Publications by authors named "Marco Tartaglia"

317 Publications

Functional correlation of genome-wide DNA methylation profiles in genetic neurodevelopmental disorders.

Hum Mutat 2022 Jul 29. Epub 2022 Jul 29.

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

An expanding range of genetic syndromes are characterized by genome-wide disruptions in DNA methylation profiles referred to as episignatures. Episignatures are distinct, highly sensitive and specific biomarkers that have recently been applied in clinical diagnosis of genetic syndromes. Episignatures are contained within the broader disorder-specific genome-wide DNA methylation changes which can share significant overlap amongst different conditions. In this study we performed functional genomic assessment and comparison of disorder-specific and overlapping genome-wide DNA methylation changes related to 65 genetic syndromes with previously described episignatures. We demonstrate evidence of disorder-specific and recurring genome-wide differentially methylated probes (DMPs) and regions (DMRs). The overall distribution of DMPs and DMRs across the majority of the neurodevelopmental genetic syndromes analyzed showed substantial enrichment in gene promoters and CpG islands, and under-representation of the more variable intergenic regions. Analysis showed significant enrichment of the DMPs and DMRs in gene pathways and processes related to neurodevelopment, including neurogenesis, synaptic signaling and synaptic transmission. This study expands beyond the diagnostic utility of DNA methylation episignatures by demonstrating correlation between the function of the mutated genes and the consequent genomic DNA methylation profiles as a key functional element in the molecular etiology of genetic neurodevelopmental disorders. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/humu.24446DOI Listing
July 2022

Characterization of Cognitive, Language and Adaptive Profiles of Children and Adolescents with Malan Syndrome.

J Clin Med 2022 Jul 14;11(14). Epub 2022 Jul 14.

Operative Unit of Medical Genetics Bianchi-Melacrino-Morelli Great Metropolitan Hospital, 89133 Reggio Calabria, Italy.

Malan Syndrome (MS) is an ultra-rare overgrowth genetic syndrome due to heterozygous variants or deletions in the Nuclear Factor I X ) gene. It is characterized by an unusual facial phenotype, generalized overgrowth, intellectual disability (ID) and behavioral problems. Even though limitations in cognitive and adaptive functioning have been previously described, systematic studies on MS cohorts are still lacking. Here, we aim to define the cognitive and adaptive behavior profile of MS children and adolescents, providing quantitative data from standardized evaluations. Subjects included in this study were evaluated from October 2020 to January 2022 and the study is based on a retrospective data archive: fifteen MS individuals were recruited and underwent evaluation with Wechsler Intelligence Scales, Leiter International Performance Scales and Griffith Mental Development Scales for cognitive profiles and with Vineland Adaptive Behavior Scales-II Edition (VABS-II) for adaptive functioning. Language skills and visuomotor integration abilities were assessed too. Comparisons and correlations between scales and subtests were performed. All the assessed MS individuals showed both low cognitive and adaptive functioning. One subject presented with mild ID, five had moderate ID and eight showed severe ID. One female toddler received a diagnosis of psychomotor delay. Linguistic skills were impaired in all individuals, with language comprehension relatively more preserved. Results revealed significant differences between VABS-II subdomains and a strong relationship between cognitive and adaptive functioning. All subjects exhibited mild to moderate ID and adaptive behavior lower than normal, with communication skills being the most affected. Regarding the daily living skills domain, personal and community subscale scores were dramatically lower than for the domestic subdomain, highlighting the importance of considering behavior within developmental and environmental contexts. Our cognitive and adaptive MS characterization provides a more accurate quantitative MS profiling, which is expected to help clinicians to better understand the complexity of this rare disorder.
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http://dx.doi.org/10.3390/jcm11144078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9316998PMC
July 2022

Hedgehog signaling reprograms hair follicle niche fibroblasts to a hyper-activated state.

Dev Cell 2022 Jul 30;57(14):1758-1775.e7. Epub 2022 Jun 30.

Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA 92697, USA; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92697, USA; Center for Complex Biological Systems, University of California, Irvine, Irvine, CA 92697, USA; NSF-Simons Center for Multiscale Cell Fate Research, University of California, Irvine, Irvine, CA 92697, USA. Electronic address:

Hair follicle stem cells are regulated by dermal papilla fibroblasts, their principal signaling niche. Overactivation of Hedgehog signaling in the niche dramatically accelerates hair growth and induces follicle multiplication in mice. On single-cell RNA sequencing, dermal papilla fibroblasts increase heterogeneity to include new Wnt5a states. Transcriptionally, mutant fibroblasts activate regulatory networks for Gli1, Alx3, Ebf1, Hoxc8, Sox18, and Zfp239. These networks jointly upregulate secreted factors for multiple hair morphogenesis and hair-growth-related pathways. Among these is non-conventional TGF-β ligand Scube3. We show that in normal mouse skin, Scube3 is expressed only in dermal papillae of growing, but not in resting follicles. SCUBE3 protein microinjection is sufficient to induce new hair growth, and pharmacological TGF-β inhibition rescues mutant hair hyper-activation phenotype. Moreover, dermal-papilla-enriched expression of SCUBE3 and its growth-activating effect are partially conserved in human scalp hair follicles. Thus, Hedgehog regulates mesenchymal niche function in the hair follicle via SCUBE3/TGF-β mechanism.
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http://dx.doi.org/10.1016/j.devcel.2022.06.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9344965PMC
July 2022

New Insights into the Neurodegeneration Mechanisms Underlying Riboflavin Transporter Deficiency (RTD): Involvement of Energy Dysmetabolism and Cytoskeletal Derangement.

Biomedicines 2022 Jun 6;10(6). Epub 2022 Jun 6.

Department of Science, LIME, University Roma Tre, 00165 Rome, Italy.

Riboflavin transporter deficiency (RTD) is a rare genetic disorder characterized by motor, sensory and cranial neuropathy. This childhood-onset neurodegenerative disease is caused by biallelic pathogenic variants in either or genes, resulting in insufficient supply of riboflavin (vitamin B2) and consequent impairment of flavoprotein-dependent metabolic pathways. Current therapy, empirically based high-dose riboflavin supplementation, ameliorates the progression of the disease, even though response to treatment is variable and partial. Recent studies have highlighted concurrent pathogenic contribution of cellular energy dysmetabolism and cytoskeletal derangement. In this context, patient specific RTD models, based on induced pluripotent stem cell (iPSC) technology, have provided evidence of redox imbalance, involving mitochondrial and peroxisomal dysfunction. Such oxidative stress condition likely causes cytoskeletal perturbation, associated with impaired differentiation of RTD motor neurons. In this review, we discuss the most recent findings obtained using different RTD models. Relevantly, the integration of data from innovative iPSC-derived in vitro models and invertebrate in vivo models may provide essential information on RTD pathophysiology. Such novel insights are expected to suggest custom therapeutic strategies, especially for those patients unresponsive to high-dose riboflavin treatments.
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http://dx.doi.org/10.3390/biomedicines10061329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9219947PMC
June 2022

The MAP3K7 gene: Further delineation of clinical characteristics and genotype/phenotype correlations.

Hum Mutat 2022 Jun 22. Epub 2022 Jun 22.

Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, The Netherlands.

Mitogen-activated protein 3 kinase 7 (MAP3K7) encodes the ubiquitously expressed transforming growth factor β-activated kinase 1, which plays a crucial role in many cellular processes. Mutationsin the MAP3K7 gene have been linked to two distinct disorders: frontometaphyseal dysplasia type 2 (FMD2) and cardiospondylocarpofacial syndrome (CSCF). The fact that different mutations can induce two distinct phenotypes suggests a phenotype/genotype correlation, but no side-by-side comparison has been done thus far to confirm this. Here, we significantly expand the cohort and the description of clinical phenotypes for patients with CSCF and FMD2 who carry mutations in MAP3K7. Our findings support that in contrast to FMD2-causing mutations, CSCF-causing mutations in MAP3K7 have a loss-of-function effect. Additionally, patients with pathogenic mutations in MAP3K7 are at risk for (severe) cardiac disease, have symptoms associated with connective tissue disease, and we show overlap in clinical phenotypes of CSCF with Noonan syndrome (NS). Together, we confirm a molecular fingerprint of FMD2- versus CSCF-causing MAP3K7 mutations and conclude that mutations in MAP3K7 should be considered in the differential diagnosis of patients with syndromic congenital cardiac defects and/or cardiomyopathy, syndromic connective tissue disorders, and in the differential diagnosis of NS.
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http://dx.doi.org/10.1002/humu.24425DOI Listing
June 2022

A deep phenotyping experience: up to date in management and diagnosis of Malan syndrome in a single center surveillance report.

Orphanet J Rare Dis 2022 06 18;17(1):235. Epub 2022 Jun 18.

Operative Unit of Medical Genetics, Bianchi-Melacrino-Morelli Hospital, V. Melacrino, 89100, Reggio Calabria, Italy.

Background: Malan syndrome (MALNS) is a recently described ultrarare syndrome lacking guidelines for diagnosis, management and monitoring of evolutive complications. Less than 90 patients are reported in the literature and limited clinical information are available to assure a proper health surveillance.

Results: A multidisciplinary team with high expertise in MALNS has been launched at the "Ospedale Pediatrico Bambino Gesù", Rome, Italy. Sixteen Italian MALNS individuals with molecular confirmed clinical diagnosis of MALNS were enrolled in the program. For all patients, 1-year surveillance in a dedicated outpatient Clinic was attained. The expert panel group enrolled 16 patients and performed a deep phenotyping analysis directed to clinically profiling the disorder and performing critical revision of previously reported individuals. Some evolutive complications were also assessed. Previously unappreciated features (e.g., high risk of bone fractures in childhood, neurological/neurovegetative symptoms, noise sensitivity and Chiari malformation type 1) requiring active surveillance were identified. A second case of neoplasm was recorded. No major cardiovascular anomalies were noticed. An accurate clinical description of 9 new MALNS cases was provided.

Conclusions: Deep phenotyping has provided a more accurate characterization of the main clinical features of MALNS and allows broadening the spectrum of disease. A minimal dataset of clinical evaluations and follow-up timeline has been proposed for proper management of patients affected by this ultrarare disorder.
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http://dx.doi.org/10.1186/s13023-022-02384-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9206304PMC
June 2022

Posterior fossa ependymoma in neurodevelopmental syndrome caused by a de novo germline pathogenic Polr2a variant.

Am J Med Genet A 2022 Jun 11. Epub 2022 Jun 11.

Department of Onco-Hematology, Cell Therapy, Gene Therapy and Hemopoietic Transplant, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Ependymoma is the third most common pediatric brain tumor. Predisposition to develop ependymomas has been reported in different hereditary diseases, but the pathogenic variants related to the familial syndromes have rarely been detected in sporadic ependymomas. De novo variants in POLR2A, the gene encoding the largest subunit of RNA polymerase II, cause a neurodevelopmental disorder with a wide range of clinical manifestations, characterized by severe infantile-onset hypotonia, developmental delay, feeding difficulties, palatal anomalies, and facial dysmorphisms. As somatic events, POLR2A mutations represent a recurrent somatic lesion in benign meningiomas. Here we describe a case of ependymoma in a 2-year-old male with a de novo pathogenic variant in POLR2A predicted to impair proper interaction of the subunit with transcription-elongation factor TFIIS, whose function is required for back-tracking of the enzyme due to elongation blocks or nucleotide misincorporation, and expected to result in an increased error and reduced elongation rates. To date, ependymoma has never been reported in patients harboring pathogenic POLR2A variants. Further information is required to explore the possibility of a differential clinical and functional impact of the pathogenic POLR2A variants and the eventual inclusion of the POLR2A neurodevelopmental disorder among the cancer predisposition syndromes with the possible development of ependymomas.
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http://dx.doi.org/10.1002/ajmg.a.62869DOI Listing
June 2022

Multidisciplinary Management of Costello Syndrome: Current Perspectives.

J Multidiscip Healthc 2022 2;15:1277-1296. Epub 2022 Jun 2.

Center for Rare Diseases and Birth Defects, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy.

Costello syndrome (CS) is a rare neurodevelopmental disorder caused by germline mutations in . It belongs among the RASopathies, a group of syndromes characterized by alterations in components of the RAS/MAPK signaling pathway and sharing overlapping phenotypes. Its typical features include a distinctive facial appearance, growth delay, intellectual disability, ectodermal, cardiac, and musculoskeletal abnormalities, and cancer predisposition. Due to the several comorbidities having a strong impact on the quality of life, a multidisciplinary team is essential in the management of such a condition from infancy to adult age, to promptly address any detected issue and to develop appropriate personalized follow-up protocols and treatment strategies. With the present paper we aim to highlight the core and ancillary medical disciplines involved in managing the health challenges characterizing CS from pediatric to adult age, according to literature and to our large clinical experience.
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http://dx.doi.org/10.2147/JMDH.S291757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9169840PMC
June 2022

Potassium Channel KCNH1 Activating Variants Cause Altered Functional and Morphological Ciliogenesis.

Mol Neurobiol 2022 Aug 31;59(8):4825-4838. Epub 2022 May 31.

Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.

The primary cilium is a non-motile sensory organelle that extends from the surface of most vertebrate cells and transduces signals regulating proliferation, differentiation, and migration. Primary cilia dysfunctions have been observed in cancer and in a group of heterogeneous disorders called ciliopathies, characterized by renal and liver cysts, skeleton and limb abnormalities, retinal degeneration, intellectual disability, ataxia, and heart disease and, recently, in autism spectrum disorder, schizophrenia, and epilepsy. The potassium voltage-gated channel subfamily H member 1 (KCNH1) gene encodes a member of the EAG (ether-à-go-go) family, which controls potassium flux regulating resting membrane potential in both excitable and non-excitable cells and is involved in intracellular signaling, cell proliferation, and tumorigenesis. KCNH1 missense variants have been associated with syndromic neurodevelopmental disorders, including Zimmermann-Laband syndrome 1 (ZLS1, MIM #135500), Temple-Baraitser syndrome (TMBTS, MIM #611816), and, recently, with milder phenotypes as epilepsy. In this work, we provide evidence that KCNH1 localizes at the base of the cilium in pre-ciliary vesicles and ciliary pocket of human dermal fibroblasts and retinal pigment epithelial (hTERT RPE1) cells and that the pathogenic missense variants (L352V and R330Q; NP_002229.1) perturb cilia morphology, assembly/disassembly, and Sonic Hedgehog signaling, disclosing a multifaceted role of the protein. The study of KCNH1 localization, its functions related to primary cilia, and the alterations introduced by mutations in ciliogenesis, cell cycle coordination, cilium morphology, and cilia signaling pathways could help elucidate the molecular mechanisms underlying neurological phenotypes and neurodevelopmental disorders not considered as classical ciliopathies but for which a significant role of primary cilia is emerging.
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http://dx.doi.org/10.1007/s12035-022-02886-4DOI Listing
August 2022

Complex Presentation of Hao-Fountain Syndrome Solved by Exome Sequencing Highlighting Co-Occurring Genomic Variants.

Genes (Basel) 2022 05 16;13(5). Epub 2022 May 16.

Area di Ricerca Genetica e Malattie Rare, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy.

Objective: The co-occurrence of pathogenic variants has emerged as a relatively common finding underlying complex phenotypes. Here, we used whole-exome sequencing (WES) to solve an unclassified multisystem clinical presentation.

Patients And Methods: A 20-year-old woman affected by moderate intellectual disability (ID), dysmorphic features, hypertrichosis, scoliosis, recurrent bronchitis, and pneumonia with bronchiectasis, colelithiasis, chronic severe constipation, and a family history suggestive of autosomal dominant recurrence of polycystic kidney disease was analyzed by WES to identify the genomic events underlying the condition.

Results: Four co-occurring genomic events fully explaining the proband's clinical features were identified. A de novo truncating variant was disclosed as the cause of Hao-Fountain syndrome, a disorder characterized by syndromic ID and distinctive behavior. Compound heterozygosity for a major cystic fibrosis-causing variant and the modulator allele, IVS8-5T, in explained the recurrent upper and lower respiratory way infections, bronchiectasis, cholelithiasis, and chronic constipation. Finally, a truncating variant co-segregating with polycystic kidney disease in the family allowed presymptomatic disease diagnosis.

Conclusions: The co-occurring variants in and variants explained the multisystem disorder of the patient. The comprehensive dissection of the phenotype and early diagnosis of autosomal dominant polycystic kidney disease allowed us to manage the -related disorder symptoms and monitor renal function and other complications associated with haploinsufficiency, addressing proper care and surveillance.
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http://dx.doi.org/10.3390/genes13050889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9141324PMC
May 2022

Biallelic variants in ZNF142 lead to a syndromic neurodevelopmental disorder.

Clin Genet 2022 Aug 8;102(2):98-109. Epub 2022 Jun 8.

Institute of Human Genetics, University of Münster, Münster, Germany.

Biallelic variants of the gene encoding for the zinc-finger protein 142 (ZNF142) have recently been associated with intellectual disability (ID), speech impairment, seizures, and movement disorders in nine individuals from five families. In this study, we obtained phenotype and genotype information of 26 further individuals from 16 families. Among the 27 different ZNF142 variants identified in the total of 35 individuals only four were missense. Missense variants may give a milder phenotype by changing the local structure of ZF motifs as suggested by protein modeling; but this correlation should be validated in larger cohorts and pathogenicity of the missense variants should be investigated with functional studies. Clinical features of the 35 individuals suggest that biallelic ZNF142 variants lead to a syndromic neurodevelopmental disorder with mild to moderate ID, varying degrees of delay in language and gross motor development, early onset seizures, hypotonia, behavioral features, movement disorders, and facial dysmorphism. The differences in symptom frequencies observed in the unpublished individuals compared to those of published, and recognition of previously underemphasized facial features are likely to be due to the small sizes of the previous cohorts, which underlines the importance of larger cohorts for the phenotype descriptions of rare genetic disorders.
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http://dx.doi.org/10.1111/cge.14165DOI Listing
August 2022

MiRLog and dbmiR: Prioritization and functional annotation tools to study human microRNA sequence variants.

Hum Mutat 2022 Sep 29;43(9):1201-1215. Epub 2022 May 29.

Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.

The recent identification of noncoding variants with pathogenic effects suggests that these variations could underlie a significant number of undiagnosed cases. Several computational methods have been developed to predict the functional impact of noncoding variants, but they exhibit only partial concordance and are not integrated with functional annotation resources, making the interpretation of these variants still challenging. MicroRNAs (miRNAs) are small noncoding RNA molecules that act as fine regulators of gene expression and play crucial functions in several biological processes, such as cell proliferation and differentiation. An increasing number of studies demonstrate a significant impact of miRNA single nucleotide variants (SNVs) both in Mendelian diseases and complex traits. To predict the functional effect of miRNA SNVs, we implemented a new meta-predictor, MiRLog, and we integrated it into a comprehensive database, dbmiR, which includes a precompiled list of all possible miRNA allelic SNVs, providing their biological annotations at nucleotide and miRNA levels. MiRLog and dbmiR were used to explore the genetic variability of miRNAs in 15,708 human genomes included in the gnomAD project, finding several ultra-rare SNVs with a potentially deleterious effect on miRNA biogenesis and function representing putative contributors to human phenotypes.
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http://dx.doi.org/10.1002/humu.24399DOI Listing
September 2022

"Atypical" Krabbe disease in two siblings harboring biallelic GALC mutations including a deep intronic variant.

Eur J Hum Genet 2022 Aug 17;30(8):984-988. Epub 2022 May 17.

Genetics and Rare Diseases Research Division, Unit of Neuromuscular and Neurodegenerative Disorders, Department of Neurosciences, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.

Krabbe disease (KD) is a rare lysosomal storage disorder caused by biallelic pathogenic variants in GALC. Most patients manifest the severe classic early-infantile form, while a small percentage of cases have later-onset types. We present two siblings with atypical clinical and neuroimaging phenotypes, compared to the classification of KD, who were found to carry biallelic loss-of-function GALC variants, including a recurrent 30 kb deletion and a previously unreported deep intronic variant that was identified by mRNA sequencing. This family represents a unique description in the KD literature and contributes to expanding the clinical and molecular spectra of this rare disorder.
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http://dx.doi.org/10.1038/s41431-022-01111-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9349273PMC
August 2022

Modeling PCDH19-CE: From 2D Stem Cell Model to 3D Brain Organoids.

Int J Mol Sci 2022 Mar 23;23(7). Epub 2022 Mar 23.

Genetics and Rare Diseases Research Division, Bambino Gesù Children's Research Hospital, IRCCS, 00165 Rome, Italy.

PCDH19 clustering epilepsy (PCDH19-CE) is a genetic disease characterized by a heterogeneous phenotypic spectrum ranging from focal epilepsy with rare seizures and normal cognitive development to severe drug-resistant epilepsy associated with intellectual disability and autism. Unfortunately, little is known about the pathogenic mechanism underlying this disease and an effective treatment is lacking. Studies with zebrafish and murine models have provided insights on the function of PCDH19 during brain development and how its altered function causes the disease, but these models fail to reproduce the human phenotype. Induced pluripotent stem cell (iPSC) technology has provided a complementary experimental approach for investigating the pathogenic mechanisms implicated in PCDH19-CE during neurogenesis and studying the pathology in a more physiological three-dimensional (3D) environment through the development of brain organoids. We report on recent progress in the development of human brain organoids with a particular focus on how this 3D model may shed light on the pathomechanisms implicated in PCDH19-CE.
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http://dx.doi.org/10.3390/ijms23073506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8998847PMC
March 2022

SHP2's gain-of-function in Werner syndrome causes childhood disease onset likely resulting from negative genetic interaction.

Clin Genet 2022 Jul 17;102(1):12-21. Epub 2022 Apr 17.

Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.

Prompt diagnosis of complex phenotypes is a challenging task in clinical genetics. Whole exome sequencing has proved to be effective in solving such conditions. Here, we report on an unpredictable presentation of Werner Syndrome (WRNS) in a 12-year-old girl carrying a homozygous truncating variant in RECQL2, the gene mutated in WRNS, and a de novo activating missense change in PTPN11, the major Noonan syndrome gene, encoding SHP2, a protein tyrosine phosphatase positively controlling RAS function and MAPK signaling, which have tightly been associated with senescence in primary cells. All the major WRNS clinical criteria were present with an extreme precocious onset and were associated with mild intellectual disability, severe growth retardation and facial dysmorphism. Compared to primary fibroblasts from adult subjects with WRNS, proband's fibroblasts showed a dramatically reduced proliferation rate and competence, and a more accelerated senescence, in line with the anticipated WRNS features occurring in the child. In vitro functional characterization of the SHP2 mutant documented its hyperactive behavior and a significantly enhanced activation of the MAPK pathway. Based on the functional interaction of WRN and MAPK signaling in processes relevant to replicative senescence, these findings disclose a unique phenotype likely resulting from negative genetic interaction.
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http://dx.doi.org/10.1111/cge.14140DOI Listing
July 2022

Expanding the molecular spectrum of pathogenic SHOC2 variants underlying Mazzanti syndrome.

Hum Mol Genet 2022 Mar 26. Epub 2022 Mar 26.

Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy.

We previously molecularly and clinically characterized Mazzanti syndrome, a RASopathy related to Noonan syndrome that is mostly caused by a single recurrent missense variant (c.4A > G, p.Ser2Gly) in SHOC2, which encodes a leucine-rich repeat (LRR)-containing protein facilitating signal flow through the RAS-mitogen-associated protein kinase (MAPK) pathway. We also documented that the pathogenic p.Ser2Gly substitution causes upregulation of MAPK signaling and constitutive targeting of SHOC2 to the plasma membrane due to the introduction of an N-myristoylation recognition motif. The almost invariant occurrence of the pathogenic c.4A > G missense change in SHOC2 is mirrored by a relatively homogeneous clinical phenotype of Mazzanti syndrome. Here we provide new data on the clinical spectrum and molecular diversity of this disorder, and functionally characterize new pathogenic variants. The clinical phenotype of six unrelated individuals carrying novel disease-causing SHOC2 variants is delineated, and public and newly collected clinical data are utilized to profile the disorder. In silico, in vitro and in vivo characterization of the newly identified variants provides evidence that the consequences of these missense changes on SHOC2 functional behavior differ from what had been observed for the canonical p.Ser2Gly change but converge towards an enhanced activation of the RAS-MAPK pathway. Our findings expand the molecular spectrum of pathogenic SHOC2 variants, provide a more accurate picture of the phenotypic expression associated with variants in this gene, and definitively establish a GoF behavior as the mechanism of disease.
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http://dx.doi.org/10.1093/hmg/ddac071DOI Listing
March 2022

Incremental net benefit of whole genome sequencing for newborns and children with suspected genetic disorders: Systematic review and meta-analysis of cost-effectiveness evidence.

Health Policy 2022 04 4;126(4):337-345. Epub 2022 Mar 4.

Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; Department of Health Sciences and Public Health, Section of Hygiene, Università Cattolica del Sacro Cuore, 00168 Rome, Italy.

Background: The introduction of massive parallel sequencing has contributed to a decline in sequencing costs. In recent years, whole-exome sequencing (WES) and whole-genome sequencing (WGS) have been increasingly adopted for diagnostic purposes in individuals with suspected genetic diseases. However, a debate is still ongoing in the scientific community about the superiority of WGS over WES in terms of cost-effectiveness. The aim of this study is to assess whether WGS, for the pediatric population with suspected genetic disorders, is cost-effective with respect to WES and chromosomal microarray (CMA) by pooling incremental net benefits.

Materials And Methods: Articles were retrieved from PubMed, Web of Science, Embase and Scopus from 2015 to 2021. The dominance ranking matrix (DRM) tool was adopted to provide a qualitative synthesis of all the included studies. Incremental net benefits (INBs) were estimated and meta-analysis was implemented to pool INBs across studies.

Results: The database search identified 1600 publications of which four articles were considered eligible for the meta-analysis. The pooled INB of WGS over WES was estimated at I$4073 (95% CI I$2426 - I$5720). The pooled INB of WGS over CMA amounted to I$6003 (95% CI I$2863 - I$9143).

Conclusions: WGS could be cost-effective in the diagnostic workup of affected infants and children. Further economic evaluations however are needed for comparing WGS versus WES and confirm the present conclusions.
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http://dx.doi.org/10.1016/j.healthpol.2022.03.001DOI Listing
April 2022

The seventh international RASopathies symposium: Pathways to a cure-expanding knowledge, enhancing research, and therapeutic discovery.

Am J Med Genet A 2022 06 9;188(6):1915-1927. Epub 2022 Mar 9.

CFC International, Stafford, Virginia, USA.

RASopathies are a group of genetic disorders that are caused by genes that affect the canonical Ras/mitogen-activated protein kinase (MAPK) signaling pathway. Despite tremendous progress in understanding the molecular consequences of these genetic anomalies, little movement has been made in translating these findings to the clinic. This year, the seventh International RASopathies Symposium focused on expanding the research knowledge that we have gained over the years to enhance new discoveries in the field, ones that we hope can lead to effective therapeutic treatments. Indeed, for the first time, research efforts are finally being translated to the clinic, with compassionate use of Ras/MAPK pathway inhibitors for the treatment of RASopathies. This biannual meeting, organized by the RASopathies Network, brought together basic scientists, clinicians, clinician scientists, patients, advocates, and their families, as well as representatives from pharmaceutical companies and the National Institutes of Health. A history of RASopathy gene discovery, identification of new disease genes, and the latest research, both at the bench and in the clinic, were discussed.
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http://dx.doi.org/10.1002/ajmg.a.62716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9117434PMC
June 2022

Recurrent de novo missense variants across multiple histone H4 genes underlie a neurodevelopmental syndrome.

Am J Hum Genet 2022 04 23;109(4):750-758. Epub 2022 Feb 23.

Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA.

Chromatin is essentially an array of nucleosomes, each of which consists of the DNA double-stranded fiber wrapped around a histone octamer. This organization supports cellular processes such as DNA replication, DNA transcription, and DNA repair in all eukaryotes. Human histone H4 is encoded by fourteen canonical histone H4 genes, all differing at the nucleotide level but encoding an invariant protein. Here, we present a cohort of 29 subjects with de novo missense variants in six H4 genes (H4C3, H4C4, H4C5, H4C6, H4C9, and H4C11) identified by whole-exome sequencing and matchmaking. All individuals present with neurodevelopmental features of intellectual disability and motor and/or gross developmental delay, while non-neurological features are more variable. Ten amino acids are affected, six recurrently, and are all located within the H4 core or C-terminal tail. These variants cluster to specific regions of the core H4 globular domain, where protein-protein interactions occur with either other histone subunits or histone chaperones. Functional consequences of the identified variants were evaluated in zebrafish embryos, which displayed abnormal general development, defective head organs, and reduced body axis length, providing compelling evidence for the causality of the reported disorder(s). While multiple developmental syndromes have been linked to chromatin-associated factors, missense-bearing histone variants (e.g., H3 oncohistones) are only recently emerging as a major cause of pathogenicity. Our findings establish a broader involvement of H4 variants in developmental syndromes.
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http://dx.doi.org/10.1016/j.ajhg.2022.02.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9069069PMC
April 2022

Clinical Utility of a Unique Genome-Wide DNA Methylation Signature for -Related Syndrome.

Int J Mol Sci 2022 Feb 5;23(3). Epub 2022 Feb 5.

Department of Pathology and Laboratory Medicine, Western University, London, ON N6A 3K7, Canada.

Wiedemann-Steiner syndrome (WDSTS) is a Mendelian syndromic intellectual disability (ID) condition associated with hypertrichosis cubiti, short stature, and characteristic facies caused by pathogenic variants in the gene. Clinical features can be inconclusive in mild and unusual WDSTS presentations with variable ID (mild to severe), facies (typical or not) and other associated malformations (bone, cerebral, renal, cardiac and ophthalmological anomalies). Interpretation and classification of rare variants can be challenging. A genome-wide DNA methylation episignature for -related syndrome could allow functional classification of variants and provide insights into the pathophysiology of WDSTS. Therefore, we assessed genome-wide DNA methylation profiles in a cohort of 60 patients with clinical diagnosis for WDSTS or Kabuki and identified a unique highly sensitive and specific DNA methylation episignature as a molecular biomarker of WDSTS. WDSTS episignature enabled classification of variants of uncertain significance in the gene as well as confirmation of diagnosis in patients with clinical presentation of WDSTS without known genetic variants. The changes in the methylation profile resulting from mutations involve global reduction in methylation in various genes, including homeobox gene promoters. These findings provide novel insights into the molecular etiology of WDSTS and explain the broad phenotypic spectrum of the disease.
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http://dx.doi.org/10.3390/ijms23031815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8836705PMC
February 2022

Mutations at the C-terminus of CDC42 cause distinct hematopoietic and autoinflammatory disorders.

J Allergy Clin Immunol 2022 Jul 12;150(1):223-228. Epub 2022 Feb 12.

Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy. Electronic address:

Background: Pathogenic missense variants in cell division control protein 42 (CDC42) differentially affect protein function, causing a clinically wide phenotypic spectrum variably affecting neurodevelopment, hematopoiesis, and immune response. More recently, 3 variants at the C-terminus of CDC42 were proposed to similarly impact protein function and cause a novel autoinflammatory disorder.

Objectives: We sought to clinically and functionally classify these variants to improve patient management.

Methods: Comparative analysis of the available clinical data and medical history of patients was performed. In vitro and in vivo studies were carried out to functionally characterize individual variants.

Results: Differently from what had previously been observed for the p.R186C change causing neonatal-onset cytopenia, autoinflammation, and recurrent hemophagocytic lymphohistiocytosis, p.C188Y and p.∗192Cext∗24 promoted accelerated protein degradation. Unprenylated CDC42 did not behave as a membrane-bound protein, whereas the residual CDC42 mutant replicated the CDC42 behavior, being targeted to the Golgi apparatus in a palmitoylation-dependent manner. Assessment of in vitro polarized migration and development in Caenorhabditis elegans documented a loss-of-function behavior of the p.C188Y and p.∗192Cext∗24 variants. Consistently, the 3 pathogenic variants were associated with different clinical presentations, with dysmorphisms, severity, and age of onset of cytopenia and extent of autoinflammation representing major differences.

Conclusions: Pathogenic variants at the CDC42 C-terminus differently impact protein stability, localization, and function, and cause different diseases, with p.R186C specifically associated with neonatal-onset pancytopenia and severe autoinflammation/hemophagocytic lymphohistiocytosis requiring emapalumab and bone marrow transplantation, and p.C188Y and p.∗192Cext∗24 causing anakinra-sensitive autoinflammation.
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http://dx.doi.org/10.1016/j.jaci.2022.01.024DOI Listing
July 2022

Metabolic profiling of Costello syndrome: Insights from a single-center cohort.

Eur J Med Genet 2022 Mar 29;65(3):104439. Epub 2022 Jan 29.

Center for Rare Diseases and Birth Defects, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Università Cattolica Sacro Cuore, Rome, Italy.

Costello syndrome (CS) is a rare disorder caused by activating dominantly acting germline variants in the HRAS gene. CS is defined by a clinical phenotype characterized by a distinctive gestalt, multiple congenital anomalies, and increased risk to develop tumors. Hypoglycemia and hypercholesterolemia have been reported to occur in affected individuals, but the underlying molecular events remain to be characterized. Here, we provided data on glucose/lipid metabolism and amino acid profile of a large single-center cohort of individuals affected by CS to systematically assess the extent of metabolic dysregulation characterizing this disorder and optimize patient management.
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http://dx.doi.org/10.1016/j.ejmg.2022.104439DOI Listing
March 2022

MEK Inhibition in a Newborn with -Associated Noonan Syndrome Ameliorates Hypertrophic Cardiomyopathy but Is Insufficient to Revert Pulmonary Vascular Disease.

Genes (Basel) 2021 12 21;13(1). Epub 2021 Dec 21.

Department of Clinical and Biological Sciences, University of Torino, 10043 Orbassano, Italy.

The :p.Ser257Leu variant is associated with severe Noonan syndrome (NS), progressive hypertrophic cardiomyopathy (HCM), and pulmonary hypertension. Trametinib, a MEK-inhibitor approved for treatment of RAS/MAPK-mutated cancers, is an emerging treatment option for HCM in NS. We report a patient with NS and HCM, treated with Trametinib and documented by global RNA sequencing before and during treatment to define transcriptional effects of MEK-inhibition. A preterm infant with HCM carrying the :p.Ser257Leu variant, rapidly developed severe congestive heart failure (CHF) unresponsive to standard treatments. Trametinib was introduced (0.022 mg/kg/day) with prompt clinical improvement and subsequent amelioration of HCM at ultrasound. The appearance of pulmonary artery aneurysm and pulmonary hypertension contributed to a rapid worsening after ventriculoperitoneal shunt device placement for posthemorrhagic hydrocephalus: she deceased for untreatable CHF at 3 months of age. Autopsy showed severe obstructive HCM, pulmonary artery dilation, disarrayed pulmonary vascular anatomy consistent with pulmonary capillary hemangiomatosis. Transcriptome across treatment, highlighted robust transcriptional changes induced by MEK-inhibition. Our findings highlight a previously unappreciated connection between pulmonary vascular disease and the severe outcome already reported in patients with -associated NS. While MEK-inhibition appears a promising therapeutic option for HCM in RASopathies, it appears insufficient to revert pulmonary hypertension.
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http://dx.doi.org/10.3390/genes13010006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8774485PMC
December 2021

Novel diagnostic DNA methylation episignatures expand and refine the epigenetic landscapes of Mendelian disorders.

HGG Adv 2022 Jan 3;3(1):100075. Epub 2021 Dec 3.

Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.

Overlapping clinical phenotypes and an expanding breadth and complexity of genomic associations are a growing challenge in the diagnosis and clinical management of Mendelian disorders. The functional consequences and clinical impacts of genomic variation may involve unique, disorder-specific, genomic DNA methylation episignatures. In this study, we describe 19 novel episignature disorders and compare the findings alongside 38 previously established episignatures for a total of 57 episignatures associated with 65 genetic syndromes. We demonstrate increasing resolution and specificity ranging from protein complex, gene, sub-gene, protein domain, and even single nucleotide-level Mendelian episignatures. We show the power of multiclass modeling to develop highly accurate and disease-specific diagnostic classifiers. This study significantly expands the number and spectrum of disorders with detectable DNA methylation episignatures, improves the clinical diagnostic capabilities through the resolution of unsolved cases and the reclassification of variants of unknown clinical significance, and provides further insight into the molecular etiology of Mendelian conditions.
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http://dx.doi.org/10.1016/j.xhgg.2021.100075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8756545PMC
January 2022

Prevalence of bladder cancer in Costello syndrome: New insights to drive clinical decision-making.

Clin Genet 2022 04 17;101(4):454-458. Epub 2022 Feb 17.

Center for Rare Diseases and Birth Defects, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy.

Costello syndrome (CS) is a rare disorder affecting development and growth characterized by cancer predisposition and caused by mutations in HRAS proto-oncogene. Somatic HRAS mutations drive bladder carcinogenesis. The aim of this study was to analyze prevalence and histological characterization of bladder cancer (BC) in a cohort of patients with CS to help clinicians plan effective management strategies. This study included 13 patients above 10 years of age with molecular diagnosis of CS. Screening cystoscopies (31 total procedures) were performed to exclude BC. Any lesion was analyzed through cold-cup biopsy or trans-urethral resection of the bladder. According to histology, patients were followed-up with urinalysis and abdominal ultrasound yearly, and cystoscopies every 12-24 months. During study enrollment, bladder lesions (often multifocal) were detected in 11/13 patients. Histological analysis documented premalignant lesions in 90% of cystoscopies performed, epithelial dysplasia in 71%, and papillary urothelial neoplasm of low-malignant potential in 19%. BC G1/low grade (Ta) were removed in 10%. Overall, 76% of patients showed a bladder lesion at first cystoscopy. The present findings document that individuals with CS aged 10 years and older have high prevalence of bladder lesions (premalignant/malignant), highlighting the importance of personalized screening protocols.
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http://dx.doi.org/10.1111/cge.14111DOI Listing
April 2022

Induced Pluripotent Stem Cells (iPSCs) and Gene Therapy: A New Era for the Treatment of Neurological Diseases.

Int J Mol Sci 2021 Dec 20;22(24). Epub 2021 Dec 20.

Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, IRCCS, 00146 Rome, Italy.

To date, gene therapy has employed viral vectors to deliver therapeutic genes. However, recent progress in molecular and cell biology has revolutionized the field of stem cells and gene therapy. A few years ago, clinical trials started using stem cell replacement therapy, and the induced pluripotent stem cells (iPSCs) technology combined with CRISPR-Cas9 gene editing has launched a new era in gene therapy for the treatment of neurological disorders. Here, we summarize the latest findings in this research field and discuss their clinical applications, emphasizing the relevance of recent studies in the development of innovative stem cell and gene editing therapeutic approaches. Even though tumorigenicity and immunogenicity are existing hurdles, we report how recent progress has tackled them, making engineered stem cell transplantation therapy a realistic option.
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http://dx.doi.org/10.3390/ijms222413674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8706293PMC
December 2021

Bone tissue homeostasis and risk of fractures in Costello syndrome: A 4-year follow-up study.

Am J Med Genet A 2022 02 15;188(2):422-430. Epub 2021 Dec 15.

Center for Rare Diseases and Birth Defects, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.

Costello syndrome (CS) is a neurodevelopmental disorder with a distinctive musculoskeletal phenotype and reduced bone mineral density (BMD) caused by activating de novo mutations in the HRAS gene. Herein, we report the results of a prospective study evaluating the efficacy of a 4-year vitamin D supplementation on BMD and bone health. A cohort of 16 individuals ranging from pediatric to adult age with molecularly confirmed CS underwent dosages of bone metabolism biomarkers (serum/urine) and dual-energy X-ray absorptiometry (DXA) scans to assess bone and body composition parameters. Results were compared to age-matched control groups. At baseline evaluation, BMD was significantly reduced (p ≤ 0.05) compared to controls, as were the 25(OH)vitD levels. Following the 4-year time interval, despite vitamin D supplementation therapy at adequate dosages, no significant improvement in BMD was observed. The present data confirm that 25(OH)vitD and BMD parameters are reduced in CS, and vitamin D supplementation is not sufficient to restore proper BMD values. Based on this evidence, routine monitoring of bone homeostasis to prevent bone deterioration and possible fractures in adult patients with CS is highly recommended.
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http://dx.doi.org/10.1002/ajmg.a.62615DOI Listing
February 2022
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