Publications by authors named "Gioacchino Scarano"

67 Publications

De Novo Inverted Duplication Deletion of 4p in a 14-Week-Old Male Fetus Aborted Due to Multiple Anomalies.

J Pediatr Genet 2021 Sep 19;10(3):245-249. Epub 2020 Jun 19.

Department of Medical Genetics, AORN San Pio, PO Gaetano Rummo, Benevento, Italy.

Inverted duplications deletions are rare, complex, and nonrecurrent chromosomal rearrangements associated with a variable phenotype. In this case report, we described the phenotype and genotype of a 14-week-old male fetus, who was aborted after discovery of multiple anomalies (septal cystic hygroma, open abdominal wall, and a nonidentifiable lower limb). At autopsy, fluorescence in situ hybridization and array comparative genomic hybridization identified an inverted duplication with terminal deletion of 4p [46,XY,der(4)del(p16.3)dup(4)(p15.2p16.3)]. Only five genotypically similar cases have been reported, and we hope our case contribution will add meaningful to the body of knowledge.
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http://dx.doi.org/10.1055/s-0040-1713156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8416190PMC
September 2021

Clinical heterogeneity of Kabuki syndrome in a cohort of Italian patients and review of the literature.

Eur J Pediatr 2021 Jul 7. Epub 2021 Jul 7.

Pediatric Unit, Translational Medicine Department, Federico II University Hospital, Naples, Italy.

Kabuki syndrome (KS) is a well-recognized disorder characterized by postnatal growth deficiency, dysmorphic facial features, skeletal anomalies, and intellectual disability. The syndrome is caused by KMT2D gene mutations or less frequently KDM6A gene mutations or deletions. We report a systematic evaluation of KS patients from Campania region of Italy; data were also compared with literature ones. We collected data of 15 subjects (8 males and 7 females with age range 10-26 years; mean age 16.9 years) with confirmed diagnosis of KS, representing the entire cohort of patients from Campania Region. Each patient performed biochemical testing and instrumental investigation. Neuro-intellectual development, cranio-facial dysmorphisms, and multisystem involvement data were collected retrospectively. For each category, type of defects and frequency of the anomalies were analyzed. Our observation shows that KS patients from Campania region have some particular and previously underscored, neurological and immunological findings. We found high prevalence of EEG's abnormalities (43%) and MRI brain abnormalities (60%). Microcephaly resulted more common in our series (33%), if compared with major cohorts described in literature. Biochemical features of immunodeficiency and autoimmune diseases including thyroid autoimmunity, polyserositis, and vitiligo were observed with high prevalence (54.5%). Low immunoglobulins levels were a frequent finding. Lymphocyte class investigation showed significantly reduced CD8 levels in one patient.Conclusions: These data confirm great heterogeneity of clinical manifestations in KS and suggest to introduce further clinical diagnostic criteria in order to perform a correct and precocious diagnosis. What is Known • Kabuki syndrome is characterized by growth deficiency, dysmorphic facial features, skeletal anomalies, and intellectual disability • Immune dysfunction is a common finding but autoimmune diseases are rarely seen • Neurological features are common What is New • Some particular facial features could help gestalt diagnosis (hypertelorism, broad nasal bridge, micrognathia, tooth agenesis, cutaneous haemangiomas and strabismus) • Higher prevalence of autoimmune disorders than previously reported • Particular neurological features are present in this cohort (EEG and MRI brain abnormalities).
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http://dx.doi.org/10.1007/s00431-021-04108-wDOI Listing
July 2021

Clinical Characterization of a 6-Year-Old Patient with Autism and Two Adjacent Duplications on 10q11.22q11.23. A Case Report.

Children (Basel) 2021 Jun 18;8(6). Epub 2021 Jun 18.

Medical Genetics Unit, A.O.R.N. San Pio, 82100 Benevento, Italy.

Autism is a neurodevelopmental disorder presenting in the first 3 years of life. Deficits occur in the core areas of social communication and interaction and restricted, repetitive patterns of behavior, interests or activities. The causes of autism are unknown, but clinical genetic studies show strong evidence in favor of the involvement of genetic factors in etiology. Molecular genetic studies report some associations with candidate genes, and candidate regions have emerged from several genome-wide linkage studies. Here, we report a clinical case of autism in a 6-year-old boy with double duplication on 10q11.22q11.23 with ASD (Autism Spectrum Disorder), intellectual disability, developmental delay, hypotonia, gross-motor skills deficit, overgrowth and mild dysmorphic features. In the literature, only five cases of ASD with 10q11.21q11.23 duplication are reported. This is the first extensive clinical description of an ASD subject with 10q11.22q11.23 duplication. Our findings suggest that 10q11.21q11.23 microduplication could represent a copy number variant that predisposes to autism.
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http://dx.doi.org/10.3390/children8060518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8235778PMC
June 2021

Diagnostic issues faced by a rare disease healthcare network during Covid-19 outbreak: data from the Campania Rare Disease Registry.

J Public Health (Oxf) 2021 05 13. Epub 2021 May 13.

Centro di Coordinamento Malattie Rare, Regione Campania Naples 80131, Italy.

Background: The aims of this study were: to investigate the capacity of the rare disease healthcare network in Campania to diagnose patients with rare diseases during the outbreak of Covid-19; and to shed light on problematic diagnoses during this period.

Methods: To describe the impact of the Covid-19 pandemic on the diagnosis of patients with rare diseases, a retrospective analysis of the Campania Region Rare Disease Registry was performed. A tailored questionnaire was sent to rare disease experts to investigate major issues during the emergency period.

Results: Prevalence of new diagnoses of rare disease in March and April 2020 was significantly lower than in 2019 (117 versus 317, P < 0.001 and 37 versus 349, P < 0.001, respectively) and 2018 (117 versus 389, P < 0.001 and 37 versus 282, P < 0.001, respectively). Eighty-two among 98 rare disease experts completed the questionnaire. Diagnostic success (95%), access to diagnosis (80%) and follow-up (72%), lack of Personal Protective Equipment (60%), lack of Covid-19 guidelines (50%) and the need for home therapy (78%) were the most important issues raised during Covid-19 outbreak.

Conclusions: This study describes the effects of the Covid-19 outbreak on the diagnosis of rare disease in a single Italian region and investigates potential issues of diagnosis and management during this period.
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http://dx.doi.org/10.1093/pubmed/fdab137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8194710PMC
May 2021

Delineation of MidXq28-duplication syndrome distal to MECP2 and proximal to RAB39B genes.

Clin Genet 2019 09 17;96(3):246-253. Epub 2019 Jun 17.

Medical Genetics Unit, Casa Sollievo della Sofferenza IRCCS, San Giovanni Rotondo (FG), Italy.

Two distinct genomic disorders have been linked to Xq28-gains, namely Xq28-duplications including MECP2 and Int22h1/Int22h2-mediated duplications involving RAB39B. Here, we describe six unrelated patients, five males and one female, with Xq28-gains distal to MECP2 and proximal to the Int22h1/Int22h2 low copy repeats. Comparison with patients carrying overlapping duplications in the literature defined the MidXq28-duplication syndrome featuring intellectual disability, language impairment, structural brain malformations, microcephaly, seizures and minor craniofacial features. The duplications overlapped for 108 kb including FLNA, RPL10 and GDI1 genes, highly expressed in brain and candidates for the neurologic phenotype.
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http://dx.doi.org/10.1111/cge.13565DOI Listing
September 2019

Small 4p16.3 deletions: Three additional patients and review of the literature.

Am J Med Genet A 2018 11 23;176(11):2501-2508. Epub 2018 Sep 23.

Medical Genetics Unit and Laboratory of Medical Genetics, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.

Wolf-Hirschhorn syndrome is a well-defined disorder due to 4p16.3 deletion, characterized by distinct facial features, intellectual disability, prenatal and postnatal growth retardation, and seizures. Genotype-phenotype correlations based on differently sized deletions have been attempted, and some candidate genes have been suggested. We report on clinical characteristics of three patients with pure interstitial submicroscopic 4p16.3 deletions, ranging in size from 68 to 166 kb, involving WHSCR1 and/or part of WHSCR2, and review published cases with overlapping 4p16.3 losses. The present study highlights a major role of NSD2 gene in the pathogenesis of the WHS main features and predicts that loss-of-function mutations affecting NSD2 gene could result in microcephaly, prenatal and postnatal growth retardation, psychomotor and language delay, and craniofacial features. Absent seizures in all subjects corroborate the suggestion that this specific feature is causally linked with at least one additional causative gene. Finally, we suggest that mir-943 could play a role in the pathogenesis of CHD in some of these patients.
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http://dx.doi.org/10.1002/ajmg.a.40512DOI Listing
November 2018

Phenotype and genotype of 87 patients with Mowat-Wilson syndrome and recommendations for care.

Genet Med 2018 09 4;20(9):965-975. Epub 2018 Jan 4.

Neuropsychiatric Department, Spedali Civili Brescia, Brescia, Italy.

Purpose: Mowat-Wilson syndrome (MWS) is a rare intellectual disability/multiple congenital anomalies syndrome caused by heterozygous mutation of the ZEB2 gene. It is generally underestimated because its rarity and phenotypic variability sometimes make it difficult to recognize. Here, we aimed to better delineate the phenotype, natural history, and genotype-phenotype correlations of MWS.

Methods: In a collaborative study, we analyzed clinical data for 87 patients with molecularly confirmed diagnosis. We described the prevalence of all clinical aspects, including attainment of neurodevelopmental milestones, and compared the data with the various types of underlying ZEB2 pathogenic variations.

Results: All anthropometric, somatic, and behavioral features reported here outline a variable but highly consistent phenotype. By presenting the most comprehensive evaluation of MWS to date, we define its clinical evolution occurring with age and derive suggestions for patient management. Furthermore, we observe that its severity correlates with the kind of ZEB2 variation involved, ranging from ZEB2 locus deletions, associated with severe phenotypes, to rare nonmissense intragenic mutations predicted to preserve some ZEB2 protein functionality, accompanying milder clinical presentations.

Conclusion: Knowledge of the phenotypic spectrum of MWS and its correlation with the genotype will improve its detection rate and the prediction of its features, thus improving patient care.
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http://dx.doi.org/10.1038/gim.2017.221DOI Listing
September 2018

Congenital Anomalies in Contaminated Sites: A Multisite Study in Italy.

Int J Environ Res Public Health 2017 03 10;14(3). Epub 2017 Mar 10.

Institute of Clinical Physiology, National Research Council, Unit of Environmental Epidemiology and Disease Registries, 56124 Pisa, Italy.

The health impact on populations residing in industrially contaminated sites (CSs) is recognized as a public health concern especially in relation to more vulnerable population subgroups. The aim of this study was to estimate the risk of congenital anomalies (CAs) in Italian CSs. Thirteen CSs covered by regional CA registries were investigated in an ecological study. The observed/expected ratios (O/E) with 90% confidence intervals (CI) for the total and specific subgroups of CAs were calculated using the regional areas as references. For the CSs with waste landfills, petrochemicals, and refineries, pooled estimates were calculated. The total number of observed cases of CAs was 7085 out of 288,184 births (prevalence 245.8 per 10,000). For some CSs, excesses for several CA subgroups were observed, in particular for genital and heart defects. The excess of genital CAs observed in Gela (O/E 2.36; 90% CI 1.73-3.15) is consistent with findings from other studies. For CSs including petrochemical and landfills, the pooled risk estimates were 1.10 (90% CI 1.01-1.19) and 1.07 (90% CI 1.02-1.13), respectively. The results are useful in identifying priority areas for analytical investigations and in supporting the promotion of policies for the primary prevention of CAs. The use of short-latency effect indicators is recommended for the health surveillance of the populations residing in CSs.
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http://dx.doi.org/10.3390/ijerph14030292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5369128PMC
March 2017

Neuroimaging findings in Mowat-Wilson syndrome: a study of 54 patients.

Genet Med 2017 06 10;19(6):691-700. Epub 2016 Nov 10.

Neuroradiology Unit, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, Italy.

Purpose: Mowat-Wilson syndrome (MWS) is a genetic disease characterized by distinctive facial features, moderate to severe intellectual disability, and congenital malformations, including Hirschsprung disease, genital and eye anomalies, and congenital heart defects, caused by haploinsufficiency of the ZEB2 gene. To date, no characteristic pattern of brain dysmorphology in MWS has been defined.

Methods: Through brain magnetic resonance imaging (MRI) analysis, we delineated a neuroimaging phenotype in 54 MWS patients with a proven ZEB2 defect, compared it with the features identified in a thorough review of published cases, and evaluated genotype-phenotype correlations.

Results: Ninety-six percent of patients had abnormal MRI results. The most common features were anomalies of corpus callosum (79.6% of cases), hippocampal abnormalities (77.8%), enlargement of cerebral ventricles (68.5%), and white matter abnormalities (reduction of thickness 40.7%, localized signal alterations 22.2%). Other consistent findings were large basal ganglia, cortical, and cerebellar malformations. Most features were underrepresented in the literature. We also found ZEB2 variations leading to synthesis of a defective protein to be favorable for psychomotor development and some epilepsy features but also associated with corpus callosum agenesis.

Conclusion: This study delineated the spectrum of brain anomalies in MWS and provided new insights into the role of ZEB2 in neurodevelopment.Genet Med advance online publication 10 November 2016.
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http://dx.doi.org/10.1038/gim.2016.176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5438871PMC
June 2017

First evidence of Smith-Magenis syndrome in mother and daughter due to a novel RAI mutation.

Am J Med Genet A 2017 Jan 28;173(1):231-238. Epub 2016 Sep 28.

U.O. di Genetica Medica, A.O.R.N. "G. Rummo", Benevento, Italy.

Smith-Magenis syndrome (SMS) is a complex genetic disorder caused by interstitial 17p11.2 deletions encompassing multiple genes, including the retinoic acid induced 1 gene-RAI1-or mutations in RAI1 itself. The clinical spectrum includes developmental delay, cognitive impairment, and behavioral abnormalities, with distinctive physical features that become more evident with age. No patients have been reported to have had offspring. We here describe a girl with developmental delay, mainly compromising the speech area, and her mother with mild intellectual disabilities and minor dysmorphic features. Both had sleep disturbance and attention deficit disorder, but no other atypical behaviors have been reported. In both, CGH-array analysis detected a 15q13.3 interstitial duplication, encompassing CHRNA7. However, the same duplication has been observed in several, apparently healthy, maternal relatives. We, thus, performed a whole exome sequencing analysis, which detected a frameshift mutation in RAI1, de novo in the mother, and transmitted to her daughter. No other family members carried this mutation. This is the first report of an SMS patient having offspring. Our experience confirms the importance of searching for alternative causative genetic mechanisms in case of confounding/inconclusive findings such as a CGH-array result of uncertain significance. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajmg.a.37989DOI Listing
January 2017

Prevalence and determinants of preconception folic acid use: an Italian multicenter survey.

Ital J Pediatr 2016 Jul 13;42(1):65. Epub 2016 Jul 13.

Alessandra Lisi International Centre on Birth Defects and Prematurity, Rome, Italy.

Background: Women in many countries are advised to use folic acid supplements before and early during pregnancy to reduce the risk of neural tube defects in their infants. This study aimed to update the prevalence and to identify possible determinants of preconception folic acid supplement use in Italian women.

Methods: The study was based on cross-sectional data from seven maternity clinics located in six Italian regions from January to June, 2012. Data on maternal characteristics and supplement use were collected for 2,189 women using a self-administered questionnaire.

Results: Preconception folic acid use was reported by 23.5 % (n = 515) of the participants. Of these, 479 (93 %) women had taken folic acid supplements on a daily basis as recommended by the health authorities. Women who both had intended their pregnancy and had requested a preconception health visit to a doctor/gynecologist were substantially more likely than the reference group to initiate folic acid supplementation before their pregnancy (48.6 versus 4.8 %). Preconception folic acid use was also associated with higher maternal age, higher education, marriage/cohabitation, lower parity, infertility treatments, and chronic disease.

Conclusions: Data from seven maternity clinics located in six Italian regions indicate that preconception folic acid supplement use in many Italian women is low. Women who do not plan their pregnancy or do not request a preconception health visit to their doctor have among the lowest prevalence of preconception folic acid use. Improving folate status in these and other supplemental non-users may have important disease preventive effects.
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http://dx.doi.org/10.1186/s13052-016-0278-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4944255PMC
July 2016

The promise of non-invasive prenatal testing needs to be monitored scientifically.

BMJ 2015 May 14;350:h2518. Epub 2015 May 14.

Medical Cytogenetics and Molecular Genetics Unit, AORN "Gaetano Rummo," 82100 Benevento, Italy.

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http://dx.doi.org/10.1136/bmj.h2518DOI Listing
May 2015

Prevalence of maternal preconception risk factors: an Italian multicenter survey.

Ital J Pediatr 2014 Nov 23;40:91. Epub 2014 Nov 23.

Objectives: Adequate preconception maternal health care is essential to reduce the risk of unwanted pregnancy outcomes and complications. Still, many women are exposed to a number of unhealthy risk factors both before and early in pregnancy. This study aimed to estimate the prevalence of a number of important preconception risk factors using data from a recent multicenter study in Italy.

Methods: The study was based on cross-sectional data from seven maternity clinics located in six different regions in Italy during the period January - June, 2012. Data on maternal preconception risk factors and characteristics were collected from 1,892 women who delivered healthy children and 320 women who were pregnant in the first trimester.

Results: About 97% of the women (n =2,212) were exposed to one or more preconception risk factors. The overall prevalence of the most essential maternal risk factors was as follows: 41% had a age ≥35 years, 36% mistimed or did not intend their pregnancy, 58% did not request a preconception health visit to their doctor, 76% did not use folic acid supplements before pregnancy, 26% smoked at the last menstrual period, 19% had a body mass index ≥25 kg/m2 before pregnancy, and 10% suffered from pregestational chronic diseases. The prevalence of certain variables varied between the maternity clinics.

Conclusions: Many Italian women are exposed to a number of preconception risk factors that have been associated with adverse pregnancy complications and outcomes. More effective intervention programs to improve preconception health in Italian women are strongly needed.
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http://dx.doi.org/10.1186/s13052-014-0091-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4264313PMC
November 2014

Arterial Tortuosity Syndrome: homozygosity for two novel and one recurrent SLC2A10 missense mutations in three families with severe cardiopulmonary complications in infancy and a literature review.

BMC Med Genet 2014 Nov 6;15:122. Epub 2014 Nov 6.

Division of Biology and Genetics, Department of Molecular and Translational Medicine, School of Medicine, University of Brescia, Viale Europa 11, 25123, Brescia, Italy.

Background: Arterial Tortuosity Syndrome (ATS) is a very rare autosomal recessive connective tissue disorder (CTD) characterized by tortuosity and elongation of the large- and medium-sized arteries and a propensity for aneurysm formation and vascular dissection. During infancy, children frequently present the involvement of the pulmonary arteries (elongation, tortuosity, stenosis) with dyspnea and cyanosis. Other CTD signs of ATS are dysmorphisms, abdominal hernias, joint hypermobility, skeletal abnormalities, and keratoconus. ATS is typically described as a severe disease with high rate of mortality due to major cardiovascular malformations. ATS is caused by mutations in the SLC2A10 gene, which encodes the facilitative glucose transporter 10 (GLUT10). Approximately 100 ATS patients have been described, and 21 causal mutations have been identified in the SLC2A10 gene.

Case Presentation: We describe the clinical findings and molecular characterization of three new ATS families, which provide insight into the clinical phenotype of the disorder; furthermore, we expand the allelic repertoire of SLC2A10 by identifying two novel mutations. We also review the ATS patients characterized by our group and compare their clinical findings with previous data.

Conclusions: Our data confirm that the cardiovascular prognosis in ATS is less severe than previously reported and that the first years of life are the most critical for possible life-threatening events. Molecular diagnosis is mandatory to distinguish ATS from other CTDs and to define targeted clinical follow-up and timely cardiovascular surgical or interventional treatment, when needed.
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http://dx.doi.org/10.1186/s12881-014-0122-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4412100PMC
November 2014

Mucopolysaccharidosis type II in a female patient with a reciprocal X;9 translocation and skewed X chromosome inactivation.

Am J Med Genet A 2014 Oct 8;164A(10):2627-32. Epub 2014 Jul 8.

U.O.C. di Genetica Medica, A.O.R.N. "G. Rummo", Benevento, Italy.

Mucopolysaccharidosis type II (MPS II or Hunter syndrome) is a rare X-linked disorder caused by deficient activity of the lysosomal enzyme, iduronate-2-sulfatase (IDS). Phenotypic expression of MPS II in female patients rarely occurs and may be the result of (i) structural abnormalities of the X chromosome, (ii) homozygosity for disease-causing mutations, or (iii) skewed X-chromosome inactivation, in which the normal IDS allele is preferentially inactivated and the abnormal IDS allele is active. We report here on a female patient with clinical MPS II manifestations, deficiency of IDS enzyme activity and a de novo balanced reciprocal X;9 translocation. As our patient has a skewed XCI pattern, but neither genomic IDS mutations nor abnormal IDS transcripts were detected, we speculate about the possible role of the chromosomal rearrangement in reducing the IDS translation efficiency.
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http://dx.doi.org/10.1002/ajmg.a.36667DOI Listing
October 2014

Prenatal diagnosis and epidemiology of multicystic kidney dysplasia in Europe.

Prenat Diagn 2014 Nov 2;34(11):1093-8. Epub 2014 Jul 2.

Paediatric Department, Hospital Lillebaelt, Kolding, Denmark.

Objectives: The aim of this study is to describe the prenatal diagnosis and epidemiology of multicystic kidney dysplasia (MCKD).

Methods: The study is based on routinely collected data from a European database of major congenital anomalies including 13 registries with cases born in 1997-2006 and covering 1 458 552 births.

Results: There were 601 MCKD cases giving an overall prevalence of 4.12 per 10 000 births with regional variation. In live births, 87% of cases had an isolated renal anomaly and 13% had associated major nonrenal anomalies (chromosomal, syndrome or other major anomalies). For the cases with isolated renal anomalies, 51/386 (11%) and 7/386 (2%) choose to terminate the pregnancy or resulted in an intrauterine fetal death, respectively. The prenatal detection rate was 88% in both unilateral and bilateral cases. Birth outcome differed with 92% of unilateral MCKD cases being liveborn compared with 33% of bilateral MCKD cases. For unilateral MCKD cases, 84% had an isolated renal anomaly compared with 51% of bilateral MCKD cases (p < 0.001).

Conclusions: Cases with unilateral MCKD are mainly liveborn, and only 16% have associated major malformations or a syndrome. Cases with bilateral MCKD are often associated with nonrenal major congenital anomalies or part of a syndrome, and only one third of bilateral MCKD cases in this study were liveborn. Prenatal detection rate of MCKD was high for both unilateral and bilateral cases. © 2014 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/pd.4433DOI Listing
November 2014

Molecular analysis of holoprosencephaly in South America.

Genet Mol Biol 2014 Mar;37(1 Suppl):250-62

Estudo Colaborativo Latino Americano de Malformações Congênitas, Departamento de Genética, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil . ; Instituto Nacional de Genética Médica Populacional, Rio de Janeiro, RJ, Brazil .

Holoprosencephaly (HPE) is a spectrum of brain and facial malformations primarily reflecting genetic factors, such as chromosomal abnormalities and gene mutations. Here, we present a clinical and molecular analysis of 195 probands with HPE or microforms; approximately 72% of the patients were derived from the Latin American Collaborative Study of Congenital Malformations (ECLAMC), and 82% of the patients were newborns. Alobar HPE was the predominant brain defect in almost all facial defect categories, except for patients without oral cleft and median or lateral oral clefts. Ethmocephaly, cebocephaly, and premaxillary agenesis were primarily observed among female patients. Premaxillary agenesis occurred in six of the nine diabetic mothers. Recurrence of HPE or microform was approximately 19%. The frequency of microdeletions, detected using Multiplex Ligation-dependant Probe Amplification (MLPA) was 17% in patients with a normal karyotype. Cytogenetics or QF-PCR analyses revealed chromosomal anomalies in 27% of the probands. Mutational analyses in genes SHH, ZIC2, SIX3 and TGIF were performed in 119 patients, revealing eight mutations in SHH, two mutations in SIX3 and two mutations in ZIC2. Thus, a detailed clinical description of new HPE cases with identified genetic anomalies might establish genotypic and phenotypic correlations and contribute to the development of additional strategies for the analysis of new cases.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3983586PMC
http://dx.doi.org/10.1590/s1415-47572014000200011DOI Listing
March 2014

Molecular analysis, pathogenic mechanisms, and readthrough therapy on a large cohort of Kabuki syndrome patients.

Hum Mutat 2014 Jul 9;35(7):841-50. Epub 2014 Apr 9.

Medical Genetics Unit, IRCCS Casa Sollievo Della Sofferenza Hospital, San Giovanni Rotondo, Italy.

Kabuki syndrome (KS) is a multiple congenital anomalies syndrome characterized by characteristic facial features and varying degrees of mental retardation, caused by mutations in KMT2D/MLL2 and KDM6A/UTX genes. In this study, we performed a mutational screening on 303 Kabuki patients by direct sequencing, MLPA, and quantitative PCR identifying 133 KMT2D, 62 never described before, and four KDM6A mutations, three of them are novel. We found that a number of KMT2D truncating mutations result in mRNA degradation through the nonsense-mediated mRNA decay, contributing to protein haploinsufficiency. Furthermore, we demonstrated that the reduction of KMT2D protein level in patients' lymphoblastoid and skin fibroblast cell lines carrying KMT2D-truncating mutations affects the expression levels of known KMT2D target genes. Finally, we hypothesized that the KS patients may benefit from a readthrough therapy to restore physiological levels of KMT2D and KDM6A proteins. To assess this, we performed a proof-of-principle study on 14 KMT2D and two KDM6A nonsense mutations using specific compounds that mediate translational readthrough and thereby stimulate the re-expression of full-length functional proteins. Our experimental data showed that both KMT2D and KDM6A nonsense mutations displayed high levels of readthrough in response to gentamicin treatment, paving the way to further studies aimed at eventually treating some Kabuki patients with readthrough inducers.
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http://dx.doi.org/10.1002/humu.22547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234006PMC
July 2014

Prevalence, prenatal diagnosis and clinical features of oculo-auriculo-vertebral spectrum: a registry-based study in Europe.

Eur J Hum Genet 2014 Aug 8;22(8):1026-33. Epub 2014 Jan 8.

Congenital Anomaly Register and Info Service Public Health Level 3 West Wing, Singleton Hospital, Wales, UK.

Oculo-auriculo-vertebral spectrum is a complex developmental disorder characterised mainly by anomalies of the ear, hemifacial microsomia, epibulbar dermoids and vertebral anomalies. The aetiology is largely unknown, and the epidemiological data are limited and inconsistent. We present the largest population-based epidemiological study to date, using data provided by the large network of congenital anomalies registries in Europe. The study population included infants diagnosed with oculo-auriculo-vertebral spectrum during the 1990-2009 period from 34 registries active in 16 European countries. Of the 355 infants diagnosed with oculo-auriculo-vertebral spectrum, there were 95.8% (340/355) live born, 0.8% (3/355) fetal deaths, 3.4% (12/355) terminations of pregnancy for fetal anomaly and 1.5% (5/340) neonatal deaths. In 18.9%, there was prenatal detection of anomaly/anomalies associated with oculo-auriculo-vertebral spectrum, 69.7% were diagnosed at birth, 3.9% in the first week of life and 6.1% within 1 year of life. Microtia (88.8%), hemifacial microsomia (49.0%) and ear tags (44.4%) were the most frequent anomalies, followed by atresia/stenosis of external auditory canal (25.1%), diverse vertebral (24.3%) and eye (24.3%) anomalies. There was a high rate (69.5%) of associated anomalies of other organs/systems. The most common were congenital heart defects present in 27.8% of patients. The prevalence of oculo-auriculo-vertebral spectrum, defined as microtia/ear anomalies and at least one major characteristic anomaly, was 3.8 per 100,000 births. Twinning, assisted reproductive techniques and maternal pre-pregnancy diabetes were confirmed as risk factors. The high rate of different associated anomalies points to the need of performing an early ultrasound screening in all infants born with this disorder.
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http://dx.doi.org/10.1038/ejhg.2013.287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4350601PMC
August 2014

Intergenerational and intrafamilial phenotypic variability in 22q11.2 deletion syndrome subjects.

BMC Med Genet 2014 Jan 2;15. Epub 2014 Jan 2.

Department of Translational Medicine, "Federico II" University, Naples, Italy.

Background: 22q11.2 deletion syndrome (22q11.2DS) is a common microdeletion syndrome, which occurs in approximately 1:4000 births. Familial autosomal dominant recurrence of the syndrome is detected in about 8-28% of the cases. Aim of this study is to evaluate the intergenerational and intrafamilial phenotypic variability in a cohort of familial cases carrying a 22q11.2 deletion.

Methods: Thirty-two 22q11.2DS subjects among 26 families were enrolled.

Results: Second generation subjects showed a significantly higher number of features than their transmitting parents (212 vs 129, P = 0.0015). Congenital heart defect, calcium-phosphorus metabolism abnormalities, developmental and speech delay were more represented in the second generation (P < 0.05). Ocular disorders were more frequent in the parent group. No significant difference was observed for the other clinical variables. Intrafamilial phenotypic heterogeneity was identified in the pedigrees. In 23/32 families, a higher number of features were found in individuals from the second generation and a more severe phenotype was observed in almost all of them, indicating the worsening of the phenotype over generations. Both genetic and epigenetic mechanisms may be involved in the phenotypic variability.

Conclusions: Second generation subjects showed a more complex phenotype in comparison to those from the first generation. Both ascertainment bias related to patient selection or to the low rate of reproductive fitness of adults with a more severe phenotype, and several not well defined molecular mechanism, could explain intergenerational and intrafamilial phenotypic variability in this syndrome.
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http://dx.doi.org/10.1186/1471-2350-15-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3893549PMC
January 2014

Disruption of the ASTN2/TRIM32 locus at 9q33.1 is a risk factor in males for autism spectrum disorders, ADHD and other neurodevelopmental phenotypes.

Hum Mol Genet 2014 May 30;23(10):2752-68. Epub 2013 Dec 30.

The Centre for Applied Genomics.

Rare copy number variants (CNVs) disrupting ASTN2 or both ASTN2 and TRIM32 have been reported at 9q33.1 by genome-wide studies in a few individuals with neurodevelopmental disorders (NDDs). The vertebrate-specific astrotactins, ASTN2 and its paralog ASTN1, have key roles in glial-guided neuronal migration during brain development. To determine the prevalence of astrotactin mutations and delineate their associated phenotypic spectrum, we screened ASTN2/TRIM32 and ASTN1 (1q25.2) for exonic CNVs in clinical microarray data from 89 985 individuals across 10 sites, including 64 114 NDD subjects. In this clinical dataset, we identified 46 deletions and 12 duplications affecting ASTN2. Deletions of ASTN1 were much rarer. Deletions near the 3' terminus of ASTN2, which would disrupt all transcript isoforms (a subset of these deletions also included TRIM32), were significantly enriched in the NDD subjects (P = 0.002) compared with 44 085 population-based controls. Frequent phenotypes observed in individuals with such deletions include autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), speech delay, anxiety and obsessive compulsive disorder (OCD). The 3'-terminal ASTN2 deletions were significantly enriched compared with controls in males with NDDs, but not in females. Upon quantifying ASTN2 human brain RNA, we observed shorter isoforms expressed from an alternative transcription start site of recent evolutionary origin near the 3' end. Spatiotemporal expression profiling in the human brain revealed consistently high ASTN1 expression while ASTN2 expression peaked in the early embryonic neocortex and postnatal cerebellar cortex. Our findings shed new light on the role of the astrotactins in psychopathology and their interplay in human neurodevelopment.
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http://dx.doi.org/10.1093/hmg/ddt669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3990173PMC
May 2014

Science, art, and mistery in the statues and in the anatomical machines of the prince of sansevero: the masterpieces of the "Sansevero Chapel".

Am J Med Genet A 2013 Nov 3;161A(11):2920-9. Epub 2013 Oct 3.

Unità Operativa di Genetica Medica, Ospedale Gaetano Rummo, Benevento, Italy.

During the 18th century in Naples, Raimondo di Sangro, Prince of Sansevero, completed works on the family chapel, the so-called "Cappella Sansevero." The chapel houses statues of extraordinary beauty and spectacularly detailed but also, in the basement, two human skeletons known as the "Anatomical Machines" ("Macchine Anatomiche"). These two skeletons, a man and a pregnant woman, are entirely surrounded by their circulatory systems, just as if these were suddenly fixed. Legend, believed as truth until few years ago, says that Prince Raimondo had prepared and injected an unknown embalming substance in the blood vessels of two of his servants convicting them to eternal fixity. Recent investigations have demonstrated that, while the bones are authentic, the blood vessels are actually extraordinary artifacts that also reproduce some congenital malformations. The dreadful aspect of these two skeletons appears to be in strident contrast with the classic beauty of the statues which glorify and celebrate the ideal of morphology. Conversely, the two Anatomical Machines, protagonists of legends and superstitions since centuries, represent a marvelous example of science mixed with art.
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http://dx.doi.org/10.1002/ajmg.a.36258DOI Listing
November 2013

Recurrence of CCHS associated PHOX2B poly-alanine expansion mutation due to maternal mosaicism.

Pediatr Pulmonol 2014 Mar 4;49(3):E45-7. Epub 2013 Mar 4.

U.O.C. Medical Genetics, Institute Giannina Gaslini, Genova, Italy.

Heterozygous in frame trinucleotide duplications within the PHOX2B gene, leading to poly-alanine expansions, cause Congenital Central Hypoventilation Syndrome. Here we report about a CCHS patient, carrying a +13Ala PHOX2B expansion, whose asymptomatic mother resulted with a low level of mosaicism for the same mutation in peripheral blood cells. Her second pregnancy ended with the spontaneous miscarriage of a fetus who had inherited the PHOX2B mutation, thus confirming germline mosaicism in the mother and the need of proper genetic counseling to CCHS families.
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http://dx.doi.org/10.1002/ppul.22790DOI Listing
March 2014

Genetic Drift: the Salernitan school of medicine: women, men, and children. A syndromological review of the oldest medical school in the western world.

Am J Med Genet A 2013 Apr 26;161A(4):809-16. Epub 2013 Feb 26.

Medical Genetics Division, General Hospital Gaetano Rummo, Benevento, Italy.

Ever since the 9th century during the High Middle Ages, the "Schola Medica Salernitana," believed to be the first medical school in the western world, flourished in Salerno, a city in southern Italy. Although an important role is attributed to several men of this school, who were recognized as wise and learned doctors, modern historiography has also reevaluated and extolled the praiseworthy role of women. Contrary to the common beliefs and expectations of a woman's "place" at the time, these women were fully titled physicians. Attention was also paid to the health and welfare of children. However, there are no apparent references to physical disabilities, a mysterious omission that seems incompatible with an institution that stood as a beacon of knowledge for centuries. Mysteries, discoveries, and potential hidden messages are mingled in a fascinating medieval codex yet to be fully deciphered. The medical school reached its maximum splendor between the years of 1000 and 1300 AD. After alternating fortunes, the Salernitan institution began a slow decline due to the explosive development of other universities, such as those in Paris, Bologna, Padua, and most significantly, the nearby University of Naples. It was eventually closed by the King of Naples, Joachim Murat, November 29, 1811.
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http://dx.doi.org/10.1002/ajmg.a.35742DOI Listing
April 2013

Proposal of a clinical score for the molecular test for Pitt-Hopkins syndrome.

Am J Med Genet A 2012 Jul 7;158A(7):1604-11. Epub 2012 Jun 7.

Istituto di Genetica Medica, Università Cattolica del Sacro Cuore, Roma, Italy.

Pitt-Hopkins syndrome (PTHS) is an emerging condition characterized by severe intellectual disability (ID), typical facial gestalt, and additional features, such as breathing abnormalities. Because of the overlapping phenotype of severe ID with absent speech, epilepsy, microcephaly, large mouth, and constipation, differential diagnosis of PTHS with respect to Angelman, Rett, and Mowat-Wilson syndromes represents a relevant clinical issue, and many patients are currently undergoing genetic tests for different conditions that are assumed to fall within the PTHS clinical spectrum. During a search for TCF4 mutations in 78 patients with a suspected PTHS, haploinsufficiency of TCF4 was identified in 18. By evaluating clinical features of patients with a proven TCF4 mutation with those of patients without, we noticed that, in addition to the typical facial gestalt, the PTHS phenotype results from the various combination of the following characteristics: ID with severe speech impairment, normal growth parameters at birth, postnatal microcephaly, breathing abnormalities, motor incoordination, ocular anomalies, constipation, seizures, typical behavior, and subtle brain abnormalities. On the basis of these observations, here we propose a clinically based score system as useful tool for driving a first choice molecular test for PTHS. This scoring system is also proposed for a clinically based diagnosis of PTHS in absence of a proven TCF4 mutation.
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http://dx.doi.org/10.1002/ajmg.a.35419DOI Listing
July 2012

NEK1 and DYNC2H1 are both involved in short rib polydactyly Majewski type but not in Beemer Langer cases.

J Med Genet 2012 Apr;49(4):227-33

Department of Genetics, INSERM U781, Hôpital Necker, Université Paris Descartes, Sorbonne Paris Cité, Paris 75015, France.

Background: The lethal short rib polydactyly syndromes (SRP type I-IV) are characterised by notably short ribs, short limbs, polydactyly, multiple anomalies of major organs, and autosomal recessive mode of inheritance. Among them, SRP type II (Majewski; MIM 263520) is characterised by short ovoid tibiae or tibial agenesis and is radiographically closely related to SRP type IV (Beemer-Langer; MIM 269860) which is distinguished by bowed radii and ulnae and relatively well tubulated tibiae. NEK1 mutations have been recently identified in SRP type II. Double heterozygosity for mutations in both NEK1 and DYNC2H1 in one SRP type II case supported possible digenic diallelic inheritance.

Methods: The aim of this study was to screen DYNC2H1 and NEK1 in 13 SRP type II cases and seven SRP type IV cases. It was not possible to screen DYNC2H1 in two patients due to insufficient amount of DNA.

Results: The study identified homozygous NEK1 mutations in 5/13 SRP type II and compound heterozygous DYNC2H1 mutations in 4/12 cases. Finally, NEK1 and DYNC2H1 were excluded in 3/12 SRP type II and in all SRP type IV cases. The main difference between the mutation positive SRP type II group and the mutation negative SRP type II group was the presence of holoprosencephaly and polymycrogyria in the mutation negative group.

Conclusion: This study confirms that NEK1 is one gene causing SRP type II but also reports mutations in DYNC2H1, expanding the phenotypic spectrum of DYNC2H1 mutations. The exclusion of NEK1 and DYNC2H1 in 3/12 SRP type II and in all SRP type IV cases further support genetic heterogeneity.
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http://dx.doi.org/10.1136/jmedgenet-2011-100717DOI Listing
April 2012

Two novel patients with Bohring-Opitz syndrome caused by de novo ASXL1 mutations.

Am J Med Genet A 2012 Apr 14;158A(4):917-21. Epub 2012 Mar 14.

Dipartimento di Scienze Ginecologiche, Ostetriche e Pediatriche, Università di Bologna, Policlinico Sant'Orsola Malpighi, U.O. Genetica Medica, Bologna, Italy.

Bohring-Opitz syndrome (BOS) is a rare condition characterized by facial anomalies, multiple malformations, failure to thrive and severe intellectual disabilities. Recently, the cause was identified on the basis of de novo heterozygous mutations in the ASXL1 gene. We report on two novel cases carrying two previously undescribed mutations (c.2407_2411del5 [p.Q803TfsX17] and c.2893C>T [p.R965X]). These new data further support ASXL1 as cause of BOS and may contribute to a more precise definition of the phenotype caused by the disruption of this gene.
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http://dx.doi.org/10.1002/ajmg.a.35265DOI Listing
April 2012

Intragenic and large NIPBL rearrangements revealed by MLPA in Cornelia de Lange patients.

Eur J Hum Genet 2012 Jul 22;20(7):734-41. Epub 2012 Feb 22.

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

Cornelia de Lange syndrome (CdLS) is a rare multisystemic congenital anomaly disorder that is characterised by intellectual disability and growth retardation, congenital heart defects, intestinal anomalies, facial dysmorphism (including synophyris and high arched eyebrows) and limb reduction defects. Mutations in three cohesin-associated genes encoding a key regulator (NIPBL, chr 5p13.2) and one structural component of the cohesin ring (SMC1A, chr Xp11) occur in about 65% of CdLS patients. NIPBL is the major causative gene, and accounts for 40-60% of CdLS patients as shown by a number of mutational screening studies that indicate a wide mutational repertoire of mainly small deletions and point mutations. Only a few data are available concerning the occurrence of large NIPBL rearrangements or intragenic deletions or duplications involving whole exons. We used multiplex ligation-dependent probe amplification (MLPA) to study 132 CdLS patients negative to the standard mutation NIPBL test out of a cohort of 200 CdLS patients. A total of 7 out of 132 patients were found to carry NIPBL alterations, including two large gene deletions extending beyond the gene, four intragenic multi- or single-exon deletions and one single-exon duplication. These findings show that MLPA leads to a 5.3% increase in the detection of mutations when used in addition to the standard NIPBL scan, and contributes per se to the molecular diagnosis of 3.5% (7/200) of clinically diagnosed CdLS patients. It is recommended that MLPA be included in the CdLS diagnostic flow chart.
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http://dx.doi.org/10.1038/ejhg.2012.7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3376273PMC
July 2012

Disease-associated mutations in the actin-binding domain of filamin B cause cytoplasmic focal accumulations correlating with disease severity.

Hum Mutat 2012 Apr 23;33(4):665-73. Epub 2012 Jan 23.

Department of Women's and Children's Health, Dunedin School of Medicine, Otago University, Dunedin, New Zealand.

Dominant missense mutations in FLNB, encoding the actin-cross linking protein filamin B (FLNB), cause a broad range of skeletal dysplasias with varying severity by an unknown mechanism. Here these FLNB mutations are shown to cluster in exons encoding the actin-binding domain (ABD) and filamin repeats surrounding the flexible hinge 1 region of the FLNB rod domain. Despite being positioned in domains that bind actin, it is unknown if these mutations perturb cytoskeletal structure. Expression of several full-length FLNB constructs containing ABD mutations resulted in the appearance of actin-containing cytoplasmic focal accumulations of the substituted protein to a degree that was correlated with the severity of the associated phenotypes. In contrast, study of mutations leading to substitutions in the FLNB rod domain that result in the same phenotypes as ABD mutations demonstrated that with only one exception disease-associated substitutions, surrounding hinge 1 demonstrated no tendency to form actin-filamin foci. The exception, a substitution in filamin repeat 6, lies within a region previously implicated in filamin-actin binding. These data are consistent with mutations in the ABD conferring enhanced actin-binding activity but suggest that substitutions affecting repeats near the flexible hinge region of FLNB precipitate the same phenotypes through a different mechanism.
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http://dx.doi.org/10.1002/humu.22012DOI Listing
April 2012

[Congenital malformations in Italy. A network to monitor the phenomenon].

Epidemiol Prev 2011 Sep-Dec;35(5-6 Suppl 2):90-1

Centro Nazionale Malattie Rare, Istituto Superiore di Sanità, Roma.

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April 2012
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