Publications by authors named "Michela Malacarne"

37 Publications

8p23.2-pter Microdeletions: Seven New Cases Narrowing the Candidate Region and Review of the Literature.

Genes (Basel) 2021 Apr 27;12(5). Epub 2021 Apr 27.

Istituto Auxologico Italiano, IRCCS, Laboratory of Medical Cytogenetics and Molecular Genetics, 20145 Milan, Italy.

To date only five patients with 8p23.2-pter microdeletions manifesting a mild-to-moderate cognitive impairment and/or developmental delay, dysmorphisms and neurobehavioral issues were reported. The smallest microdeletion described by Wu in 2010 suggested a critical region (CR) of 2.1 Mb including several genes, out of which , , , and are the main candidates. Here we present seven additional patients with 8p23.2-pter microdeletions, ranging from 71.79 kb to 4.55 Mb. The review of five previously reported and nine Decipher patients confirmed the association of the CR with a variable clinical phenotype characterized by intellectual disability/developmental delay, including language and speech delay and/or motor impairment, behavioral anomalies, autism spectrum disorder, dysmorphisms, microcephaly, fingers/toes anomalies and epilepsy. Genotype analysis allowed to narrow down the 8p23.3 candidate region which includes only , and genes, accounting for the main signs of the broad clinical phenotype associated to 8p23.2-pter microdeletions. This region is more restricted compared to the previously proposed CR. Overall, our data favor the hypothesis that is the actual strongest candidate for neurodevelopmental/behavioral phenotypes. Additional patients will be necessary to validate the pathogenic role of and better define how the two contiguous genes, and , might contribute to the clinical phenotype.
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http://dx.doi.org/10.3390/genes12050652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8146486PMC
April 2021

Expanding the phenotype associated with interstitial 6p25.1p24.3 microdeletion: a new case and review of the literature.

J Genet 2021 ;100

Laboratory of Human Genetics, IRCCS Giannina Gaslini, Largo G.Gaslini, 16147 Genoa, Italy.

Interstitial 6p25.1p24.3 microdeletions are rare events and a clear karyotype/phenotype correlation has not yet been determined. In this study, we present the clinical and molecular description of a child with a 6p25.1p24.3 microdeletion, characterized by array-CGH, associated with mild intellectual disability, facial dysmorphisms, hypopigmentation of the skin of the abdomen, heart defects, mild pontine hypoplasia and hypotonia. This deleted region contains 14 OMIM genes (, , , , , , , , , , and ). To the best of our knowledge until now only six cases have been reported presenting an interstitial microdeletion, but a unique case carries a deleted region containing the same genes of our patient. We compared clinical features and genetic data with that of the previously reported patient. We also analysed the gene content of the deleted region to investigate the possible role of specific genes in the clinical phenotype of our patient.
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July 2021

12q14.3 microdeletion involving HMGA2 gene cause a Silver-Russell syndrome-like phenotype: a case report and review of the literature.

Ital J Pediatr 2020 Jul 28;46(1):108. Epub 2020 Jul 28.

U.O.S.D. Medical Genetics, AOOR Villa Sofia-Cervello, Palermo, Italy.

Background: Silver-Russell Syndrome (SRS) is a genetic disorder characterized by intrauterine and postnatal growth restriction and normal head circumference with consequent relative macrocephaly. Addictional findings are protruding forehead in early life, body asymmetry (of upper and lower limbs) and substantial feeding difficulties. Although several genetic mechanisms that cause the syndrome are known, more than 40% of patients with a SRS-like phenotype remain without an etiological diagnosis. In the last few years, different clinical reports have suggested that mutations or deletions of the HMGA2 gene can be responsible for a SRS-like phenotype in patients with negative results of the common diagnostic tests for this syndrome.

Case Presentation: We present a 3-year-old male patient with clinical diagnosis of Silver-Russell Syndrome (SRS) associated with a de novo heterozygous deletion of the long arm of the chromosome 12 (12q14.3) encompassing the HMGA2 gene.

Conclusions: Our report confirms the etiological role of HMGA2 as a disease gene in the development of a SRS-like phenotype.
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http://dx.doi.org/10.1186/s13052-020-00866-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7389890PMC
July 2020

1p31.1 microdeletion including only NEGR1 gene in two patients.

Eur J Med Genet 2020 Jun 21;63(6):103919. Epub 2020 Mar 21.

Laboratory of Cytogenetics, IRCCS Istituto Giannina Gaslini, Genoa, Italy; Laboratorio di Genetica Umana, IRCCS Istituto Giannina Gaslini, Genoa, Italy.

Neuronal growth regulator 1 (NEGR1), a member of the immunoglobulin superfamily cell adhesion molecule subgroup IgLON, has been involved in neuronal growth and connectivity. Genetic variants, in or near the NEGR1 locus, have been associated with obesity and, more recently, with learning difficulties, intellectual disability, and psychiatric disorders. Here, we described the only second report of NEGR1 gene disruption in 1p31.1 microdeletion in two patients. Patient 1 is a 14-year-old female with neurological and psychiatric features present also in her family. Patient 2 is a 5-month-old infant showing global hypotonia as unique neurological features till now. This patient also carries 7p22.1 duplication, of paternal origin, that could be responsible for some malformations present in the child. We hypothesize a role of NEGR1 in producing the phenotype of our patients and compare them with other cases previously reported in the literature and DECIPHER database to better identify a possible genotype-phenotype correlation.
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http://dx.doi.org/10.1016/j.ejmg.2020.103919DOI Listing
June 2020

Testing single/combined clinical categories on 5110 Italian patients with developmental phenotypes to improve array-based detection rate.

Mol Genet Genomic Med 2020 01 18;8(1):e1056. Epub 2019 Dec 18.

Dipartimento di Medicina e Chirurgia, Università di Milano-Bicocca, Monza, Italy.

Background: Chromosomal microarray analysis (CMA) is nowadays widely used in the diagnostic path of patients with clinical phenotypes. However, there is no ascertained evidence to date on how to assemble single/combined clinical categories of developmental phenotypic findings to improve the array-based detection rate.

Methods: The Italian Society of Human Genetics coordinated a retrospective study which included CMA results of 5,110 Italian patients referred to 17 genetics laboratories for variable combined clinical phenotypes.

Results: Non-polymorphic copy number variants (CNVs) were identified in 1512 patients (30%) and 615 (32%) present in 552 patients (11%) were classified as pathogenic. CNVs were analysed according to type, size, inheritance pattern, distribution among chromosomes, and association to known syndromes. In addition, the evaluation of the detection rate of clinical subgroups of patients allowed to associate dysmorphisms and/or congenital malformations combined with any other single clinical sign to an increased detection rate, whereas non-syndromic neurodevelopmental signs and non-syndromic congenital malformations to a decreased detection rate.

Conclusions: Our retrospective study resulted in confirming the high detection rate of CMA and indicated new clinical markers useful to optimize their inclusion in the diagnostic and rehabilitative path of patients with developmental phenotypes.
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http://dx.doi.org/10.1002/mgg3.1056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6978242PMC
January 2020

Copy number variations in candidate genomic regions confirm genetic heterogeneity and parental bias in Hirschsprung disease.

Orphanet J Rare Dis 2019 11 25;14(1):270. Epub 2019 Nov 25.

U.O.C. Genetica Medica, IRCCS, Istituto Giannina Gaslini, 16148, Genoa, Italy.

Background: Hirschsprung Disease (HSCR) is a congenital defect of the intestinal innervations characterized by complex inheritance. Many susceptibility genes including RET, the major HSCR gene, and several linked regions and associated loci have been shown to contribute to disease pathogenesis. Nonetheless, a proportion of patients still remains unexplained. Copy Number Variations (CNVs) have already been involved in HSCR, and for this reason we performed Comparative Genomic Hybridization (CGH), using a custom array with high density probes.

Results: A total of 20 HSCR candidate regions/genes was tested in 55 sporadic patients and four patients with already known chromosomal aberrations. Among 83 calls, 12 variants were experimentally validated, three of which involving the HSCR crucial genes SEMA3A/3D, NRG1, and PHOX2B. Conversely RET involvement in HSCR does not seem to rely on the presence of CNVs while, interestingly, several gains and losses did co-occur with another RET defect, thus confirming that more than one predisposing event is necessary for HSCR to develop. New loci were also shown to be involved, such as ALDH1A2, already found to play a major role in the enteric nervous system. Finally, all the inherited CNVs were of maternal origin.

Conclusions: Our results confirm a wide genetic heterogeneity in HSCR occurrence and support a role of candidate genes in expression regulation and cell signaling, thus contributing to depict further the molecular complexity of the genomic regions involved in the Enteric Nervous System development. The observed maternal transmission bias for HSCR associated CNVs supports the hypothesis that in females these variants might be more tolerated, requiring additional alterations to develop HSCR disease.
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http://dx.doi.org/10.1186/s13023-019-1205-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6878652PMC
November 2019

Children and adults affected by Cri du Chat syndrome: Care's recommendations.

Pediatr Rep 2019 Feb 26;11(1):7839. Epub 2019 Feb 26.

SOC Pediatria, Ospedale Castelli, Verbania, Italy.

Our objective is to collect data and information for a better care and follow up in Cri du Chat patients. We conducted a literature review in August 2017 and then discuss the outcomes within the ABC (Associazione Bambini Cri du Chat, Italian CdC families support group). A proposal for clinical, laboratory and imaging work up should be performed at various ages in CdC patients. Follow up and rehabilitation should continue lifelong as some improvements can be obtained also in older ages and not to lose acquired skills.
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http://dx.doi.org/10.4081/pr.2019.7839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397997PMC
February 2019

Expanding the phenotype of reciprocal 1q21.1 deletions and duplications: a case series.

Ital J Pediatr 2017 Jul 19;43(1):61. Epub 2017 Jul 19.

Department of Sciences for Health Promotion and Mother and Child Care "Giuseppe D'Alessandro", University of Palermo, Palermo, Italy.

Background: Recurrent reciprocal 1q21.1 deletions and duplications have been associated with variable phenotypes. Phenotypic features described in association with 1q21.1 microdeletions include developmental delay, craniofacial dysmorphism and congenital anomalies. The 1q21.1 reciprocal duplication has been associated with macrocephaly or relative macrocephaly, frontal bossing, hypertelorism, developmental delay, intellectual disability and autism spectrum disorder.

Methods: Our study describes seven patients, who were referred to us for developmental delay/intellectual disability, dysmorphic features and, in some cases, congenital anomalies, in whom we identified 1q21.1 CNVs by array-CGH.

Results: Our data confirm the extreme phenotypic variability associated with 1q21.1 microdeletion and microduplication. We observed common phenotypic features, described in previous studies, but we also described, for the first time, congenital hypothyroidism in association with 1q21.1 deletion and trigonocephaly associated with 1q21.1 duplication.

Conclusions: The aim of this study is to contribute to the definition of the phenotype associated with reciprocal 1q21.1 deletions and duplications.
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http://dx.doi.org/10.1186/s13052-017-0380-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5518118PMC
July 2017

Custom Array Comparative Genomic Hybridization: the Importance of DNA Quality, an Expert Eye, and Variant Validation.

Int J Mol Sci 2017 Mar 10;18(3). Epub 2017 Mar 10.

UOC Genetica Medica, Istituto Giannina Gaslini, L. go G. Gaslini 5, 16148 Genoa, Italy.

The presence of false positive and false negative results in the Array Comparative Genomic Hybridization (aCGH) design is poorly addressed in literature reports. We took advantage of a custom aCGH recently carried out to analyze its design performance, the use of several Agilent aberrations detection algorithms, and the presence of false results. Our study provides a confirmation that the high density design does not generate more noise than standard designs and, might reach a good resolution. We noticed a not negligible presence of false negative and false positive results in the imbalances call performed by the Agilent software. The Aberration Detection Method 2 (ADM-2) algorithm with a threshold of 6 performed quite well, and the array design proved to be reliable, provided that some additional filters are applied, such as considering only intervals with average absolute log₂ratio above 0.3. We also propose an additional filter that takes into account the proportion of probes with log₂ratio exceeding suggestive values for gain or loss. In addition, the quality of samples was confirmed to be a crucial parameter. Finally, this work raises the importance of evaluating the samples profiles by eye and the necessity of validating the imbalances detected.
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http://dx.doi.org/10.3390/ijms18030609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5372625PMC
March 2017

Brachydactyly type E in an Italian family with 6p25 trisomy.

Eur J Med Genet 2017 Mar 19;60(3):195-199. Epub 2017 Jan 19.

Service of Medical Genetics, Cardarelli Hospital, Naples, Italy.

Brachydactyly type E is a congenital limb malformation characterized by small hands and feet as a result of shortened metacarpals and metatarsals. Genetic causes of this anomaly are heterogeneous and only partially characterized. In this report we describe an Italian family in which four subjects share brachydactyly type E and a 3 Mb microduplication in region 6p25. The duplication involves the gene FOXC1, expressed during the osteoblast differentiation, which appears a potential candidate gene for brachydactyly.
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http://dx.doi.org/10.1016/j.ejmg.2017.01.006DOI Listing
March 2017

Psychomotor Development in Cri du Chat Syndrome: Comparison in Two Italian Cohorts with Different Rehabilitation Methods.

ScientificWorldJournal 2016 28;2016:3125283. Epub 2016 Nov 28.

Department of Molecular Medicine, University of Pavia and IRCCS, S. Matteo, Pavia, Italy.

The Cri du Chat syndrome (CdC) is a rare genetic disorder caused by variable size deletions of the short arm of chromosome 5 (5p-). It is well known that home-reared patients show better performances as compared to institutionalised cases, and it was reported that continuous educational intervention can ameliorate their performances. To assess the efficacy of educational intervention and to develop new CdC oriented programs of rehabilitation, we compare the results obtained for many developmental skills in two groups of CdC patients undergoing two different rehabilitation programs. Using data on the development of a group of CdC patients obtained by validated Italian translation for the Denver Developmental Screening Test II, we compared a group of 13 patients undergoing an educational program developed for CdC patients, the Mayer Project (MP), with a second group of 15 cases in whom caring was not specifically oriented. A positive impact of the MP was reported by parents, observing an improvement in social skills obtained, even if no significant differences were observed when the items of the Denver Test are studied. The need for personalized care in CdC patients and the choice of different methods to compare the results are also discussed.
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http://dx.doi.org/10.1155/2016/3125283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5149647PMC
November 2017

The crucial role of FBXO28 in the pathogenesis of the 1q41q42 microdeletion syndrome.

Am J Med Genet A 2016 Nov 17;170(11):3041-3042. Epub 2016 May 17.

Division of Child Neurology, Department of Pediatrics, Sapienza University of Rome, Rome, Italy.

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http://dx.doi.org/10.1002/ajmg.a.37753DOI Listing
November 2016

Paternal uniparental disomy chromosome 14-like syndrome due a maternal de novo 160 kb deletion at the 14q32.2 region not encompassing the IG- and the MEG3-DMRs: Patient report and genotype-phenotype correlation.

Am J Med Genet A 2015 Dec 3;167A(12):3130-8. Epub 2015 Sep 3.

Department of Sciences for Health Promotion and Mother and Child Care, Università di Palermo, Palermo, Italy.

The human chromosome 14q32 carries a cluster of imprinted genes which include the paternally expressed genes (PEGs) DLK1 and RTL1, as well as the maternally expressed genes (MEGs) MEG3, RTL1as, and MEG8. PEGs and MEGs expression at the 14q32.2-imprinted region are regulated by two differentially methylated regions (DMRs): the IG-DMR and the MEG3-DMR, which are respectively methylated on the paternal and unmethylated on the maternal chromosome 14 in most cells. Genetic and epigenetic abnormalities affecting these imprinted gene clusters result in two different phenotypes currently known as maternal upd(14) syndrome and paternal upd(14) syndrome. However, only few patients carrying a maternal deletion at the 14q32.2-imprinted critical region have been reported so far. Here we report on the first patient with a maternal de novo deletion of 160 kb at the 14q32.2 chromosome that does not involves the IG-DMR or the MEG3-DMR but elicits a full upd(14)pat syndrome's phenotype encompassing the three mentioned MEGs. By the analysis of this unique genotype-phenotype correlation, we further widen the spectrum of the congenital anomalies associated to this rare disorder and we propose that the paternally expressed imprinted RTL1 gene, as well as its maternally expressed RTL1as antisense transcript, may play a prominent causative role.
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http://dx.doi.org/10.1002/ajmg.a.37293DOI Listing
December 2015

4p16.1-p15.31 duplication and 4p terminal deletion in a 3-years old Chinese girl: Array-CGH, genotype-phenotype and neurological characterization.

Eur J Paediatr Neurol 2015 Jul 23;19(4):477-83. Epub 2015 Feb 23.

Department of Sciences for Health Promotion and Mother and Child Care, University of Palermo, Palermo, Italy.

Background: Microscopically chromosome rearrangements of the short arm of chromosome 4 include the two known clinical entities: partial trisomy 4p and deletions of the Wolf-Hirschhorn critical regions 1 and 2 (WHSCR-1 and WHSCR-2, respectively), which cause cranio-facial anomalies, congenital malformations and developmental delay/intellectual disability.

Methods/results: We report on clinical findings detected in a Chinese patient with a de novo 4p16.1-p15.32 duplication in association with a subtle 4p terminal deletion of 6 Mb in size. This unusual chromosome imbalance resulted in WHS classical phenotype, while clinical manifestations of 4p trisomy were practically absent.

Conclusion: This observation suggests the hypothesis that haploinsufficiency of sensitive dosage genes with regulatory function placed in WHS critical region, is more pathogenic than concomitant 4p duplicated segment. Additionally clinical findings in our patient confirm a variable penetrance of major malformations and neurological features in Chinese children despite of WHS critical region's deletion.
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http://dx.doi.org/10.1016/j.ejpn.2015.02.002DOI Listing
July 2015

Microdeletion 2q23.3q24.1: exploring genotype-phenotype correlations.

Congenit Anom (Kyoto) 2015 May;55(2):107-11

Pediatric Highly Intensive Care Unit, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.

We report a case of a 13-year-old girl with a 5.4 Mb de novo deletion, encompassing bands 2q23.3q24.1, identified by array-comparative genomic hybridization. She presented with minor facial and digital anomalies, mild developmental delay during infancy, and behavioral disorders. Few of the reported cases overlap this deletion and all only partially. We tried to compare the clinical features of the patient with the other cases, even though not all of them were molecularly characterized in detail. Considering the neuropsychiatric involvement of the proband and the clinical descriptions of other similar cases, we attempted to identify the genes more probably involved in neurological development and function in the deleted region, particularly GALNT13, KCNJ3 and NR4A2, which are expressed in neuronal cells.
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http://dx.doi.org/10.1111/cga.12080DOI Listing
May 2015

Structural chromosomal abnormalities detected during CVS analysis and their role in the prenatal ascertainment of cryptic subtelomeric rearrangements.

Am J Med Genet A 2013 Oct 6;161A(10):2559-63. Epub 2013 Aug 6.

Cytogenetic Laboratory, Unit of Obstetrics and Gynecology, Policlinico Sant'Orsola-Malpighi, University of Bologna, Bologna, Italy.

Mosaic structural chromosomal abnormalities observed along the trophoblast-mesenchyme-fetal axis, although rare, pose a difficult problem for their prognostic interpretation in prenatal diagnosis. Additional issues are raised by the presence of mosaic imbalances of the same chromosome showing different sizes in the different tissues, that is, deletions and duplications in the cytotrophoblast and mesenchyme of chorionic villi (CV). Some of these cytogenetic rearrangements originate from the post-zygotic breakage of a dicentric chromosome or of the product of its first anaphasic breakage. Selection of the most viable cell line may result in confined placental mosaicism of the most severe imbalance, favoring the presence of the cell lines with the mildest duplications or deletions in the fetal tissues. We document three cases of ambiguous results in CV analysis due to the presence of different cell lines involving structural rearrangements of the same chromosome which were represented differently in the trophoblast and the mesenchyme. Observation by conventional karyotype of a grossly rearranged chromosome in one of the CV preparations (direct or culture) was crucial to call attention to the involved chromosomal region in other tissues (villi or amniotic fluid), allowing the prenatal diagnosis through molecular cytogenetic methods of subtelomeric rearrangements [del(7)(q36qter); del(11)(q25qter); del(20)(p13pter)]. This would have surely been undiagnosed with the routine banding technique. In conclusion, the possibility to diagnose complex abnormalities leading to cryptic subtelomeric rearrangements, together with a better knowledge of the initial/intermediate products leading to the final abnormal cryptic deletion should be added to the advantages of the CV sampling technique.
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http://dx.doi.org/10.1002/ajmg.a.36035DOI Listing
October 2013

3q26.33-3q27.2 microdeletion: a new microdeletion syndrome?

Eur J Med Genet 2013 Apr 26;56(4):216-21. Epub 2013 Jan 26.

Division of Medical Genetics, Galliera Hospital, Via Volta 6, 16128 Genova, Italy.

We describe three unrelated patients of European descent carrying an overlapping 3q26.33-3q27.2 microdeletion who share common clinical features: neonatal hypotonia, severe feeding problems, specific facial features, abnormal dentition, recurrent upper airways infections, developmental delay and severe growth impairment. One of the patients carries a smaller deletion and presents a milder phenotype. We propose that 3q26.33-3q27.2 microdeletion may represent a novel condition caused by the haploinsufficiency of dosage sensitive genes, several of which are involved in brain development.
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http://dx.doi.org/10.1016/j.ejmg.2013.01.005DOI Listing
April 2013

14q13.1-21.1 deletion encompassing the HPE8 locus in an adolescent with intellectual disability and bilateral microphthalmia, but without holoprosencephaly.

Am J Med Genet A 2012 Jun 11;158A(6):1427-33. Epub 2012 May 11.

Centro di Riferimento Regionale per la Sindrome di Down e le Altre Patologie Cromosomiche e Genetiche-Azienda Ospedaliera Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.

Interstitial deletions involving 14q13.1q21.1 are rare. In the literature at least 10 cases involving this region have been described and all patients showed a phenotype within the holoprosencephaly (HPE) spectrum. Previous studies suggested the HPE8 region as a candidate locus for HPE at 14q13. We report an adolescent with a 14q13.1q21.1 deletion encompassing the HPE8 region associated with intellectual disability (ID), bilateral microphthalmia, and coloboma, without cerebral anomalies typical of HPE. Except for ocular defects (i.e., microphthalmia, coloboma) consistent with HPE-type anomalies, the minor facial dysmorphia was not suggestive for HPE and the absence of cerebral anomalies should rule out this diagnosis. The deletion of the potential HPE candidate genes NPAS3, EAPP, SNX6, and TULIP1, raises doubts about their pathologic role in determining HPE. It is likely that deletions of HPE genes are not sufficient to cause HPE, and that multiple genetic, chromosomal, and environmental factors interact to determine the variable clinical expression of HPE. This is the first case of a 14q deletion encompassing the HPE8 locus with the only features consistent with HPE-type anomalies affecting the ocular system (i.e., microphthalmia, coloboma), and without cerebral anomalies specific for HPE. The inclusion of potential HPE candidate genes in the deletion raises the question whether this patient is affected by a less severe form of HPE (HPE microform), or whether he has a new ID/MCA deletion syndrome.
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http://dx.doi.org/10.1002/ajmg.a.35334DOI Listing
June 2012

Characterization of a complex rearrangement involving chromosomes 1, 4 and 8 by FISH and array-CGH.

J Appl Genet 2012 Aug 29;53(3):285-8. Epub 2012 Apr 29.

Laboratorio di Genetica Umana, E.O. Ospedali Galliera, Genova, Italy.

Complex chromosomal rearrangements (CCRs) are structural aberrations involving more than two chromosomes with at least three breakpoints. CCRs can be divided into familial and de novo. Balanced CCR are extremely rare in humans and are at high risk of producing unbalanced gametes. Individuals with balanced CCR are usually phenotipically normal but report fertility problems, recurrent miscarriages or congenital anomalies in newborn offsprings as consequence of either meiotic failure or imbalanced chromosomes segregation.We describe the case of an unbalanced CCR involving chromosomes 1, 4 and 8 found in a girl with developmental delay, hexadactilia and microcephaly. The rearrangement, apparently balanced at a standard karyotype analysis and of maternal origin, was demonstrated to be unbalanced by array-CGH and FISH. In conclusion our study underlines the importance of the combined use of a quantitative technique, as array-CGH, to detect criptic segmental aneuploidies, and a qualitative tool, as FISH analysis, to physically map the localization of the chromosome segments involved, in order to realize the exact nature that underlies a chromosomal rearrangement.
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http://dx.doi.org/10.1007/s13353-012-0097-xDOI Listing
August 2012

19q13 microdeletion syndrome: Further refining the critical region.

Eur J Med Genet 2012 Jun 10;55(6-7):429-32. Epub 2012 Apr 10.

Division of Medical Genetics, Galliera Hospital, Via Volta 6, Genoa, Italy.

The 19q13 microdeletion syndrome is a recently identified disorder of which very few cases have been reported so far. Growth deficiency, microcephaly, ectodermal anomalies and intellectual disability are the major features reported in all the described cases. The critical region has been estimated to span 750 Kb. We report an Italian patient carrying a de novo 1.37 Mb deletion in chromosome 19q13, who presented all the cardinal features of the syndrome, and multiple pituitary hormone deficiency. Our findings might contribute to further refine the critical region to 460 Kb and restrict the list of candidate genes.
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http://dx.doi.org/10.1016/j.ejmg.2012.03.002DOI Listing
June 2012

Interstitial deletion of chromosome 2p15-16.1: report of two patients and critical review of current genotype-phenotype correlation.

Eur J Med Genet 2012 Apr 18;55(4):238-44. Epub 2012 Feb 18.

U.O. Pediatria e TIN Dipartimento Materno-Infantile, Università degli Studi di Palermo via Alfonso Giordano 3, 90127 Palermo, Italy.

Unlabelled: We report two individuals with developmental delay and dysmorphic features, in whom array-based comparative genomic hybridization (array CGH) led to the identification of a 2p15p16.1 de novo deletion. In the first patient (Patient 1) a familial deletion of 6q12, inherited from her father, was also detected. In the second patient (Patient 2) in addition to the 2p15p16.1 microdeletion a de novo deletion in Xq28 was detected. Both individuals shared dysmorphic features and developmental delay with the six reported patients with a 2p15p16.1 microdeletion described in medical literature.

Conclusion: in the first patient a 642 kb 2p16.1 deletion (from 60.604 to 61.246 Mb), and a 930 kb 6q12 familial deletion, was detected and in the second a 2.5 Mb 2p15p16.1 deletion (from 60.258 to 62.763 Mb), with a Xq28 deletion, was discovered. The common dysmorphic features and neurodevelopmental delay found in these patients are in agreement with the clinical phenotype of a microdeletion syndrome involving 2p15p16.1. Our data confirm the hypothesis suggesting that 2p15p16.1 deletion is a contiguous gene syndrome.
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http://dx.doi.org/10.1016/j.ejmg.2012.01.014DOI Listing
April 2012

Clinical significance of rare copy number variations in epilepsy: a case-control survey using microarray-based comparative genomic hybridization.

Arch Neurol 2012 Mar 14;69(3):322-30. Epub 2011 Nov 14.

Laboratory of Neurogenetics, Department of Neuroscience, Institute G. Gaslini, Largo Gaslini 5, Genoa, Italy.

Objective: To perform an extensive search for genomic rearrangements by microarray-based comparative genomic hybridization in patients with epilepsy.

Design: Prospective cohort study.

Setting: Epilepsy centers in Italy.

Patients: Two hundred seventy-nine patients with unexplained epilepsy, 265 individuals with nonsyndromic mental retardation but no epilepsy, and 246 healthy control subjects were screened by microarray-based comparative genomic hybridization.

Main Outcome Measures: Identification of copy number variations (CNVs) and gene enrichment.

Results: Rare CNVs occurred in 26 patients (9.3%) and 16 healthy control subjects (6.5%) (P = .26). The CNVs identified in patients were larger (P = .03) and showed higher gene content (P = .02) than those in control subjects. The CNVs larger than 1 megabase (P = .002) and including more than 10 genes (P = .005) occurred more frequently in patients than in control subjects. Nine patients (34.6%) among those harboring rare CNVs showed rearrangements associated with emerging microdeletion or microduplication syndromes. Mental retardation and neuropsychiatric features were associated with rare CNVs (P = .004), whereas epilepsy type was not. The CNV rate in patients with epilepsy and mental retardation or neuropsychiatric features is not different from that observed in patients with mental retardation only. Moreover, significant enrichment of genes involved in ion transport was observed within CNVs identified in patients with epilepsy.

Conclusions: Patients with epilepsy show a significantly increased burden of large, rare, gene-rich CNVs, particularly when associated with mental retardation and neuropsychiatric features. The limited overlap between CNVs observed in the epilepsy group and those observed in the group with mental retardation only as well as the involvement of specific (ion channel) genes indicate a specific association between the identified CNVs and epilepsy. Screening for CNVs should be performed for diagnostic purposes preferentially in patients with epilepsy and mental retardation or neuropsychiatric features.
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http://dx.doi.org/10.1001/archneurol.2011.1999DOI Listing
March 2012

The first case of myoclonic epilepsy in a child with a de novo 22q11.2 microduplication.

Am J Med Genet A 2011 Dec 14;155A(12):3054-9. Epub 2011 Oct 14.

Dipartimento Materno Infantile, Università di Palermo, Palermo, Italy.

Chromosome 22, particularly the q11.2 sub-band, has long been recognized as responsible for multiple congenital anomaly disorders. In particular, its susceptibility to subtle microdeletions or, more rarely, microduplications has been attributed to the presence of several low-copy repeats spanning the region as mediators of nonallelic homologous recombination that result in 22q11.2 rearrangements. While recent data suggest that the frequency of 22q11.2 microduplications could be approximately half of all deletions, now only 50 unrelated cases have been reported thus far. However, it is reasonable to suppose that microduplications of 22q11.2 may be largely undetected as a result of a less-distinct, unpredictable, and/or milder phenotype ranging from normal to mild learning difficulties with/without other multiple defects. We report on the first case of myoclonic epilepsy in a 10-year-old boy carrying a de novo 22q11.2 microduplication. Emphasizing that this rare association could be one of the many unrecognized aspects underlying this new emerging syndrome and once again its clinical heterogeneity, we suggest further investigation of the function of the RAB36 gene and propose that in the screening of individuals with developmental delay, minor behavioral problems mild dysmorphology and seizures, investigation of 22q11.2 microduplications should be considered.
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http://dx.doi.org/10.1002/ajmg.a.34275DOI Listing
December 2011

A 12.4 Mb direct duplication in 19q12-q13 in a boy with cardiac and CNS malformations and developmental delay.

J Appl Genet 2011 Aug 3;52(3):335-9. Epub 2011 Mar 3.

Neonatology Unit, Department of Mother & Child, University of Modena, Via del Pozzo 71, Modena, Italy.

The interstitial duplication of the long arm of chromosome 19 is a rare abnormality, characterized by developmental delay and dysmorphic features, also reported in association with cardiac, urinary, and CNS malformations. We describe a new case of de novo 19q12-q13.2 duplication characterized by fluorescent in situ hybridization (FISH) and array comparative genomic hybridization (CGH) and, by reviewing the data from previous articles, we report a tentative genotype/phenotype correlation. Four previously described cases showed the same or overlapping 19q duplications and shared with our patient common dysmorphisms, psychomotor retardation, and CNS malformations. The present description of a new case of 19q12-q13.2 duplication with a molecular cytogenetic and genomic characterization adds further elements to the understanding of the impact of the genomic segment on the phenotype.
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http://dx.doi.org/10.1007/s13353-011-0033-5DOI Listing
August 2011

The refinement of the critical region for the 2q31.2q32.3 deletion syndrome indicates candidate genes for mental retardation and speech impairment.

Am J Med Genet B Neuropsychiatr Genet 2010 Oct;153B(7):1342-6

Division of Medical Genetics, Galliera Hospital, Genova, Italy.

Current literature provides more than 30 patients with interstitial deletions in chromosome 2q31q33. Only a few of them were studied using high-resolution methods. Among these, two patients had presented with a particular consistence of some clinical features associated to a deletion between bands q31.2 and q32.3 of chromosome 2. This clinical pattern, labeled as "2q31.2q32.3 syndrome," consists of multiple dysmorphisms, developmental delay, mental retardation and behavioural disturbances. We report an adult female patient with a 4.4 Mb deletion in the 2q31.2q32.3 region, showing facial dysmorphisms, mental retardation and absence of speech. The region overlaps with the deletion found in the two cases previously reported. The critical region points to a few genes, namely NEUROD1, ZNF804A, PDE1A, and ITGA4, which are good candidates to explain the cognitive and behavioural phenotype, as well as the severe speech impairment associated with the 2q31.2q32.3 deletion.
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http://dx.doi.org/10.1002/ajmg.b.31107DOI Listing
October 2010

Array-CGH defined chromosome 1p duplication in a patient with autism spectrum disorder, mild mental deficiency, and minor dysmorphic features.

Am J Med Genet A 2010 Feb;152A(2):486-9

Unità Operativa di Pediatria e Terapia Intensiva Neonatale, Dipartimento Materno Infantile, Università degli Studi di Palermo, Palermo, Italy.

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http://dx.doi.org/10.1002/ajmg.a.33212DOI Listing
February 2010

Array CGH defined interstitial deletion on chromosome 14: a new case.

Eur J Pediatr 2010 Jul 21;169(7):845-51. Epub 2010 Jan 21.

Dipartimento Materno Infantile, Università di Palermo, via Cardinale Rampolla 1, 90142, Palermo, Italy.

Interstitial deletions of the long arm of chromosome 14 are relatively rare. We report a 8.5-year-old girl with dysmorphic facial features and mental retardation associated with a de novo interstitial deletion of chromosome 14. The comparison between our patient and all published patients is reviewed. The genetic investigations have allowed us to define the critical chromosomal region and to start an accurate follow-up.
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http://dx.doi.org/10.1007/s00431-009-1128-4DOI Listing
July 2010

10qter deletion: a new case.

Am J Med Genet A 2008 Sep;146A(18):2435-8

Dipartimento Materno Infantile, Università di Palermo, Palermo, Italy.

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http://dx.doi.org/10.1002/ajmg.a.32467DOI Listing
September 2008
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