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author:("tassan, Elisa")
1.  Concomitant deletion of chromosome 16p13.11 and triplication of chromosome 19p13.3 in a child with developmental disorders, intellectual disability, and epilepsy 
Background
Rare copy number variations (CNVs) are today recognized as an important cause of various neurodevelopmental disorders, including mental retardation and epilepsy. In some cases, a second CNV may contribute to a more severe clinical presentation.
Results
Here we describe a patient with epilepsy, mental retardation, developmental disorders, and dysmorphic features, who inherited a deletion of 16p13.11 and a triplication of 19p13.3 from his father and mother, respectively. The mother presented mild mental retardation and language delay too.
Conclusions
We discuss the phenotypic consequences of the two CNVs and suggest that their synergistic effect is likely responsible for the complicated clinical features observed in our patient.
doi:10.1186/s13039-015-0115-x
PMCID: PMC4335438
Deletion; 16p13.11; Triplication; 19p13.3; Array-CGH; Developmental disorders; Intellectual disability; Epilepsy
2.  Interstitial 7q31.1 copy number variations disrupting IMMP2L gene are associated with a wide spectrum of neurodevelopmental disorders 
Background
Since the introduction of the array-CGH technique in the diagnostic workup of mental retardation, new recurrent copy number variations and novel microdeletion/microduplication syndromes were identified. These findings suggest that some genomic disorders have high penetrance but a wide range of phenotypic severity.
Results
We present the clinical and molecular description of four unrelated patients affected by neurodevelopmental disorders and overlapping 7q31.1 microdeletion/microduplication, identified by array-CGH and involving only part of the IMMP2L gene.
Conclusion
IMMP2L encodes an inner mitochondrial membrane protease-like protein, which is required for processing of cytochromes inside mitochondria. Numerous studies reported that this gene is implicated in behavioural disorders such as autistic spectrum disorders, attention-deficit hyperactivity disorders, and Gilles de la Tourette syndrome. We discuss the functions of the gene suggesting that IMMP2L may act as risk factor for neurological disease.
doi:10.1186/s13039-014-0054-y
PMCID: PMC4255718  PMID: 25478008
IMMP2L; Neurodevelopmental disorders; Copy number variation; Array-CGH
3.  Phenotypic and genetic characterization of a patient with a de novo interstitial 14q24.1q24.3 deletion 
Background
Interstitial deletions of chromosome bands 14q24.1q24.3 are very rare with only three reported cases.
Results
We describe a 7-year-old boy with a 5.345 Mb de novo interstitial deletion at 14q24.1q24.3 band detected by array-CGH who had a complex phenotype characterized by seizures, congenital heart defects, dysmorphisms, psychomotor delay, and bronchopulmonary, skeletal, and brain anomalies.
Conclusion
The deleted region contains numerous genes, but we focused our attention on three of them (C14orf169, NUMB, and PSEN1), which could account, at least partially, for the phenotype of the boy. We therefore discuss the involvement of these genes and the observed phenotype compared to that of previously described patients.
doi:10.1186/1755-8166-7-49
PMCID: PMC4115490  PMID: 25076984
Interstitial 14q24.1q24.3 deletion; De novo; Array-CGH; Genotype-phenotype correlation
4.  De novo deletion of chromosome 11q12.3 in monozygotic twins affected by Poland Syndrome 
BMC Medical Genetics  2014;15:63.
Background
Poland Syndrome (PS) is a rare disorder characterized by hypoplasia/aplasia of the pectoralis major muscle, variably associated with thoracic and upper limb anomalies. Familial recurrence has been reported indicating that PS could have a genetic basis, though the genetic mechanisms underlying PS development are still unknown.
Case presentation
Here we describe a couple of monozygotic (MZ) twin girls, both presenting with Poland Syndrome. They carry a de novo heterozygous 126 Kbp deletion at chromosome 11q12.3 involving 5 genes, four of which, namely HRASLS5, RARRES3, HRASLS2, and PLA2G16, encode proteins that regulate cellular growth, differentiation, and apoptosis, mainly through Ras-mediated signaling pathways.
Conclusions
Phenotype concordance between the monozygotic twin probands provides evidence supporting the genetic control of PS. As genes controlling cell growth and differentiation may be related to morphological defects originating during development, we postulate that the observed chromosome deletion could be causative of the phenotype observed in the twin girls and the deleted genes could play a role in PS development.
doi:10.1186/1471-2350-15-63
PMCID: PMC4051386  PMID: 24885342
Chromosome 11q deletion; Congenital abnormalities; Monozygotic twins; Poland syndrome; CNV; HRASLS5; HRASLS2; RARRES3; PLA2G16
5.  Constitutional chromosomal events at 22q11 and 15q26 in a child with a pilocytic astrocytoma of the spinal cord 
We report on a 9-years-old patient with mild intellectual disability, facial dimorphisms, bilateral semicircular canal dysplasia, periventricular nodular heterotopias, bilateral hippocampal malrotation and abnormal cerebellar foliation, who developed mild motor impairment and gait disorder due to a pilocytic astrocytoma of the spinal cord. Array-CGH analysis revealed two paternal inherited chromosomal events: a 484.3 Kb duplication on chromosome 15q26.3 and a 247 Kb deletion on 22q11.23. Further, a second de novo 1.5 Mb deletion on 22q11.21 occurred. Chromosome 22 at q11.2 and chromosome 15 at q24q26 are considered unstable regions subjected to copy number variations, i.e. structural alterations of genome, mediated by low copy repeat sequences or segmental duplications. The link between some structural CNVs, which compromise fundamental processes controlling DNA stability, and genomic disorders suggest a plausible scenario for cancer predisposition.
Evaluation of the genes at the breakpoints cannot account simultaneously for the phenotype and tumour development in this patient. The two paternal inherited CNVs arguably are not pathogenic and do not contribute to the clinical manifestations. Similarly, although the de novo large deletion at 22q11.21 overlaps with the Di George (DGS) critical region and results in haploinsufficiency of genes compromising critical processes for DNA stability, this case lacks several hallmarks of DGS.
doi:10.1186/1755-8166-7-31
PMCID: PMC4032172  PMID: 24860619
Pilocytic astrocytoma; Spinal cord; Semicircular canal dysplasia; 15q duplication; 22q11.2 deletion
6.  A rare 3q13.31 microdeletion including GAP43 and LSAMP genes 
Background
Interstitial deletions affecting the proximal long arm of chromosome 3 have been rarely reported in the literature. The deleted segments vary in localization and size with different breakpoints making genotype-phenotype correlation very difficult. Until now, a girl with a 1.9-Mb interstitial deletion of 3q13.2q13.31 and 14 novel patients with deletions in 3q11q23 have been reported.
Results
Here we report on a 7-year-old girl with neuropsychiatric disorders and renal, vascular and skeletal anomalies. Array-CGH analysis revealed a small rare inherited 3q13.31 deletion containing only two genes, GAP43 and LSAMP. The mutation analysis of the two genes was negative on the other non-deleted chromosome. GAP43 is considered a crucial component for an effective regenerative response in the nervous system and its mRNA is localized exclusively to nerve tissue where the protein is linked to the synaptosomal membrane. LSAMP is a 64- to 68-kD neuronal surface glycoprotein found in cortical and subcortical regions of the limbic system that acts as an adhesion molecule and guides the development of specific patterns of neuronal connection. The deleted region is adjacent to a “desert gene” region extending 2.099 Mb.
Conclusions
We discuss the effects of GAP43 and LSAMP haploinsufficiency, proposing that their deletion may be responsible for the main phenotype. Further cases with similar microdeletion are expected to be diagnosed and will help to better characterize the clinical spectrum of phenotypes associated with 3q13.31 microdeletion.
doi:10.1186/1755-8166-6-52
PMCID: PMC3906914  PMID: 24279697
3q31.31microdeletion; GAP43 gene; LSAMP gene; Genotype-phenotype correlation
7.  Genotype-Phenotype Correlation of 2q37 Deletions Including NPPC Gene Associated with Skeletal Malformations 
PLoS ONE  2013;8(6):e66048.
Coordinated bone growth is controlled by numerous mechanisms which are only partially understood because of the involvement of many hormones and local regulators. The C-type Natriuretic Peptide (CNP), encoded by NPPC gene located on chromosome 2q37.1, is a molecule that regulates endochondral ossification of the cartilaginous growth plate and influences longitudinal bone growth. Two independent studies have described three patients with a Marfan-like phenotype presenting a de novo balanced translocation involving the same chromosomal region 2q37.1 and overexpression of NPPC. We report on two partially overlapping interstitial 2q37 deletions identified by array CGH. The two patients showed opposite phenotypes characterized by short stature and skeletal overgrowth, respectively. The patient with short stature presented a 2q37 deletion causing the loss of one copy of the NPPC gene and the truncation of the DIS3L2 gene with normal CNP plasma concentration. The deletion identified in the patient with a Marfan-like phenotype interrupted the DIS3L2 gene without involving the NPPC gene. In addition, a strongly elevated CNP plasma concentration was found in this patient. A possible role of NPPC as causative of the two opposite phenotypes is discussed in this study.
doi:10.1371/journal.pone.0066048
PMCID: PMC3689787  PMID: 23805197
8.  Parental Imbalances Involving Chromosomes 15q and 22q May Predispose to the Formation of De Novo Pathogenic Microdeletions and Microduplications in the Offspring 
PLoS ONE  2013;8(3):e57910.
Microarray-based comparative genomic hybridization (array-CGH) led to the discovery of genetic abnormalities among patients with complex phenotype and normal karyotype. Also several apparently normal individuals have been found to be carriers of cryptic imbalances, hence the importance to perform parental investigations after the identification of a deletion/duplication in a proband. Here, we report the molecular cytogenetic characterization of two individuals in which the microdeletions/duplications present in their parents could have predisposed and facilitated the formation of de novo pathogenic different copy number variations (CNVs). In family 1, a 4-year-old girl had a de novo pathogenic 10.5 Mb duplication at 15q21.2q22.2, while her mother showed a 2.262 Mb deletion at 15q13.2q13.3; in family 2, a 9-year-old boy had a de novo 1.417 Mb deletion at 22q11.21 and a second paternal deletion of 247 Kb at 22q11.23 on the same chromosome 22. Chromosome 22 at band q11.2 and chromosome 15 at band q11q13 are considered unstable regions. We could hypothesize that 15q13.2q13.3 and 22q11.21 deletions in the two respective parents might have increased the risk of rearrangements in their children. This study highlights the difficulty to make genetic counseling and predict the phenotypic consequences in these situations.
doi:10.1371/journal.pone.0057910
PMCID: PMC3590287  PMID: 23483941
9.  Identification of a rare 17p13.3 duplication including the BHLHA9 and YWHAE genes in a family with developmental delay and behavioural problems 
BMC Medical Genetics  2012;13:93.
Background
Deletions and duplications of the PAFAH1B1 and YWHAE genes in 17p13.3 are associated with different clinical phenotypes. In particular, deletion of PAFAH1B1 causes isolated lissencephaly while deletions involving both PAFAH1B1 and YWHAE cause Miller-Dieker syndrome. Isolated duplications of PAFAH1B1 have been associated with mild developmental delay and hypotonia, while isolated duplications of YWHAE have been associated with autism. In particular, different dysmorphic features associated with PAFAH1B1 or YWHAE duplication have suggested the need to classify the patient clinical features in two groups according to which gene is involved in the chromosomal duplication.
Methods
We analyze the proband and his family by classical cytogenetic and array-CGH analyses. The putative rearrangement was confirmed by fluorescence in situ hybridization.
Results
We have identified a family segregating a 17p13.3 duplication extending 329.5 kilobases by FISH and array-CGH involving the YWHAE gene, but not PAFAH1B1, affected by a mild dysmorphic phenotype with associated autism and mental retardation. We propose that BHLHA9, YWHAE, and CRK genes contribute to the phenotype of our patient. The small chromosomal duplication was inherited from his mother who was affected by a bipolar and borderline disorder and was alcohol addicted.
Conclusions
We report an additional familial case of small 17p13.3 chromosomal duplication including only BHLHA9, YWHAE, and CRK genes. Our observation and further cases with similar microduplications are expected to be diagnosed, and will help better characterise the clinical spectrum of phenotypes associated with 17p13.3 microduplications.
doi:10.1186/1471-2350-13-93
PMCID: PMC3495055  PMID: 23035971
Familial 17p13.3 duplication syndrome; PAFAH1B1 and YWHAE genes; Array-CGH

Results 1-9 (9)