Publications by authors named "Corrado Romano"

114 Publications

Seroepidemiological Survey on the Impact of Smoking on SARS-CoV-2 Infection and COVID-19 Outcomes: Protocol for the Troina Study.

JMIR Res Protoc 2021 Nov 22;10(11):e32285. Epub 2021 Nov 22.

Oasi Research Institute, IRCCS, Troina, Italy.

Background: After the global spread of SARS-CoV-2, research has highlighted several aspects of the pandemic, focusing on clinical features and risk factors associated with infection and disease severity. However, emerging results on the role of smoking in SARS-CoV-2 infection susceptibility or COVID-19 outcomes are conflicting, and their robustness remains uncertain.

Objective: In this context, this study aims at quantifying the proportion of SARS-CoV-2 antibody seroprevalence, studying the changes in antibody levels over time, and analyzing the association between the biochemically verified smoking status and SARS-CoV-2 infection.

Methods: The research design involves a 6-month prospective cohort study with a serial sampling of the same individuals. Each participant will be surveyed about their demographics and COVID-19-related information, and blood sampling will be collected upon recruitment and at specified follow-up time points (ie, after 8 and 24 weeks). Blood samples will be screened for the presence of SARS-CoV-2-specific antibodies and serum cotinine, being the latter of the principal metabolite of nicotine, which will be used to assess participants' smoking status.

Results: The study is ongoing. It aims to find a higher antibody prevalence in individuals at high risk for viral exposure (ie, health care personnel) and to refine current estimates on the association between smoking status and SARS-CoV-2/COVID-19.

Conclusions: The added value of this research is that the current smoking status of the population to be studied will be biochemically verified to avoid the bias associated with self-reported smoking status. As such, the results from this survey may provide an actionable metric to study the role of smoking in SARS-CoV-2 infection and COVID-19 outcomes, and therefore to implement the most appropriate public health measures to control the pandemic. Results may also serve as a reference for future clinical research, and the methodology could be exploited in public health sectors and policies.

International Registered Report Identifier (irrid): DERR1-10.2196/32285.
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http://dx.doi.org/10.2196/32285DOI Listing
November 2021

A study of gene expression by RNA-seq in patients with prostate cancer and in patients with Parkinson disease: an example of inverse comorbidity.

Mol Biol Rep 2021 Nov 10;48(11):7627-7631. Epub 2021 Oct 10.

Oasi Research Institute-IRCCS, Troina, EN, Italy.

Background: Prostate cancer (PCa) is one of the leading causes of death in Western countries. Environmental and genetic factors play a pivotal role in PCa etiology. Timely identification of the genetic causes is useful for an early diagnosis. Parkinson's disease (PD) is the most frequent neurodegenerative movement disorder; it is associated with the presence of Lewy bodies and genetic factors are involved in its pathogenesis. Several studies have indicated that the expression of target genes in patients with PD is inversely related to cancer development; this phenomenon has been named "inverse comorbidity". The present study was undertaken to evaluate whether a genetic dysregulation occurs in opposite directions in patients with PD or PCa.

Methods And Results: In the present study, next-generation sequencing transcriptome analysis was used to assess whether a genetic dysregulation in opposite directions occurs in patients with PD or PCa. The genes SLC30A1, ADO, SRGAP2C, and TBC1D12 resulted up-regulated in patients with PD compared to healthy donors as controls and down-regulated in patients with PCa compared with the same control group.

Conclusions: These results support the hypothesis of the presence of inverse comorbidity between PD and PCa.
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http://dx.doi.org/10.1007/s11033-021-06723-0DOI Listing
November 2021

Role of long non-coding RNAs in Down syndrome patients: a transcriptome analysis study.

Hum Cell 2021 Nov 12;34(6):1662-1670. Epub 2021 Sep 12.

Oasi Research Institute-IRCCS, Troina, EN, Italy.

Down syndrome (DS) is defined by the presence of a third copy of chromosome 21. Several comorbidities can be found in these patients, such as intellectual disability (ID), muscle weakness, hypotonia, congenital heart disease, and autoimmune diseases. The molecular mechanisms playing a role in the development of such comorbidities are still unclear. The regulation and expression of genes that map to chromosome 21 are dynamic and complex, so it is important to perform global gene expression studies with high statistical power to fully characterize the transcriptome in DS patients. This study was undertaken to evaluate mRNAs and lncRNA expression in patients with DS versus a matched cohort of healthy subjects. RNA sequencing was used to perform this transcriptome study. Differential expression analysis revealed 967 transcripts with padj ≤ 0.05. Among them, 447 transcripts were differentially expressed in patients with DS compared to controls. Particularly, 203 transcripts were down expressed (151 protein-coding mRNAs, 45 lncRNAs, 1 microRNA, 1 mitochondrial tRNA, 1 ribozyme, and 1 small nuclear RNA) and 244 were over expressed (210 protein-coding mRNAs and 34 lncRNAs). Interestingly, deregulated lncRNAs are involved in pathways that play a role in developmental disorders, neurological diseases, DNA replication and repair mechanisms, and cancer development in DS patients. In conclusion, these results suggest a role of lncRNAs in the phenotype of DS patients.
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http://dx.doi.org/10.1007/s13577-021-00602-3DOI Listing
November 2021

CCR3 gene overexpression in patients with Down syndrome.

Mol Biol Rep 2021 Jun 28;48(6):5335-5338. Epub 2021 Jun 28.

Oasi Research Institute-IRCCS, Troina, EN, Italy.

Chromosome 21 trisomy or Down syndrome (DS) is the most common genetic cause of intellectual disability (ID). DS is also associated with hypotonia, muscle weakness, autoimmune diseases, and congenital heart disease. C-C chemokine receptor type 3 (CCR3) plays a role in inflammatory, autoimmune, and neuronal migration mechanisms. The present study aimed to evaluate the expression of the CCR3 gene by NGS and qRT-PCR in patients with DS and normal controls (NC). The CCR3 gene was over-expressed in DS patients compared to NC. These data suggest that an over-expression of the CCR3 gene is associated with the phenotype of patients with DS.
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http://dx.doi.org/10.1007/s11033-021-06503-wDOI Listing
June 2021

Prader-Willi Syndrome with Angelman Syndrome in the Offspring.

Medicina (Kaunas) 2021 May 8;57(5). Epub 2021 May 8.

Oasi Research Institute-IRCCS, 94018 Troina, Italy.

We report the second case, to the best of our knowledge, of a mother with Prader-Willi syndrome (PWS) who gave birth to a daughter with Angelman syndrome (AS). The menarche occurred when she was 16, and the following menstrual cycles were irregular, but she never took sexual hormone replacement therapy. At the age of 26, our patient with PWS became pregnant. The diagnosis was confirmed by molecular genetic testing that revealed a ~5.7 Mb deletion in the 15q11.1-15q13 region on the paternal allele in the mother with PWS and the maternal one in the daughter with AS, respectively. Both the mother with PWS and the daughter with AS showed peculiar clinical and genetic features of the two syndromes. Our case report reaffirms the possible fertility in PWS; therefore, it is very important to develop appropriate socio-sexual education programs and fertility assessments in order to guarantee the expression of a healthy sexuality.
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http://dx.doi.org/10.3390/medicina57050460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8150800PMC
May 2021

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

Genes (Basel) 2021 04 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

Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders.

Genome Med 2021 04 19;13(1):63. Epub 2021 Apr 19.

The Atwal Clinic: Genomic & Personalized Medicine, Jacksonville, FL, USA.

Background: With the increasing number of genomic sequencing studies, hundreds of genes have been implicated in neurodevelopmental disorders (NDDs). The rate of gene discovery far outpaces our understanding of genotype-phenotype correlations, with clinical characterization remaining a bottleneck for understanding NDDs. Most disease-associated Mendelian genes are members of gene families, and we hypothesize that those with related molecular function share clinical presentations.

Methods: We tested our hypothesis by considering gene families that have multiple members with an enrichment of de novo variants among NDDs, as determined by previous meta-analyses. One of these gene families is the heterogeneous nuclear ribonucleoproteins (hnRNPs), which has 33 members, five of which have been recently identified as NDD genes (HNRNPK, HNRNPU, HNRNPH1, HNRNPH2, and HNRNPR) and two of which have significant enrichment in our previous meta-analysis of probands with NDDs (HNRNPU and SYNCRIP). Utilizing protein homology, mutation analyses, gene expression analyses, and phenotypic characterization, we provide evidence for variation in 12 HNRNP genes as candidates for NDDs. Seven are potentially novel while the remaining genes in the family likely do not significantly contribute to NDD risk.

Results: We report 119 new NDD cases (64 de novo variants) through sequencing and international collaborations and combined with published clinical case reports. We consider 235 cases with gene-disruptive single-nucleotide variants or indels and 15 cases with small copy number variants. Three hnRNP-encoding genes reach nominal or exome-wide significance for de novo variant enrichment, while nine are candidates for pathogenic mutations. Comparison of HNRNP gene expression shows a pattern consistent with a role in cerebral cortical development with enriched expression among radial glial progenitors. Clinical assessment of probands (n = 188-221) expands the phenotypes associated with HNRNP rare variants, and phenotypes associated with variation in the HNRNP genes distinguishes them as a subgroup of NDDs.

Conclusions: Overall, our novel approach of exploiting gene families in NDDs identifies new HNRNP-related disorders, expands the phenotypes of known HNRNP-related disorders, strongly implicates disruption of the hnRNPs as a whole in NDDs, and supports that NDD subtypes likely have shared molecular pathogenesis. To date, this is the first study to identify novel genetic disorders based on the presence of disorders in related genes. We also perform the first phenotypic analyses focusing on related genes. Finally, we show that radial glial expression of these genes is likely critical during neurodevelopment. This is important for diagnostics, as well as developing strategies to best study these genes for the development of therapeutics.
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http://dx.doi.org/10.1186/s13073-021-00870-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056596PMC
April 2021

Recommendations for neonatologists and pediatricians working in first level birthing centers on the first communication of genetic disease and malformation syndrome diagnosis: consensus issued by 6 Italian scientific societies and 4 parents' associations.

Ital J Pediatr 2021 Apr 19;47(1):94. Epub 2021 Apr 19.

Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties "G. D'Alessandro", University of Palermo, Palermo, Italy.

Background: Genetic diseases are chronic conditions with relevant impact on the lives of patients and their families. In USA and Europe it is estimated a prevalence of 60 million affected subjects, 75% of whom are in developmental age. A significant number of newborns are admitted in the Neonatal Intensive Care Units (NICU) for reasons different from prematurity, although the prevalence of those with genetic diseases is unknown. It is, then, common for the neonatologist to start a diagnostic process on suspicion of a genetic disease or malformation syndrome, or to make and communicate these diagnoses. Many surveys showed that the degree of parental satisfaction with the methods of communication of diagnosis is low. Poor communication may have short and long-term negative effects on health and psychological and social development of the child and his family. We draw up recommendations on this issue, shared by 6 Italian Scientific Societies and 4 Parents' Associations, aimed at making the neonatologist's task easier at the difficult time of communication to parents of a genetic disease/malformation syndrome diagnosis for their child.

Methods: We used the method of the consensus paper. A multidisciplinary panel of experts was first established, based on the clinical and scientific sharing of the thematic area of present recommendations. They were suggested by the Boards of the six Scientific Societies that joined the initiative: Italian Societies of Pediatrics, Neonatology, Human Genetics, Perinatal Medicine, Obstetric and Gynecological Ultrasound and Biophysical Methodologies, and Pediatric Genetic Diseases and Congenital Disabilities. To obtain a deeper and global vision of the communication process, and to reach a better clinical management of patients and their families, representatives of four Parents' Associations were also recruited: Italian Association of Down People, Cornelia de Lange National Volunteer Association, Italian Federation of Rare Diseases, and Williams Syndrome People Association. They worked from September 2019 to November 2020 to achieve a consensus on the recommendations for the communication of a new diagnosis of genetic disease.

Results: The consensus of experts drafted a final document defining the recommendations, for the neonatologist and/or the pediatrician working in a fist level birthing center, on the first communication of genetic disease or malformation syndrome diagnosis. Although there is no universal communication technique to make the informative process effective, we tried to identify a few relevant strategic principles that the neonatologist/pediatrician may use in the relationship with the family. We also summarized basic principles and significant aspects relating to the modalities of interaction with families in a table, in order to create an easy tool for the neonatologist to be applied in the daily care practice. We finally obtained an intersociety document, now published on the websites of the Scientific Societies involved.

Conclusions: The neonatologist/pediatrician is often the first to observe complex syndromic pictures, not always identified before birth, although today more frequently prenatally diagnosed. It is necessary for him to know the aspects of genetic diseases related to communication and bioethics, as well as the biological and clinical ones, which together outline the cornerstones of the multidisciplinary care of these patients. This consensus provide practical recommendations on how to make the first communication of a genetic disease /malformation syndrome diagnosis. The proposed goal is to make easier the informative process, and to implement the best practices in the relationship with the family. A better doctor-patient/family interaction may improve health outcomes of the child and his family, as well as reduce legal disputes with parents and the phenomenon of defensive medicine.
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http://dx.doi.org/10.1186/s13052-021-01044-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054427PMC
April 2021

GPR56 gene down-regulation in patients with Klinefelter syndrome: a candidate for infertility?

Minerva Endocrinol 2020 Dec 17. Epub 2020 Dec 17.

Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.

Purpose: The etiology of azoospermia in patients with Klinefelter syndrome (KS) is still unknown. The protein codified by the G protein-couple receptor 56 (GPR56) belongs to the adhesion family of G protein-coupled receptors (GPRs). Its mutations are involved in the pathogenesis of intellectual disability and, according to animal studies, infertility. As the expression of GPR56 in patients with KS has not been investigated so far, this study was undertaken with the purpose of evaluating its expression in peripheral blood mononuclear cells (PBMCs) of patients with KS and normal controls.

Materials And Methods: This age-matched case-control study was performed in 10 patients with KS and 10 controls. Patients and controls underwent to blood sampling for next-generation sequencing (NGS) analysis, and differentially expressed mRNAs were identified using DESeq2 v.1.12. QRT-PCR was used to validate the results obtained by NGS analysis. TaqMan Gene Expression Assay primers were used to carry out the Realtime PCR analysis for GPR56.

Results: GPR56 was down-regulated by -2,081-fold (q-value<0.05) in PBMCs of patients with KS compared to controls. NGS data were confirmed by QRT-PCR.

Conclusions: The possible contribution of the GPR56 gene down-regulation in the pathogenesis of spermatogenic failure in patients with KS is worthy to be further explored.
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http://dx.doi.org/10.23736/S0391-1977.20.03357-XDOI Listing
December 2020

Clinical spectrum and follow-up in six individuals with Lamb-Shaffer syndrome (SOX5).

Am J Med Genet A 2021 02 9;185(2):608-613. Epub 2020 Dec 9.

Medical Genetics Unit, Policlinico di S. Orsola, University of Bologna, Bologna, Italy.

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http://dx.doi.org/10.1002/ajmg.a.62001DOI Listing
February 2021

gene downregulation in peripheral blood mononuclear cells of patients with Klinefelter syndrome.

Asian J Androl 2021 Mar-Apr;23(2):157-162

Department of Clinical and Experimental Medicine, University of Catania, Catania 95123, Italy.

Klinefelter syndrome (KS) is the most common sex chromosome disorder in men. It is characterized by germ cell loss and other variable clinical features, including autoimmunity. The sex-determining region of Y (SRY)-box 13 (Sox13) gene is expressed in mouse spermatogonia. In addition, it has been identified as islet cell autoantigen 12 (ICA12), which is involved in the pathogenesis of autoimmune diseases, including type 1 diabetes mellitus (DM) and primary biliary cirrhosis. Sox13 expression has never been investigated in patients with KS. In this age-matched, case-control study performed on ten patients with KS and ten controls, we found that SOX13 is significantly downregulated in peripheral blood mononuclear cells of patients with KS compared to controls. This finding might be consistent with the germ cell loss typical of patients with KS. However, the role of Sox13 in the pathogenesis of germ cell loss and humoral autoimmunity in patients with KS deserves to be further explored.
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http://dx.doi.org/10.4103/aja.aja_37_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7991811PMC
November 2021

Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders.

Nat Commun 2020 10 1;11(1):4932. Epub 2020 Oct 1.

Oasi Research Institute-IRCCS, Troina, Italy.

Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case-control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By combining these with published data, we assess a total of 125 genes in over 16,000 NDD cases and compare the mutation burden to nonpsychiatric controls from ExAC. We identify 48 genes (25 newly reported) showing significant burden of ultra-rare (MAF < 0.01%) gene-disruptive mutations (FDR 5%), six of which reach family-wise error rate (FWER) significance (p < 1.25E-06). Among these 125 targeted genes, we also reevaluate DNM excess in 17,426 NDD trios with 6,499 new autism trios. We identify 90 genes enriched for DNMs (FDR 5%; e.g., GABRG2 and UIMC1); of which, 61 reach FWER significance (p < 3.64E-07; e.g., CASZ1). In addition to doubling the number of patients for many NDD risk genes, we present phenotype-genotype correlations for seven risk genes (CTCF, HNRNPU, KCNQ3, ZBTB18, TCF12, SPEN, and LEO1) based on this large-scale targeted sequencing effort.
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http://dx.doi.org/10.1038/s41467-020-18723-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530681PMC
October 2020

Long non-coding RNA GAS5 expression in patients with Down syndrome.

Int J Med Sci 2020 23;17(10):1315-1319. Epub 2020 May 23.

Oasi Research Institute-IRCCS, Troina (EN), Italy.

Trisomy 21, also known as Down Syndrome (DS), is the most common chromosome abnormality and causes intellectual disability. Long non-coding RNA (lncRNA) growth arrest-specific 5 (), whose differential expression has recently been reported in patients with Klinefelter syndrome, has been addressed to play a role in the development of inflammatory and autoimmune diseases, vascular endothelial cells apoptosis and atherosclerosis, all being common features in patients with DS. Therefore, the aim of this study was to assess the lncRNA expression profile in DS patients and in controls. lncRNA levels were evaluated by qRT-PCR assay in 23 patients with DS and 23 age-matched controls. A significant lncRNA down-regulation was observed in patients with DS by RT-PCR analysis, The RNA sequencing experiments confirmed the qRT-PCR data. LncRNA down-expression may play a role in the development of some typical features of the patients with DS and, particularly, in inflammatory and autoimmune diseases.
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http://dx.doi.org/10.7150/ijms.45386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330673PMC
March 2021

Study of the MDM2 -410T-G polymorphism (rs2279744) by pyrosequencing in mothers of Down Syndrome subjects.

Hum Cell 2020 Jul 18;33(3):476-478. Epub 2020 May 18.

Oasi Research Institute-IRCCS, Troina, EN, Italy.

Trisomy 21 or Down syndrome (DS) is the most frequent genetic etiology of intellectual disability in humans. MDM2 gene expression has a potential role as a risk factor for human aneuploidy. -410T-G (rs2279744) functional polymorphism in MDM2 gene impacts on the mechanisms of chromosomal non-disjunction. We analyzed, within a case-control study, such polymorphism in mothers of subjects with DS. Nucleotide polymorphism was detected by pyrosequencing technology. The distribution of MDM2-410T-G polymorphism showed no significant difference among mothers of subjects with DS and controls. Our results suggest that MDM2 -410T-G polymorphism is not a risk factor for DS in mothers.
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http://dx.doi.org/10.1007/s13577-020-00374-2DOI Listing
July 2020

Humanin gene expression in fibroblast of Down syndrome subjects.

Int J Med Sci 2020 18;17(3):320-324. Epub 2020 Jan 18.

Oasi Research Institute-IRCCS, Troina (EN), Italy.

Down syndrome (DS) is characterized by trisomy of chromosome 21 and peculiar phenotype. Humanin (HN) is a mitochondrial short 24-residue polypeptide whit anti-apoptotic and neuroprotective effects. In this study we evaluated HN protein expression and HN mRNA levels in cultured fibroblasts from DS patients and normal controls. Our results obtained by immunocytochemistry, western-blot and qRT-PCR analysis show a significant HN up-regulation in DS patients. These results confirm previous studies and suggest a role for HN may in the DS phenotype.
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http://dx.doi.org/10.7150/ijms.39145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053358PMC
January 2021

Disruptive mutations in TANC2 define a neurodevelopmental syndrome associated with psychiatric disorders.

Nat Commun 2019 10 15;10(1):4679. Epub 2019 Oct 15.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.

Postsynaptic density (PSD) proteins have been implicated in the pathophysiology of neurodevelopmental and psychiatric disorders. Here, we present detailed clinical and genetic data for 20 patients with likely gene-disrupting mutations in TANC2-whose protein product interacts with multiple PSD proteins. Pediatric patients with disruptive mutations present with autism, intellectual disability, and delayed language and motor development. In addition to a variable degree of epilepsy and facial dysmorphism, we observe a pattern of more complex psychiatric dysfunction or behavioral problems in adult probands or carrier parents. Although this observation requires replication to establish statistical significance, it also suggests that mutations in this gene are associated with a variety of neuropsychiatric disorders consistent with its postsynaptic function. We find that TANC2 is expressed broadly in the human developing brain, especially in excitatory neurons and glial cells, but shows a more restricted pattern in Drosophila glial cells where its disruption affects behavioral outcomes.
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http://dx.doi.org/10.1038/s41467-019-12435-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6794285PMC
October 2019

Disruptive variants of associate with autism and interfere with neuronal development and synaptic transmission.

Sci Adv 2019 09 25;5(9):eaax2166. Epub 2019 Sep 25.

Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China.

RNA binding proteins are key players in posttranscriptional regulation and have been implicated in neurodevelopmental and neuropsychiatric disorders. Here, we report a significant burden of heterozygous, likely gene-disrupting variants in (encoding a highly constrained RNA binding protein) among patients with autism and related neurodevelopmental disabilities. Analysis of 17 patients identifies common phenotypes including autism, intellectual disability, language and motor delay, seizures, macrocephaly, and variable ocular abnormalities. HITS-CLIP revealed that Csde1-binding targets are enriched in autism-associated gene sets, especially FMRP targets, and in neuronal development and synaptic plasticity-related pathways. Csde1 knockdown in primary mouse cortical neurons leads to an overgrowth of the neurites and abnormal dendritic spine morphology/synapse formation and impaired synaptic transmission, whereas mutant and knockdown experiments in result in defects in synapse growth and synaptic transmission. Our study defines a new autism-related syndrome and highlights the functional role of CSDE1 in synapse development and synaptic transmission.
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http://dx.doi.org/10.1126/sciadv.aax2166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6760934PMC
September 2019

Enabling Global Clinical Collaborations on Identifiable Patient Data: The Minerva Initiative.

Front Genet 2019 29;10:611. Epub 2019 Jul 29.

Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.

The clinical utility of computational phenotyping for both genetic and rare diseases is increasingly appreciated; however, its true potential is yet to be fully realized. Alongside the growing clinical and research availability of sequencing technologies, precise deep and scalable phenotyping is required to serve unmet need in genetic and rare diseases. To improve the lives of individuals affected with rare diseases through deep phenotyping, global big data interrogation is necessary to aid our understanding of disease biology, assist diagnosis, and develop targeted treatment strategies. This includes the application of cutting-edge machine learning methods to image data. As with most digital tools employed in health care, there are ethical and data governance challenges associated with using identifiable personal image data. There are also risks with failing to deliver on the patient benefits of these new technologies, the biggest of which is posed by data siloing. The Minerva Initiative has been designed to enable the public good of deep phenotyping while mitigating these ethical risks. Its open structure, enabling collaboration and data sharing between individuals, clinicians, researchers and private enterprise, is key for delivering precision public health.
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http://dx.doi.org/10.3389/fgene.2019.00611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6681681PMC
July 2019

De novo variants in FBXO11 cause a syndromic form of intellectual disability with behavioral problems and dysmorphisms.

Eur J Hum Genet 2019 05 24;27(5):738-746. Epub 2019 Jan 24.

Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.

Determining pathogenicity of genomic variation identified by next-generation sequencing techniques can be supported by recurrent disruptive variants in the same gene in phenotypically similar individuals. However, interpretation of novel variants in a specific gene in individuals with mild-moderate intellectual disability (ID) without recognizable syndromic features can be challenging and reverse phenotyping is often required. We describe 24 individuals with a de novo disease-causing variant in, or partial deletion of, the F-box only protein 11 gene (FBXO11, also known as VIT1 and PRMT9). FBXO11 is part of the SCF (SKP1-cullin-F-box) complex, a multi-protein E3 ubiquitin-ligase complex catalyzing the ubiquitination of proteins destined for proteasomal degradation. Twenty-two variants were identified by next-generation sequencing, comprising 2 in-frame deletions, 11 missense variants, 1 canonical splice site variant, and 8 nonsense or frameshift variants leading to a truncated protein or degraded transcript. The remaining two variants were identified by array-comparative genomic hybridization and consisted of a partial deletion of FBXO11. All individuals had borderline to severe ID and behavioral problems (autism spectrum disorder, attention-deficit/hyperactivity disorder, anxiety, aggression) were observed in most of them. The most relevant common facial features included a thin upper lip and a broad prominent space between the paramedian peaks of the upper lip. Other features were hypotonia and hyperlaxity of the joints. We show that de novo variants in FBXO11 cause a syndromic form of ID. The current series show the power of reverse phenotyping in the interpretation of novel genetic variances in individuals who initially did not appear to have a clear recognizable phenotype.
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http://dx.doi.org/10.1038/s41431-018-0292-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6462006PMC
May 2019

Biallelic intragenic duplication in ADGRB3 (BAI3) gene associated with intellectual disability, cerebellar atrophy, and behavioral disorder.

Eur J Hum Genet 2019 04 18;27(4):594-602. Epub 2019 Jan 18.

Oasi Research Institute-IRCCS, Troina, Italy.

In recent years, chromosomal microarray analysis has permitted the discovery of rearrangements underlying several neurodevelopmental disorders and still represents the first diagnostic test for unexplained neurodevelopmental disabilities. Here we report a family of consanguineous parents showing psychiatric disorders and their two sons both affected by intellectual disability, ataxia, and behavioral disorder. SNP/CGH array analysis in this family demonstrated in both siblings a biallelic duplication inherited from the heterozygous parents, disrupting the ADGRB3 gene. ADGRB3, also known as BAI3, belongs to the subfamily of adhesion G protein-coupled receptors (adhesion GPCRs) that regulate many aspects of the central nervous system, including axon guidance, myelination, and synapse formation. Single nucleotide polymorphisms and copy number variants involving ADGRB3 have recently been associated with psychiatric disorders. These findings further support this association and also suggest that biallelic variants affecting the function of the ADGRB3 gene may also cause cognitive impairments and ataxia.
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http://dx.doi.org/10.1038/s41431-018-0321-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6460634PMC
April 2019

Mutations in ACTL6B, coding for a subunit of the neuron-specific chromatin remodeling complex nBAF, cause early onset severe developmental and epileptic encephalopathy with brain hypomyelination and cerebellar atrophy.

Hum Genet 2019 Feb 17;138(2):187-198. Epub 2019 Jan 17.

Oasi Research Institute-IRCCS, Troina, Italy.

Developmental and epileptic encephalopathies (DEEs) are genetically heterogenous conditions, often characterized by early onset, EEG interictal epileptiform abnormalities, polymorphous and drug-resistant seizures, and neurodevelopmental impairments. In this study, we investigated the genetic defects in two siblings who presented with severe DEE, microcephaly, spastic tetraplegia, diffuse brain hypomyelination, cerebellar atrophy, short stature, and kyphoscoliosis. Whole exome next-generation sequencing (WES) identified in both siblings a homozygous non-sense variant in the ACTL6B gene (NM_016188:c.820C>T;p.Gln274*) coding for a subunit of the neuron-specific chromatin remodeling complex nBAF. To further support these findings, a targeted ACTL6B sequencing assay was performed on a cohort of 85 unrelated DEE individuals, leading to the identification of a homozygous missense variant (NM_016188:c.1045G>A;p.Gly349Ser) in a patient. This variant did not segregate in the unaffected siblings in this family and was classified as deleterious by several prediction softwares. Interestingly, in both families, homozygous patients shared a rather homogeneous phenotype. Very few patients with ACTL6B gene variants have been sporadically reported in WES cohort studies of patients with neurodevelopmental disorders and/or congenital brain malformations. However, the limited number of patients with incomplete clinical information yet reported in the literature did not allow to establish a strong gene-disease association. Here, we provide additional genetic and clinical data on three new cases that support the pathogenic role of ACTL6B gene mutation in a syndromic form of DEE.
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http://dx.doi.org/10.1007/s00439-019-01972-3DOI Listing
February 2019

Evidence for long noncoding RNA GAS5 up-regulationin patients with Klinefelter syndrome.

BMC Med Genet 2019 01 7;20(1). Epub 2019 Jan 7.

Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.

Background: Klinefelter syndrome (KS) is characterized by the presence of at least one supernumerary X chromosome. KS typical symptoms include tall stature, gynecomastia, hypogonadism and azoospermia. KS patients show a higher risk of developing metabolic and cardiovascular diseases, inflammatory and autoimmune disorders, osteoporosis and cancer. Long non-coding RNA (lncRNA) growth arrest-specific 5 (GAS5) has been shown to be involved in several biologic processes, including inflammatory and autoimmune diseases, vascular endothelial cells apoptosis and atherosclerosis, as well as cellular growth and proliferation, cellular development and cell-to-cell signaling and interaction. The lncRNA GAS5 expression profile in KS patients has never been evaluated so far.

Methods: To accomplish this, GAS5 mRNA levels were evaluated by Next Generation Sequencing (NGS) technology and qRT-PCR assay in 10 patients with KS and 10 age-matched controls.

Results: NGS results showed a significantly lncRNAGAS5up-regulation by 5.171-fold in patients with KS. Theresults of qRT-PCR confirmed the NGS data.

Conclusions: These findings showed the occurrence of lncRNA GAS5 over-expression in KS patients. Whether this lncRNA is involved in the pathogenesis of inflammation and autoimmune diseases, atherogenesis or germ cell depletion in KS patients is not known. Further studies are needed.
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http://dx.doi.org/10.1186/s12881-018-0744-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6322229PMC
January 2019

Rare variants in the genetic background modulate cognitive and developmental phenotypes in individuals carrying disease-associated variants.

Genet Med 2019 04 7;21(4):816-825. Epub 2018 Sep 7.

CHU Nantes, Medical genetics department, Nantes, France.

Purpose: To assess the contribution of rare variants in the genetic background toward variability of neurodevelopmental phenotypes in individuals with rare copy-number variants (CNVs) and gene-disruptive variants.

Methods: We analyzed quantitative clinical information, exome sequencing, and microarray data from 757 probands and 233 parents and siblings who carry disease-associated variants.

Results: The number of rare likely deleterious variants in functionally intolerant genes ("other hits") correlated with expression of neurodevelopmental phenotypes in probands with 16p12.1 deletion (n=23, p=0.004) and in autism probands carrying gene-disruptive variants (n=184, p=0.03) compared with their carrier family members. Probands with 16p12.1 deletion and a strong family history presented more severe clinical features (p=0.04) and higher burden of other hits compared with those with mild/no family history (p=0.001). The number of other hits also correlated with severity of cognitive impairment in probands carrying pathogenic CNVs (n=53) or de novo pathogenic variants in disease genes (n=290), and negatively correlated with head size among 80 probands with 16p11.2 deletion. These co-occurring hits involved known disease-associated genes such as SETD5, AUTS2, and NRXN1, and were enriched for cellular and developmental processes.

Conclusion: Accurate genetic diagnosis of complex disorders will require complete evaluation of the genetic background even after a candidate disease-associated variant is identified.
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http://dx.doi.org/10.1038/s41436-018-0266-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6405313PMC
April 2019

Expression of miR-132 in Down syndrome subjects.

Hum Cell 2018 Jul 8;31(3):268-270. Epub 2018 May 8.

Oasi Research Institute-IRCCS, Troina, Italy.

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http://dx.doi.org/10.1007/s13577-018-0209-yDOI Listing
July 2018

Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP.

Biol Psychiatry 2019 02 15;85(4):287-297. Epub 2018 Mar 15.

Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.

Background: In genome-wide screening studies for de novo mutations underlying autism and intellectual disability, mutations in the ADNP gene are consistently reported among the most frequent. ADNP mutations have been identified in children with autism spectrum disorder comorbid with intellectual disability, distinctive facial features, and deficits in multiple organ systems. However, a comprehensive clinical description of the Helsmoortel-Van der Aa syndrome is lacking.

Methods: We identified a worldwide cohort of 78 individuals with likely disruptive mutations in ADNP from January 2014 to October 2016 through systematic literature search, by contacting collaborators, and through direct interaction with parents. Clinicians filled in a structured questionnaire on genetic and clinical findings to enable correlations between genotype and phenotype. Clinical photographs and specialist reports were gathered. Parents were interviewed to complement the written questionnaires.

Results: We report on the detailed clinical characterization of a large cohort of individuals with an ADNP mutation and demonstrate a distinctive combination of clinical features, including mild to severe intellectual disability, autism, severe speech and motor delay, and common facial characteristics. Brain abnormalities, behavioral problems, sleep disturbance, epilepsy, hypotonia, visual problems, congenital heart defects, gastrointestinal problems, short stature, and hormonal deficiencies are common comorbidities. Strikingly, individuals with the recurrent p.Tyr719* mutation were more severely affected.

Conclusions: This overview defines the full clinical spectrum of individuals with ADNP mutations, a specific autism subtype. We show that individuals with mutations in ADNP have many overlapping clinical features that are distinctive from those of other autism and/or intellectual disability syndromes. In addition, our data show preliminary evidence of a correlation between genotype and phenotype.
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http://dx.doi.org/10.1016/j.biopsych.2018.02.1173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6139063PMC
February 2019

Truncating Variants in NAA15 Are Associated with Variable Levels of Intellectual Disability, Autism Spectrum Disorder, and Congenital Anomalies.

Am J Hum Genet 2018 05 12;102(5):985-994. Epub 2018 Apr 12.

Kennedy Krieger Institute, 801 North Broadway Baltimore, MD 21205, USA.

N-alpha-acetylation is a common co-translational protein modification that is essential for normal cell function in humans. We previously identified the genetic basis of an X-linked infantile lethal Mendelian disorder involving a c.109T>C (p.Ser37Pro) missense variant in NAA10, which encodes the catalytic subunit of the N-terminal acetyltransferase A (NatA) complex. The auxiliary subunit of the NatA complex, NAA15, is the dimeric binding partner for NAA10. Through a genotype-first approach with whole-exome or genome sequencing (WES/WGS) and targeted sequencing analysis, we identified and phenotypically characterized 38 individuals from 33 unrelated families with 25 different de novo or inherited, dominantly acting likely gene disrupting (LGD) variants in NAA15. Clinical features of affected individuals with LGD variants in NAA15 include variable levels of intellectual disability, delayed speech and motor milestones, and autism spectrum disorder. Additionally, mild craniofacial dysmorphology, congenital cardiac anomalies, and seizures are present in some subjects. RNA analysis in cell lines from two individuals showed degradation of the transcripts with LGD variants, probably as a result of nonsense-mediated decay. Functional assays in yeast confirmed a deleterious effect for two of the LGD variants in NAA15. Further supporting a mechanism of haploinsufficiency, individuals with copy-number variant (CNV) deletions involving NAA15 and surrounding genes can present with mild intellectual disability, mild dysmorphic features, motor delays, and decreased growth. We propose that defects in NatA-mediated N-terminal acetylation (NTA) lead to variable levels of neurodevelopmental disorders in humans, supporting the importance of the NatA complex in normal human development.
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http://dx.doi.org/10.1016/j.ajhg.2018.03.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5986698PMC
May 2018

The epilepsy phenotypic spectrum associated with a recurrent CUX2 variant.

Ann Neurol 2018 05 30;83(5):926-934. Epub 2018 Apr 30.

Department of Medical Genetics, Lyon University Hospital and GENDEV team CNRS UMR 5292, INSERM U1028, CRNL, and University Claude Bernard Lyon 1, GHE, Lyon, France.

Objective: Cut homeodomain transcription factor CUX2 plays an important role in dendrite branching, spine development, and synapse formation in layer II to III neurons of the cerebral cortex. We identify a recurrent de novo CUX2 p.Glu590Lys as a novel genetic cause for developmental and epileptic encephalopathy (DEE).

Methods: The de novo p.Glu590Lys variant was identified by whole-exome sequencing (n = 5) or targeted gene panel (n = 4). We performed electroclinical and imaging phenotyping on all patients.

Results: The cohort comprised 7 males and 2 females. Mean age at study was 13 years (0.5-21.0). Median age at seizure onset was 6 months (2 months to 9 years). Seizure types at onset were myoclonic, atypical absence with myoclonic components, and focal seizures. Epileptiform activity on electroencephalogram was seen in 8 cases: generalized polyspike-wave (6) or multifocal discharges (2). Seizures were drug resistant in 7 or controlled with valproate (2). Six patients had a DEE: myoclonic DEE (3), Lennox-Gastaut syndrome (2), and West syndrome (1). Two had a static encephalopathy and genetic generalized epilepsy, including absence epilepsy in 1. One infant had multifocal epilepsy. Eight had severe cognitive impairment, with autistic features in 6. The p.Glu590Lys variant affects a highly conserved glutamine residue in the CUT domain predicted to interfere with CUX2 binding to DNA targets during neuronal development.

Interpretation: Patients with CUX2 p.Glu590Lys display a distinctive phenotypic spectrum, which is predominantly generalized epilepsy, with infantile-onset myoclonic DEE at the severe end and generalized epilepsy with severe static developmental encephalopathy at the milder end of the spectrum. Ann Neurol 2018;83:926-934.
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http://dx.doi.org/10.1002/ana.25222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6021218PMC
May 2018

Next Generation Sequencing expression profiling of mitochondrial subunits in men with Klinefelter syndrome.

Int J Med Sci 2018 1;15(1):31-35. Epub 2018 Jan 1.

Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.

Klinefelter syndrome (KS) is one of the most common sex-chromosome disorders as it affects up to 1 in every 600-1000 newborn males. Men with KS carry one extra X chromosome and they usually present a 47,XXY karyotype, but less frequent variants have also been reported in literature. KS typical symptoms include tall stature, gynecomastia, broad hips, hypogonadism and absent spermatogenesis. The syndrome is also related to a wide range of cognitive deficits, among which language-based learning disabilities and verbal cognition impairment are frequently diagnosed. The present study was carried out to investigate the role of mitochondrial subunits in KS, since the molecular mechanisms underlying KS pathogenesis are not fully understood. The study was performed by the next generation sequencing analysis and qRT-PCR assay. We were able to identify a significant down-expression of mitochondrial encoded NADH: ubiquinone oxidoreductase core subunit 6 (MT-ND6) in men with KS. It is known that defects of the mtDNA encoding mitochondrial subunits are responsible for the malfunction of Complex I, which will eventually lead to the Complex I deficiency, the most common respiratory chain defect in human disorders. Since it has been shown that decreased Complex I protein levels could induce apoptosis, wehypothesizethat the above-mentioned MT-ND6 down-expression contributes to the wide range of phenotypes observed in men with KS.
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http://dx.doi.org/10.7150/ijms.21075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5765737PMC
August 2018
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