot analysis. Six BWS cases suspected to carry mosaic paternal uniparental disomy of chromosome 11 were confirmed by SNP array, which detected mosaicism till 10~\%. Regarding the clinical presentation, borderline SRS were representative of the syndromic phenotype, with exception of one patient, whereas BWS cases showed low frequency of the most common features except hemihyperplasia.

CONCLUSIONS: A conclusive molecular diagnosis was reached in borderline methylation cases, increasing the detection rate by 6~\% for SRS and 5~\% for BWS cases. The introduction of complementary techniques and additional tissue analyses into routine diagnostic work-up should facilitate the identification of cases undiagnosed because of mosaicism, a distinctive feature of epigenetic disorders.

}, keywords = {Beckwith-Wiedemann Syndrome, Blotting, Southern, Child, Child, Preschool, Chromosomes, Human, Pair 11, CpG Islands, DNA Methylation, Epigenesis, Genetic, Female, Humans, Infant, Male, Mosaicism, Multiplex Polymerase Chain Reaction, Oligonucleotide Array Sequence Analysis, Silver-Russell Syndrome}, issn = {1868-7075}, doi = {10.1186/s13148-016-0183-8}, author = {Russo, Silvia and Calzari, Luciano and Mussa, Alessandro and Mainini, Ester and Cassina, Matteo and Di Candia, Stefania and Clementi, Maurizio and Guzzetti, Sara and Tabano, Silvia and Miozzo, Monica and Sirchia, Silvia and Finelli, Palma and Prontera, Paolo and Maitz, Silvia and Sorge, Giovanni and Calcagno, Annalisa and Maghnie, Mohamad and Divizia, Maria Teresa and Melis, Daniela and Manfredini, Emanuela and Ferrero, Giovanni Battista and Pecile, Vanna and Larizza, Lidia} } @article {8063, title = {When Feeding Difficulties Are due to Genetics: The Case of Familial Partial 9q Duplication.}, journal = {J Investig Med High Impact Case Rep}, volume = {3}, year = {2015}, month = {2015 Jan-Mar}, pages = {2324709615574949}, abstract = {

Chromosomal abnormalities may cause growth failure before or since birth. 9q duplication is reported as a cause of intrauterine growth restriction, mild dysmporphism, and intellectual disabilities. We report a case of a maternally inherited 9q21.31q21.33 duplication causing prenatal and postnatal growth restriction with feeding refusal and mild facial dysmorphisms, prenatally diagnosed by single-nucleotide polymorphism array analysis. Hypothesis of the possible pathogenic mechanisms are discussed.

}, issn = {2324-7096}, doi = {10.1177/2324709615574949}, author = {Travan, Laura and Rocca, Maria Santa and Buonomo, Francesca and Cleva, Lisa and Pecile, Vanna and De Cunto, Angela} } @article {3499, title = {Next generation sequencing in nonsyndromic intellectual disability: from a negative molecular karyotype to a possible causative mutation detection.}, journal = {Am J Med Genet A}, volume = {164A}, year = {2014}, month = {2014 Jan}, pages = {170-6}, abstract = {

The identification of causes underlying intellectual disability (ID) is one of the most demanding challenges for clinical Geneticists and Researchers. Despite molecular diagnostics improvements, the vast majority of patients still remain without genetic diagnosis. Here, we report the results obtained using Whole Exome and Target Sequencing on nine patients affected by isolated ID without pathological copy number variations, which were accurately selected from an initial cohort of 236 patients. Three patterns of inheritance were used to search for: (1) de novo, (2) X-linked, and (3) autosomal recessive variants. In three of the nine proband-parent trios analyzed, we identified and validated two de novo and one X-linked potentially causative mutations located in three ID-related genes. We proposed three genes as ID candidate, carrying one de novo and three X-linked mutations. Overall, this systematic proband-parent trio approach using next generation sequencing could explain a consistent percentage of patients with isolated ID, thus increasing our knowledge on the molecular bases of this disease and opening new perspectives for a better diagnosis, counseling, and treatment.

}, keywords = {Computational Biology, Exome, Female, Genes, Recessive, Genes, X-Linked, Genome-Wide Association Study, High-Throughput Nucleotide Sequencing, Humans, Intellectual Disability, Karyotype, Male, Mutation, Workflow}, issn = {1552-4833}, doi = {10.1002/ajmg.a.36274}, author = {Athanasakis, Emmanouil and Licastro, Danilo and Faletra, Flavio and Fabretto, Antonella and Dipresa, Savina and Vozzi, Diego and Morgan, Anna and d{\textquoteright}Adamo, Adamo P and Pecile, Vanna and Biarn{\'e}s, Xevi and Gasparini, Paolo} } @article {3529, title = {A novel deletion mutation involving TMEM38B in a patient with autosomal recessive osteogenesis imperfecta.}, journal = {Gene}, volume = {545}, year = {2014}, month = {2014 Jul 25}, pages = {290-2}, abstract = {

Osteogenesis imperfecta (OI) is a hereditary bone disease characterized by decreased bone density and multiple fractures, usually inherited in an autosomal dominant manner. Several gene encoding proteins related to collagen metabolism have been described in some cases of autosomal recessive OI (including CRTAP, LEPRE1, PPIB, FKBP65, SERPINF1, BMP1, WNT1, FKBP10). Recently, TMEM38B, a gene that encodes TRIC-B, a monovalent cation-specific channel involved in calcium flux from intracellular stores and in cell differentiation, has been associated with autosomal recessive OI. Here, we describe the second deletion-mutation involving the TMEM38B gene in an 11 year-old Albanian female with a clinical phenotype of OI, born to parents with suspected consanguinity. SNP array analysis revealed a homozygous region larger than 2 Mb that overlapped with the TMEM38B locus and was characterized by a 35 kb homozygous deletion involving exons 1 and 2 of TMEM38B gene.

}, keywords = {Child, Chromosomes, Human, Pair 19, DNA Mutational Analysis, Exons, Female, Genes, Recessive, Homozygote, Humans, Ion Channels, Osteogenesis Imperfecta, Sequence Deletion}, issn = {1879-0038}, doi = {10.1016/j.gene.2014.05.028}, author = {Rubinato, Elisa and Morgan, Anna and D{\textquoteright}Eustacchio, Angela and Pecile, Vanna and Gortani, Giulia and Gasparini, Paolo and Faletra, Flavio} } @article {1802, title = {Contribution of SNP arrays in diagnosis of deletion 2p11.2-p12.}, journal = {Gene}, volume = {492}, year = {2012}, month = {2012 Jan 15}, pages = {315-8}, abstract = {

Deletions of the short arm of chromosome 2 are exceedingly rare, having been reported in few patients. Furthermore most cases with deletion in 2p11.2-p12 have been studied using standard karyotype and so it is not possible to delineate the precise size of deletions. Here, we describe a 9-year-old girl with a 9.4 Mb de novo interstitial deletion of region 2p11.2-p12 identified by SNP array analysis. The deleted region encompasses over 40 known genes, including LRRTM1, CTNNA2 and REEP1, haploinsufficiency of which could explain some clinical features of this patient such as mental retardation, speech delay and gait abnormalities. A comparison of our case with previously reported patients who present deletions in 2p11.2-p12 was carried out. Our case adds new information to the deletion of 2p11.2-p12, improving the knowledge on this rearrangement.

}, keywords = {Abnormalities, Multiple, Child, Chromosomes, Human, Pair 2, Female, Humans, Intellectual Disability, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide, Sequence Deletion}, issn = {1879-0038}, doi = {10.1016/j.gene.2011.10.035}, author = {Rocca, Maria Santa and Fabretto, Antonella and Faletra, Flavio and Carlet, Ombretta and Skabar, Aldo and Gasparini, Paolo and Pecile, Vanna} } @article {1867, title = {De novo 6.9 Mb interstitial deletion on chromosome 4q31.1-q32.1 in a girl with severe speech delay and dysmorphic features.}, journal = {Am J Med Genet A}, volume = {158A}, year = {2012}, month = {2012 Apr}, pages = {882-7}, abstract = {

Deletion of the terminal part of long arm of chromosome 4 is a condition characterized by facial dysmorphisms, cardiac and limb defects, and developmental delay. Deletions usually involve the terminal part of the chromosome and most frequently are interstitial. Here, we report a de novo interstitial deletion resulting in a microdeletion of 6.9 Mb involving 4q31.3-q32.1 segment, detected by SNPs-Array technique in a 4-year-old female showing severe speech delay, mild facial dysmorphisms, and joint laxity. Phenotype-genotype relationships looking at the genes involved in this part of the chromosome were also carried out and data compared with those previously described.

}, keywords = {Abnormalities, Multiple, Child, Preschool, Chromosome Deletion, Chromosomes, Human, Pair 4, Developmental Disabilities, Female, Genotype, Humans, Language Development Disorders, Phenotype, Sequence Deletion}, issn = {1552-4833}, doi = {10.1002/ajmg.a.35239}, author = {Fabretto, Antonella and Santa Rocca, Maria and Perrone, Maria Dolores and Skabar, Aldo and Pecile, Vanna and Gasparini, Paolo} } @article {1807, title = {Does the 1.5 Mb microduplication in chromosome band Xp22.31 have a pathogenetic role? New contribution and a review of the literature.}, journal = {Am J Med Genet A}, volume = {158A}, year = {2012}, month = {2012 Feb}, pages = {461-4}, keywords = {Chromosome Breakpoints, Chromosome Duplication, Chromosomes, Human, X, Hand Deformities, Congenital, Humans, Intellectual Disability, Karyotyping, Muscle Hypotonia, Polymorphism, Single Nucleotide, Protein Tyrosine Phosphatases}, issn = {1552-4833}, doi = {10.1002/ajmg.a.34398}, author = {Faletra, Flavio and d{\textquoteright}Adamo, Adamo Pio and Santa Rocca, Maria and Carrozzi, Marco and Perrone, Maria Dolores and Pecile, Vanna and Gasparini, Paolo} } @article {1662, title = {A new case of duplication of the MDS region identified by high-density SNP arrays and a review of the literature.}, journal = {J Appl Genet}, volume = {52}, year = {2011}, month = {2011 Feb}, pages = {77-80}, keywords = {1-Alkyl-2-acetylglycerophosphocholine Esterase, Child, Female, Gene Duplication, Humans, Microtubule-Associated Proteins, Myelodysplastic Syndromes, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide, Prognosis}, issn = {2190-3883}, doi = {10.1007/s13353-010-0004-2}, author = {Faletra, Flavio and Devescovi, Raffaella and Pecile, Vanna and Fabretto, Antonella and Carrozzi, Marco and Gasparini, Paolo} }