Publications by authors named "Emanuele Agolini"

69 Publications

Childhood-onset dystonia-causing KMT2B variants result in a distinctive genomic hypermethylation profile.

Clin Epigenetics 2021 Aug 11;13(1):157. Epub 2021 Aug 11.

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

Background: Dystonia is a clinically and genetically heterogeneous movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements and/or postures. Heterozygous variants in lysine methyltransferase 2B (KMT2B), encoding a histone H3 methyltransferase, have been associated with a childhood-onset, progressive and complex form of dystonia (dystonia 28, DYT28). Since 2016, more than one hundred rare KMT2B variants have been reported, including frameshift, nonsense, splice site, missense and other in-frame changes, many having an uncertain clinical impact.

Results: We characterize the genome-wide peripheral blood DNA methylation profiles of a cohort of 18 patients with pathogenic and unclassified KMT2B variants. We resolve the "episignature" associated with KMT2B haploinsufficiency, proving that this approach is robust in diagnosing clinically unsolved cases, properly classifying them with respect to other partially overlapping dystonic phenotypes, other rare neurodevelopmental disorders and healthy controls. Notably, defective KMT2B function in DYT28 causes a non-random DNA hypermethylation across the genome, selectively involving promoters and other regulatory regions positively controlling gene expression.

Conclusions: We demonstrate a distinctive DNA hypermethylation pattern associated with DYT28, provide an epigenetic signature for this disorder enabling accurate diagnosis and reclassification of ambiguous genetic findings and suggest potential therapeutic approaches.
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http://dx.doi.org/10.1186/s13148-021-01145-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8359374PMC
August 2021

Whole Exome Sequencing Is the Minimal Technological Approach in Probands Born to Consanguineous Couples.

Genes (Basel) 2021 06 24;12(7). Epub 2021 Jun 24.

Medical Genetics Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy.

We report on two siblings suffering from different pathogenic conditions, born to consanguineous parents. A multigene panel for brain malformations and microcephaly identified the homozygous splicing variant NM_005886.3:c.1416+1del in the gene in the older sister. On the other hand, exome sequencing revealed the homozygous frameshift variant NM_005245.4:c.9729del in the gene in the younger sister, who had a more complex phenotype: in addition to bilateral anophthalmia and heart defects, she showed a right split foot with 4 toes, 5 metacarpals, second toe duplication and preaxial polydactyly on the right hand. These features have been never reported before in patients with pathogenic variants and support the role of this gene in the development of limb buds. Notably, each parent was heterozygous for both of these variants, which were ultra-rare and rare, respectively. This study raises awareness about the value of using whole exome/genome sequencing rather than targeted gene panels when testing affected offspring born to consanguineous couples. In this way, exomic data from the parents are also made available for carrier screening, to identify heterozygous pathogenetic and likely pathogenetic variants in genes responsible for other recessive conditions, which may pose a risk for subsequent pregnancies.
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http://dx.doi.org/10.3390/genes12070962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8303193PMC
June 2021

Unique variants in CLCN3, encoding an endosomal anion/proton exchanger, underlie a spectrum of neurodevelopmental disorders.

Am J Hum Genet 2021 08 28;108(8):1450-1465. Epub 2021 Jun 28.

Erasmus University Medical Center, Department of Clinical Genetics, 3000 CA Rotterdam, the Netherlands.

The genetic causes of global developmental delay (GDD) and intellectual disability (ID) are diverse and include variants in numerous ion channels and transporters. Loss-of-function variants in all five endosomal/lysosomal members of the CLC family of Cl channels and Cl/H exchangers lead to pathology in mice, humans, or both. We have identified nine variants in CLCN3, the gene encoding CIC-3, in 11 individuals with GDD/ID and neurodevelopmental disorders of varying severity. In addition to a homozygous frameshift variant in two siblings, we identified eight different heterozygous de novo missense variants. All have GDD/ID, mood or behavioral disorders, and dysmorphic features; 9/11 have structural brain abnormalities; and 6/11 have seizures. The homozygous variants are predicted to cause loss of ClC-3 function, resulting in severe neurological disease similar to the phenotype observed in Clcn3 mice. Their MRIs show possible neurodegeneration with thin corpora callosa and decreased white matter volumes. Individuals with heterozygous variants had a range of neurodevelopmental anomalies including agenesis of the corpus callosum, pons hypoplasia, and increased gyral folding. To characterize the altered function of the exchanger, electrophysiological analyses were performed in Xenopus oocytes and mammalian cells. Two variants, p.Ile607Thr and p.Thr570Ile, had increased currents at negative cytoplasmic voltages and loss of inhibition by luminal acidic pH. In contrast, two other variants showed no significant difference in the current properties. Overall, our work establishes a role for CLCN3 in human neurodevelopment and shows that both homozygous loss of ClC-3 and heterozygous variants can lead to GDD/ID and neuroanatomical abnormalities.
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http://dx.doi.org/10.1016/j.ajhg.2021.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8387284PMC
August 2021

TSPEAR variants are primarily associated with ectodermal dysplasia and tooth agenesis but not hearing loss: A novel cohort study.

Am J Med Genet A 2021 08 27;185(8):2417-2433. Epub 2021 May 27.

Faculté de Chirurgie Dentaire, Université de Strasbourg, Strasbourg, France.

Biallelic loss-of-function variants in the thrombospondin-type laminin G domain and epilepsy-associated repeats (TSPEAR) gene have recently been associated with ectodermal dysplasia and hearing loss. The first reports describing a TSPEAR disease association identified this gene is a cause of nonsyndromic hearing loss, but subsequent reports involving additional affected families have questioned this evidence and suggested a stronger association with ectodermal dysplasia. To clarify genotype-phenotype associations for TSPEAR variants, we characterized 13 individuals with biallelic TSPEAR variants. Individuals underwent either exome sequencing or panel-based genetic testing. Nearly all of these newly reported individuals (11/13) have phenotypes that include tooth agenesis or ectodermal dysplasia, while three newly reported individuals have hearing loss. Of the individuals displaying hearing loss, all have additional variants in other hearing-loss-associated genes, specifically TMPRSS3, GJB2, and GJB6, that present competing candidates for their hearing loss phenotype. When presented alongside previous reports, the overall evidence supports the association of TSPEAR variants with ectodermal dysplasia and tooth agenesis features but creates significant doubt as to whether TSPEAR variants are a monogenic cause of hearing loss. Further functional evidence is needed to evaluate this phenotypic association.
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http://dx.doi.org/10.1002/ajmg.a.62347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8361973PMC
August 2021

ANKRD11 variants: KBG syndrome and beyond.

Clin Genet 2021 08 14;100(2):187-200. Epub 2021 May 14.

Centro Fondazione Mariani per il Bambino Fragile ASST-Lariana Sant'Anna Hospital, Department of Pediatrics, San Fermo della Battaglia (Como), Italy.

Mutations affecting the transcriptional regulator Ankyrin Repeat Domain 11 (ANKRD11) are mainly associated with the multisystem developmental disorder known as KBG syndrome, but have also been identified in individuals with Cornelia de Lange syndrome (CdLS) and other developmental disorders caused by variants affecting different chromatin regulators. The extensive functional overlap of these proteins results in shared phenotypical features, which complicate the assessment of the clinical diagnosis. Additionally, re-evaluation of individuals at a later age occasionally reveals that the initial phenotype has evolved toward clinical features more reminiscent of a developmental disorder different from the one that was initially diagnosed. For this reason, variants in ANKRD11 can be ascribed to a broader class of disorders that fall within the category of the so-called chromatinopathies. In this work, we report on the clinical characterization of 23 individuals with variants in ANKRD11. The subjects present primarily with developmental delay, intellectual disability and dysmorphic features, and all but two received an initial clinical diagnosis of either KBG syndrome or CdLS. The number and the severity of the clinical signs are overlapping but variable and result in a broad spectrum of phenotypes, which could be partially accounted for by the presence of additional molecular diagnoses and distinct pathogenic mechanisms.
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http://dx.doi.org/10.1111/cge.13977DOI Listing
August 2021

Molecular Characterization of Medulloblastoma in a Patient with Neurofibromatosis Type 1: Case Report and Literature Review.

Diagnostics (Basel) 2021 Apr 2;11(4). Epub 2021 Apr 2.

Department of Onco-Hematology and Cell and Gene Therapy, Bambino Gesù Children's Hospital (IRCCS), 00165 Rome, Italy.

Brain tumors are the most common solid neoplasms of childhood. They are frequently reported in children with Neurofibromatosis type 1 (NF1). The most frequent central nervous system malignancies described in NF1 are optic pathway gliomas and brainstem gliomas. Medulloblastoma (MB) in NF1 patients is extremely rare, and to our knowledge, only 10 cases without molecular characterization are described in the literature to date. We report the case of a 14-year-old girl with NF1 that came to our attention for an incidental finding of a lesion arising from cerebellar vermis. The mass was completely resected, revealing a localized classic medulloblastoma (MB), subgroup 4. She was treated as a standard-risk MB with a dose-adapted personalized protocol. The treatment proved to be effective, with minor toxicity. Brain and spine MRI one year after diagnosis confirmed the complete remission of the disease. To our knowledge, this is the only case of MB reported in a patient with NF1 with molecular characterization by the methylation profile. The association between NF1 and MB, although uncommon, may not be an accidental occurrence.
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http://dx.doi.org/10.3390/diagnostics11040647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8067061PMC
April 2021

Deciphering Genetic Variants of Warfarin Metabolism in Children With Ventricular Assist Devices.

Pediatr Cardiol 2021 Jun 10;42(5):1082-1087. Epub 2021 Apr 10.

Heart Failure, Transplant and Mechanical Assistance Program Unit, Bambino Gesù Children Hospital, Rome, Italy.

Warfarin is prescribed in patients with ventricular assist devices (VADs). Dosage depends on several factors including the underlying genotype. These include polymorphisms of genes encoding cytochrome P450 enzymes, the main ones being CYP2C9, VKORC1, and CYP4F2. The objectives of this study were to evaluate the prevalence of CY2CP9 1*2*3*, VKORC1, and CYP4F2 in children with VADs and the time to reach the target international normalized ratio. We performed a retrospective/prospective study in children with VADs. We recorded polymorphisms, disease, type of VAD, ethnicity, age, gender, height, weight, INR values, bleeding, and thromboembolic episodes. Informed consent was obtained. We enrolled 34 children (19 male, 15 female), with a median age of 2 years (range 0.3-17 years) and median weight of 6.9Kg. The Berlin Heart was the most commonly implanted VAD (22/34; 64%), and the most common diagnosis was dilated cardiomyopathy. Statistical analysis confirmed a significant partial correlation with VKORC1 CC (p = 0.019). The CYP2C9*2 CT genotype showed a late rise in target INR values (p = 0.06), while the CYP2C9*2 CC showed a tendency toward an early INR rise (p = 0.024). We provide new information on the contribution of the warfarin polymorphisms in children with VAD implantation. Pharmacogenomic dosing for children using warfarin has the potential to improve clinical care in VAD patients. Patients with the CYP2C9*2 CT genotype may need more time or higher doses to reach target INR, while clinicians may need to be aware of the potential for a rapid rise in INR in patients with the CYP2C9*2 CC genotype.
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http://dx.doi.org/10.1007/s00246-021-02585-2DOI Listing
June 2021

Inhibition of HECT E3 ligases as potential therapy for COVID-19.

Cell Death Dis 2021 03 24;12(4):310. Epub 2021 Mar 24.

Infection, Antimicrobials, Modelling, Evolution (IAME), INSERM, UMRS1137, University of Paris, Paris, France.

SARS-CoV-2 is responsible for the ongoing world-wide pandemic which has already taken more than two million lives. Effective treatments are urgently needed. The enzymatic activity of the HECT-E3 ligase family members has been implicated in the cell egression phase of deadly RNA viruses such as Ebola through direct interaction of its VP40 Protein. Here we report that HECT-E3 ligase family members such as NEDD4 and WWP1 interact with and ubiquitylate the SARS-CoV-2 Spike protein. Furthermore, we find that HECT family members are overexpressed in primary samples derived from COVID-19 infected patients and COVID-19 mouse models. Importantly, rare germline activating variants in the NEDD4 and WWP1 genes are associated with severe COVID-19 cases. Critically, I3C, a natural NEDD4 and WWP1 inhibitor from Brassicaceae, displays potent antiviral effects and inhibits viral egression. In conclusion, we identify the HECT family members of E3 ligases as likely novel biomarkers for COVID-19, as well as new potential targets of therapeutic strategy easily testable in clinical trials in view of the established well-tolerated nature of the Brassicaceae natural compounds.
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http://dx.doi.org/10.1038/s41419-021-03513-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987752PMC
March 2021

Expansion of the clinical and molecular spectrum of an XPD-related disorder linked to biallelic mutations in ERCC2 gene.

Clin Genet 2021 Jun 5;99(6):842-848. Epub 2021 Apr 5.

Department of Hematology/Oncology, Gene and Cell Therapy, Bambino Gesù Children's Hospital, IRCSS, Rome, Italy.

Bi-allelic inactivation of XPD protein, a nucleotide excision repair (NER) signaling pathway component encoded by ERCC2 gene, has been associated with several defective DNA repair phenotypes, including xeroderma pigmentosum, photosensitive trichothiodystrophy, and cerebro-oculo-facio-skeletal syndrome. We report a pediatric patient harboring two compound heterozygous variants in ERCC2 gene, c.361-1G>A and c.2125A>C (p.Thr709Pro), affected by severe postnatal growth deficiency, microcephaly, facial dysmorphisms and pilocytic astrocytoma of the brainstem. Some of these features point to a DNA repair syndrome, and altogether delineate a phenotype differentiating from disorders known to be associated with ERCC2 mutations. The DNA repair efficiency following UV irradiation in the proband's skin fibroblasts was defective indicating that the new set of ERCC2 alleles impacts on NER efficiency. Sequencing analysis on tumor DNA did not reveal any somatic deleterious point variant in cancer-related genes, while SNP-array analysis disclosed a 2 Mb microduplication involving the 7q34 region, spanning from KIAA1549 to BRAF, and resulting in the KIAA1549:BRAF fusion protein, a marker of pilocytic astrocytoma. In conclusion, this report expands the clinical and mutational spectrum of ERCC2-related disorders.
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http://dx.doi.org/10.1111/cge.13957DOI Listing
June 2021

Rhabdoid Tumor Predisposition Syndrome: From Clinical Suspicion to General Management.

Front Oncol 2021 22;11:586288. Epub 2021 Feb 22.

Department of Paediatric Haematology/Oncology, IRCCS Bambino Gesù Children's Hospital, Rome, Italy.

Rhabdoid tumors are rare aggressive malignancies in infants and young children with a poor prognosis. The most common anatomic localizations are the central nervous system, the kidneys, and other soft tissues. Rhabdoid tumors share germline and somatic mutations in or, more rarely, , members of the SWI/SNF chromatin-remodeling complex. Rhabdoid tumor predisposition syndrome (RTPS) is a condition characterized by a high risk of developing rhabdoid tumors, among other features. RTPS1 is characterized by pathogenic variants in the gene, while RTPS2 has variants in . Interestingly, germline variants of and have been identified also in patients with Coffin-Siris syndrome. Children with RTPS typically present with tumors before 1 year of age and in a high percentage of cases develop synchronous or multifocal tumors with aggressive clinical features. The diagnosis of RTPS should be considered in patients with rhabdoid tumors, especially if they have multiple primary tumors and/or in individuals with a family history. Because germline mutations result in an increased risk of carriers developing rhabdoid tumors, genetic counseling, and surveillance for all family members with this condition is recommended.
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http://dx.doi.org/10.3389/fonc.2021.586288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937887PMC
February 2021

Disruption of RFX family transcription factors causes autism, attention-deficit/hyperactivity disorder, intellectual disability, and dysregulated behavior.

Genet Med 2021 06 3;23(6):1028-1040. Epub 2021 Mar 3.

Division of Medical Genetics, Nemours/A.I. DuPont Hospital for Children, Wilmington, DE, USA.

Purpose: We describe a novel neurobehavioral phenotype of autism spectrum disorder (ASD), intellectual disability, and/or attention-deficit/hyperactivity disorder (ADHD) associated with de novo or inherited deleterious variants in members of the RFX family of genes. RFX genes are evolutionarily conserved transcription factors that act as master regulators of central nervous system development and ciliogenesis.

Methods: We assembled a cohort of 38 individuals (from 33 unrelated families) with de novo variants in RFX3, RFX4, and RFX7. We describe their common clinical phenotypes and present bioinformatic analyses of expression patterns and downstream targets of these genes as they relate to other neurodevelopmental risk genes.

Results: These individuals share neurobehavioral features including ASD, intellectual disability, and/or ADHD; other frequent features include hypersensitivity to sensory stimuli and sleep problems. RFX3, RFX4, and RFX7 are strongly expressed in developing and adult human brain, and X-box binding motifs as well as RFX ChIP-seq peaks are enriched in the cis-regulatory regions of known ASD risk genes.

Conclusion: These results establish a likely role of deleterious variation in RFX3, RFX4, and RFX7 in cases of monogenic intellectual disability, ADHD and ASD, and position these genes as potentially critical transcriptional regulators of neurobiological pathways associated with neurodevelopmental disease pathogenesis.
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http://dx.doi.org/10.1038/s41436-021-01114-zDOI Listing
June 2021

HLA-haploidentical TCRαβ+/CD19+-depleted stem cell transplantation in children and young adults with Fanconi anemia.

Blood Adv 2021 03;5(5):1333-1339

Department of Pediatric Hemato-Oncology and Cell and Gene Therapy, Scientific Institute for Research and Healthcare (IRCCS) Bambino Gesù Children's Hospital, Rome, Italy.

We report on the outcome of 24 patients with Fanconi anemia (FA) lacking an HLA matched related or unrelated donor, given an HLA-haploidentical T-cell receptor αβ (TCRαβ+) and CD19+ cell-depleted hematopoietic stem cell transplantation (HSCT) in the context of a prospective, single-center phase 2 trial. Sustained primary engraftment was achieved in 22 (91.6%) of 24 patients, with median time to neutrophil recovery of 12 days (range, 9-15 days) and platelet recovery of 10 days (range, 7-14 days). Cumulative incidences of grade 1 to 2 acute graft-versus-host disease (GVHD) and chronic GVHD were 17.4% (95% confidence interval [CI], 5.5%-35.5%) and 5.5% (95% CI, 0.8%-33.4%), respectively. The conditioning regimen, which included fludarabine, low-dose cyclophosphamide and, in most patients, single-dose irradiation was well tolerated; no fatal transplant-related toxicity was observed. With a median follow-up of 5.2 years (range, 0.3-8.7 years), the overall and event-free survival probabilities were 100% and 86.3% (95% CI, 62.8%-95.4%), respectively (2 graft failures and 1 case of poor graft function were considered as events). The 2 patients who experienced primary graft failure underwent a subsequent successful HSCT from the other parent. This is the first report of FA patients given TCRαβ+/CD19+-depleted haplo-HSCT in the context of a prospective trial, and the largest series of T-cell-depleted haplo-HSCT in FA reported to date. This trial was registered at www.clinicaltrials.gov as #NCT01810120.
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http://dx.doi.org/10.1182/bloodadvances.2020003707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948273PMC
March 2021

PRKRA-Related Disorders: Bilateral Striatal Degeneration in Addition to DYT16 Spectrum.

Mov Disord 2021 04 19;36(4):1038-1040. Epub 2021 Feb 19.

Child Neurology Unit, COALA (Center for Diagnosis and Treatment of Leukodystrophies), V. Buzzi Children's Hospital, Milan, Italy.

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http://dx.doi.org/10.1002/mds.28492DOI Listing
April 2021

Biallelic hypomorphic variants in ALDH1A2 cause a novel lethal human multiple congenital anomaly syndrome encompassing diaphragmatic, pulmonary, and cardiovascular defects.

Hum Mutat 2021 May 1;42(5):506-519. Epub 2021 Apr 1.

Faculty of Health and Medical Sciences, Centre of Medical Research, Harry Perkins Institute of Medical Research, University of Western Australia, Nedlands, Western Australia, Australia.

This study shows a causal association between ALDH1A2 variants and a novel, severe multiple congenital anomaly syndrome in humans that is neonatally lethal due to associated pulmonary hypoplasia and respiratory failure. In two families, exome sequencing identified compound heterozygous missense variants in ALDH1A2. ALDH1A2 is involved in the conversion of retinol (vitamin A) into retinoic acid (RA), which is an essential regulator of diaphragm and cardiovascular formation during embryogenesis. Reduced RA causes cardiovascular, diaphragmatic, and associated pulmonary defects in several animal models, matching the phenotype observed in our patients. In silico protein modeling showed probable impairment of ALDH1A2 for three of the four substitutions. In vitro studies show a reduction of RA. Few pathogenic variants in genes encoding components of the retinoic signaling pathway have been described to date, likely due to embryonic lethality. Thus, this study contributes significantly to knowledge of the role of this pathway in human diaphragm and cardiovascular development and disease. Some clinical features in our patients are also observed in Fryns syndrome (MIM# 229850), syndromic microphthalmia 9 (MIM# 601186), and DiGeorge syndrome (MIM# 188400). Patients with similar clinical features who are genetically undiagnosed should be tested for recessive ALDH1A2-deficient malformation syndrome.
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http://dx.doi.org/10.1002/humu.24179DOI Listing
May 2021

Medulloblastoma Associated with Down Syndrome: From a Rare Event Leading to a Pathogenic Hypothesis.

Diagnostics (Basel) 2021 Feb 7;11(2). Epub 2021 Feb 7.

Department of Onco-Hematology and Cell and Gene Therapy, Bambino Gesù Children's Hospital IRCCS, Piazza Sant'Onofrio 4, 00146 Rome, Italy.

Down syndrome (DS) is the most common chromosome abnormality with a unique cancer predisposition syndrome pattern: a higher risk to develop acute leukemia and a lower incidence of solid tumors. In particular, brain tumors are rarely reported in the DS population, and biological behavior and natural history are not well described and identified. We report a case of a 10-year-old child with DS who presented with a medulloblastoma (MB). Histological examination revealed a classic MB with focal anaplasia and the molecular profile showed the presence of a variant associated with the wingless (WNT) molecular subgroup with a good prognosis in contrast to our case report that has shown an early metastatic relapse. The nearly seven-fold decreased risk of MB in children with DS suggests the presence of protective biological mechanisms. The cerebellum hypoplasia and the reduced volume of cerebellar granule neuron progenitor cells seem to be a possible favorable condition to prevent MB development via inhibition of neuroectodermal differentiation. Moreover, the NOTCH/WNT dysregulation in DS, which is probably associated with an increased risk of leukemia, suggests a pivotal role of this pathway alteration in the pathogenesis of MB; therefore, this condition should be further investigated in future studies by molecular characterizations.
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http://dx.doi.org/10.3390/diagnostics11020254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915142PMC
February 2021

DICER1 Syndrome and Cancer Predisposition: From a Rare Pediatric Tumor to Lifetime Risk.

Front Oncol 2020 21;10:614541. Epub 2021 Jan 21.

Department of Onco - Hematology and Cell and Gene Therapy, Bambino Gesù Pediatric Hospital (IRCCS), Roma, Italy.

DICER1 syndrome is a rare genetic condition predisposing to hereditary cancer and caused by variants in the gene. The risk to present a neoplasm before the age of 10 years is 5.3 and 31.5% before the age of 60. variants have been associated with a syndrome involving familial pleuropulmonary blastoma (PPB), a rare malignant tumor of the lung, which occurs primarily in children under the age of 6 years and represents the most common life-threatening manifestation of DICER1 syndrome. Type I, II, III, and Ir (type I regressed) PPB are reported with a 5-year overall survival ranging from 53 to 100% (for type Ir). gene should be screened in all patients with PPB and considered in other tumors mainly in thyroid neoplasms (multinodular goiter, thyroid cancer, adenomas), ovarian tumors (Sertoli-Leydig cell tumor, sarcoma, and gynandroblastoma), and cystic nephroma. A prompt identification of this syndrome is necessary to plan a correct follow-up and screening during lifetime.
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http://dx.doi.org/10.3389/fonc.2020.614541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859642PMC
January 2021

Fetal early motor neuron disruption and prenatal molecular diagnosis in a severe BICD2-opathy.

Am J Med Genet A 2021 05 5;185(5):1509-1514. Epub 2021 Feb 5.

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

BICD2 (BICD Cargo Adaptor 2, MIM*609797) mutations are associated with severe prenatal-onset forms of spinal muscular atrophy, lower extremity-predominant 2B (SMALED2B MIM 618291) or milder forms with childhood-onset (SMALED2A MIM 615290). Etiopathogenesis is not fully clarified and a wide spectrum of phenotypic presentations is reported, ranging from extreme prenatal forms with adverse outcome, to slow progressive late-onset forms. We report a fetus at 22 gestational weeks with evidence of Arthrogryposis Multiplex Congenita on ultrasound, presenting with fixed extended lower limbs and flexed upper limbs, bilateral clubfoot and absent fetal movements. A trio-based prenatal Exome Sequencing was performed, disclosing a de novo heterozygous pathogenic in frame deletion (NM_015250.3: c.1636_1638delAAT; p.Asn546del) in BICD2. After pregnancy termination, quantitative analysis on NeuN immunostained spinal cord sections of the ventral horns, revealed that neuronal density was markedly reduced compared to the one of an age-matched normal fetus and an age-matched type-I Spinal Muscular Atrophy sample, used as a comparative model. The present case, the first prenatally diagnosed and neuropathologically characterized, showed an early motor neuron loss in SMALED2B, providing further insight into the pathological basis of BICD2-opathies.
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http://dx.doi.org/10.1002/ajmg.a.62111DOI Listing
May 2021

Clinical presentation and molecular characterization of a novel patient with variant POC1A-related syndrome.

Clin Genet 2021 04 13;99(4):540-546. Epub 2021 Jan 13.

Medical Genetics, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, Rome, Italy.

Biallelic pathogenic variants in POC1A result in SOFT (Short-stature, Onychodysplasia, Facial-dysmorphism, and hypoTrichosis) and variant POC1A-related (vPOC1A) syndromes. The latter, nowadays described in only two unrelated subjects, is associated with a restricted spectrum of variants falling in exon 10, which is naturally skipped in a specific POC1A mRNA. The synthesis of an amount of a POC1A isoform from this transcript in individuals with vPOC1A syndrome has been believed as the likely explanation for such a genotype-phenotype correlation. Here, we illustrate the clinical and molecular findings in a woman who resulted to be compound heterozygous for a recurrent frameshift variant in exon 10 and a novel variant in exon 9 of POC1A. Phenotypic characteristics of this woman included severe hyperinsulinemic dyslipidemia, acanthosis nigricans, moderate growth restriction, and dysmorphisms. These manifestations overlap the clinical features of the two previously published individuals with vPOC1A syndrome. RT-PCR analysis on peripheral blood and subsequent sequencing of the obtained amplicons demonstrated a variety of POC1A alternative transcripts that resulted to be expressed in the proband, in the healthy mother, and in controls. We illustrate the possible consequences of the two POC1A identified variants in an attempt to explain pleiotropy in vPOC1A syndrome.
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http://dx.doi.org/10.1111/cge.13911DOI Listing
April 2021

Exon-Trapping Assay Improves Clinical Interpretation of and Intronic Variants in Stickler Syndrome Type 2 and Otospondylomegaepiphyseal Dysplasia.

Genes (Basel) 2020 12 17;11(12). Epub 2020 Dec 17.

Division of Medical Genetics, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Foggia, Italy.

Stickler syndrome (SS) is a hereditary connective tissue disorder affecting bones, eyes, and hearing. Type 2 SS and the SS variant otospondylomegaepiphyseal dysplasia (OSMED) are caused by deleterious variants in and , respectively. In both genes, available database information indicates a high rate of potentially deleterious intronic variants, but published evidence of their biological effect is usually insufficient for a definite clinical interpretation. We report four previously unpublished intronic variants in (c.2241 + 5G>T, c.2809 - 2A>G, c.3168 + 5G>C) and (c.4392 + 1G>A) identified in type 2 SS/OSMED individuals. The pathogenic effect of these variants was first predicted in silico and then investigated by an exon-trapping assay. We demonstrated that all variants can induce exon in-frame deletions, which lead to the synthesis of shorter collagen XI α1 or 2 chains. Lacking residues are located in the α-triple helical region, which has a crucial role in regulating collagen fibrillogenesis. In conclusion, this study suggests that these alternative and transcripts might result in aberrant triple helix collagen. Our approach may help to improve the diagnostic molecular pathway of -related disorders.
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http://dx.doi.org/10.3390/genes11121513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766184PMC
December 2020

Cancer Predisposition Syndromes Associated With Pediatric High-Grade Gliomas.

Front Pediatr 2020 12;8:561487. Epub 2020 Nov 12.

Neurosurgery Unit, Department of Neurological and Psychiatric Sciences, Istituto di Ricovero e Cura a Carattere Scientifico Bambino Gesù Children's Hospital, Rome, Italy.

Pediatric High-Grade Gliomas (pHGG) are among the deadliest childhood brain tumors and can be associated with an underlying cancer predisposing syndrome. The thorough understanding of these syndromes can aid the clinician in their prompt recognition, leading to an informed genetic counseling for families and to a wider understanding of a specific genetic landscape of the tumor for target therapies. In this review, we summarize the main pHGG-associated cancer predisposing conditions, providing a guide for suspecting these syndromes and referring for genetic counseling.
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http://dx.doi.org/10.3389/fped.2020.561487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690624PMC
November 2020

Heterozygous Variants in KDM4B Lead to Global Developmental Delay and Neuroanatomical Defects.

Am J Hum Genet 2020 12 23;107(6):1170-1177. Epub 2020 Nov 23.

Division of Newborn Medicine, Department of Pediatrics, Boston Children's Hospital, Boston, MA 02115, USA; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA. Electronic address:

KDM4B is a lysine-specific demethylase with a preferential activity on H3K9 tri/di-methylation (H3K9me3/2)-modified histones. H3K9 tri/di-demethylation is an important epigenetic mechanism responsible for silencing of gene expression in animal development and cancer. However, the role of KDM4B on human development is still poorly characterized. Through international data sharing, we gathered a cohort of nine individuals with mono-allelic de novo or inherited variants in KDM4B. All individuals presented with dysmorphic features and global developmental delay (GDD) with language and motor skills most affected. Three individuals had a history of seizures, and four had anomalies on brain imaging ranging from agenesis of the corpus callosum with hydrocephalus to cystic formations, abnormal hippocampi, and polymicrogyria. In mice, lysine demethylase 4B is expressed during brain development with high levels in the hippocampus, a region important for learning and memory. To understand how KDM4B variants can lead to GDD in humans, we assessed the effect of KDM4B disruption on brain anatomy and behavior through an in vivo heterozygous mouse model (Kdm4b), focusing on neuroanatomical changes. In mutant mice, the total brain volume was significantly reduced with decreased size of the hippocampal dentate gyrus, partial agenesis of the corpus callosum, and ventriculomegaly. This report demonstrates that variants in KDM4B are associated with GDD/ intellectual disability and neuroanatomical defects. Our findings suggest that KDM4B variation leads to a chromatinopathy, broadening the spectrum of this group of Mendelian disorders caused by alterations in epigenetic machinery.
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http://dx.doi.org/10.1016/j.ajhg.2020.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820620PMC
December 2020

Cancer Predisposition Syndromes and Medulloblastoma in the Molecular Era.

Front Oncol 2020 29;10:566822. Epub 2020 Oct 29.

Department of Hematology/Oncology, Cell and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Medulloblastoma is the most common malignant brain tumor in children. In addition to sporadic cases, medulloblastoma may occur in association with cancer predisposition syndromes. This review aims to provide a complete description of inherited cancer syndromes associated with medulloblastoma. We examine their epidemiological, clinical, genetic, and diagnostic features and therapeutic approaches, including their correlation with medulloblastoma. Furthermore, according to the most recent molecular advances, we describe the association between the various molecular subgroups of medulloblastoma and each cancer predisposition syndrome. Knowledge of the aforementioned conditions can guide pediatric oncologists in performing adequate cancer surveillance. This will allow clinicians to promptly diagnose and treat medulloblastoma in syndromic children, forming a team with all specialists necessary for the correct management of the other various manifestations/symptoms related to the inherited cancer syndromes.
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http://dx.doi.org/10.3389/fonc.2020.566822DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658916PMC
October 2020

YIF1B mutations cause a post-natal neurodevelopmental syndrome associated with Golgi and primary cilium alterations.

Brain 2020 10;143(10):2911-2928

King Faisal Specialist Hospital and Research Center, Developmental Genetics Unit, Riyadh 11211, Saudi Arabia.

Human post-natal neurodevelopmental delay is often associated with cerebral alterations that can lead, by themselves or associated with peripheral deficits, to premature death. Here, we report the clinical features of 10 patients from six independent families with mutations in the autosomal YIF1B gene encoding a ubiquitous protein involved in anterograde traffic from the endoplasmic reticulum to the cell membrane, and in Golgi apparatus morphology. The patients displayed global developmental delay, motor delay, visual deficits with brain MRI evidence of ventricle enlargement, myelination alterations and cerebellar atrophy. A similar profile was observed in the Yif1b knockout (KO) mouse model developed to identify the cellular alterations involved in the clinical defects. In the CNS, mice lacking Yif1b displayed neuronal reduction, altered myelination of the motor cortex, cerebellar atrophy, enlargement of the ventricles, and subcellular alterations of endoplasmic reticulum and Golgi apparatus compartments. Remarkably, although YIF1B was not detected in primary cilia, biallelic YIF1B mutations caused primary cilia abnormalities in skin fibroblasts from both patients and Yif1b-KO mice, and in ciliary architectural components in the Yif1b-KO brain. Consequently, our findings identify YIF1B as an essential gene in early post-natal development in human, and provide a new genetic target that should be tested in patients developing a neurodevelopmental delay during the first year of life. Thus, our work is the first description of a functional deficit linking Golgipathies and ciliopathies, diseases so far associated exclusively to mutations in genes coding for proteins expressed within the primary cilium or related ultrastructures. We therefore propose that these pathologies should be considered as belonging to a larger class of neurodevelopmental diseases depending on proteins involved in the trafficking of proteins towards specific cell membrane compartments.
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http://dx.doi.org/10.1093/brain/awaa235DOI Listing
October 2020

Correspondence on "Pathogenic variants in USP7 cause a neurodevelopmental disorder with speech delays, altered behavior, and neurologic anomalies" by Fountain et al.

Genet Med 2021 02 5;23(2):421-422. Epub 2020 Oct 5.

Department of Biomedical, Dental, Morphological and Functional Imaging Sciences, University of Messina, Messina, Italy.

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http://dx.doi.org/10.1038/s41436-020-00978-xDOI Listing
February 2021

COVID-19 and Genetic Variants of Protein Involved in the SARS-CoV-2 Entry into the Host Cells.

Genes (Basel) 2020 08 27;11(9). Epub 2020 Aug 27.

Department of Biomedicine and Prevention, Tor Vergata University Hospital, 00133 Rome, Italy.

The recent global COVID-19 public health emergency is caused by SARS-CoV-2 infections and can manifest extremely variable clinical symptoms. Host human genetic variability could influence susceptibility and response to infection. It is known that ACE2 acts as a receptor for this pathogen, but the viral entry into the target cell also depends on other proteins. The aim of this study was to investigate the variability of genes coding for these proteins involved in the SARS-CoV-2 entry into the cells. We analyzed 131 COVID-19 patients by exome sequencing and examined the genetic variants of and genes. In total we identified seventeen variants. In gene, we observed a missense variant (c.893G>A) statistically more frequent compared to the EUR GnomAD reference population and a missense mutation (c.1906A>G) not found in the GnomAD database. In gene, we observed a significant difference in the frequency of c.331G>A, c.23G>T, and c.589G>A variant alleles in COVID-19 patients, compared to the corresponding allelic frequency in GnomAD. Genetic variants in these genes could influence the entry of the SARS-CoV-2. These data also support the hypothesis that host genetic variability may contribute to the variability in infection susceptibility and severity.
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http://dx.doi.org/10.3390/genes11091010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565048PMC
August 2020

Low-Grade Gliomas in Patients with Noonan Syndrome: Case-Based Review of the Literature.

Diagnostics (Basel) 2020 Aug 12;10(8). Epub 2020 Aug 12.

Department of Paediatric Haematology/Oncology, Cell and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy.

Noonan syndrome (NS) is a congenital autosomic dominant condition characterized by a variable spectrum from a clinical and genetical point of view. Germline mutations in more than ten genes involved in RAS-MAPK signal pathway have been demonstrated to cause the disease. An higher risk for leukemia and solid malignancies, including brain tumors, is related to NS. A review of the published literature concerning low grade gliomas (LGGs) in NS is presented. We described also a 13-year-old girl with NS associated with a recurrent mutation in , who developed three different types of brain tumors, i.e., an optic pathway glioma, a glioneuronal neoplasm of the left temporal lobe and a cerebellar pilocytic astrocytoma. Molecular characterization of the glioneuronal tumor allowed to detect high levels of phosphorylated MTOR (pMTOR); therefore, a therapeutic approach based on an mTOR inhibitor (everolimus) was elected. The treatment was well tolerated and proved to be effective, leading to a stabilization of the tumor, which was surgical removed. The positive outcome of the present case suggests considering this approach for patients with RASopathies and brain tumors with hyperactivated MTOR signaling.
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http://dx.doi.org/10.3390/diagnostics10080582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460327PMC
August 2020

Episignatures Stratifying Helsmoortel-Van Der Aa Syndrome Show Modest Correlation with Phenotype.

Am J Hum Genet 2020 09 5;107(3):555-563. Epub 2020 Aug 5.

Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address:

Helsmoortel-Van der Aa syndrome (HVDAS) is a neurodevelopmental condition associated with intellectual disability/developmental delay, autism spectrum disorder, and multiple medical comorbidities. HVDAS is caused by mutations in activity-dependent neuroprotective protein (ADNP). A recent study identified genome-wide DNA methylation changes in 22 individuals with HVDAS, adding to the group of neurodevelopmental disorders with an epigenetic signature. This methylation signature segregated those with HVDAS into two groups based on the location of the mutations. Here, we conducted an independent study on 24 individuals with HVDAS and replicated the existence of the two mutation-dependent episignatures. To probe whether the two distinct episignatures correlate with clinical outcomes, we used deep behavioral and neurobiological data from two prospective cohorts of individuals with a genetic diagnosis of HVDAS. We found limited phenotypic differences between the two HVDAS-affected groups and no evidence that individuals with more widespread methylation changes are more severely affected. Moreover, in spite of the methylation changes, we observed no profound alterations in the blood transcriptome of individuals with HVDAS. Our data warrant caution in harnessing methylation signatures in HVDAS as a tool for clinical stratification, at least with regard to behavioral phenotypes.
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http://dx.doi.org/10.1016/j.ajhg.2020.07.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477006PMC
September 2020

Biallelic mutations in the gene cause a novel primary ciliopathy.

J Med Genet 2021 Aug 3;58(8):526-533. Epub 2020 Aug 3.

Clinical Genetics Unit, Department of Women's and Children's Health, University of Padova, Padova, Italy

Background: Dysfunction in non-motile cilia is associated with a broad spectrum of developmental disorders characterised by clinical heterogeneity. While over 100 genes have been associated with primary ciliopathies, with wide phenotypic overlap, some patients still lack a molecular diagnosis.

Objective: To investigate and functionally characterise the molecular cause of a malformation disorder observed in two sibling fetuses characterised by microphthalmia, cleft lip and palate, and brain anomalies.

Methods: A trio-based whole exome sequencing (WES) strategy was used to identify candidate variants in the gene. In silico, in vitro and in vivo () studies were carried out to explore the impact of mutations on protein structure and function, and relevant biological processes.

Results: encodes a member of the Crescerin1 family of proteins regulating microtubule dynamics. Its orthologue in , , is expressed in a subset of sensory neurons and localises in the dendritic cilium where it is required for chemosensation. Nematode lines harbouring the corresponding missense variant in were generated by CRISPR/Cas9 technology. Although chemotaxis ability on a NaCl gradient was not affected, point mutants displayed impaired lipophilic dye uptake, with shorter and altered cilia in sensory neurons. Finally, in vitro analysis of microtubule polymerisation in the presence of wild-type or mutant TOG2 domain revealed a faster polymerisation associated with the mutant protein, suggesting aberrant tubulin binding.

Conclusions: Our data are in favour of a causative role of variants in the pathogenesis of this novel disorder, connecting this gene with primary ciliopathy.
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http://dx.doi.org/10.1136/jmedgenet-2020-106833DOI Listing
August 2021

Microcephalic osteodysplastic primordial dwarfism type II and pachygyria: Morphometric analysis in a 2-year-old girl.

Am J Med Genet A 2020 10 3;182(10):2372-2376. Epub 2020 Aug 3.

Medical Physics Department, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Microcephalic osteodysplastic primordial dwarfism (MOPD) type II is a rare disorder characterized by skeletal dysplasia, severe proportionate short stature, insulin resistance and cerebrovascular abnormalities including cerebral aneurysms and moyamoya disease. MOPD type II is caused by mutations in the pericentrin (PCNT) gene, which encodes a protein involved in centrosomes function. We report a 2 year old girl affected by MOPD type II caused by two compound heterozygous loss-of-function variants in PCNT gene, of which one is a novel variant (c.5304delT; p.Gly1769AlafsTer34). The patient presented atypical brain magnetic resonance imaging (MRI) findings consistent with pachygyria. This was confirmed by morphometric analysis of cortical thickness (CT) and gyrification index by comparing MRI data of the patient with a group of eight age-matched healthy controls. The statistical analysis revealed a significant and diffuse increase of CT with an anterior-predominant pattern and diffuse reduced gyrification (p < .05). These findings provide new evidences to the emergent concept that malformations of cortical development are complex disorders and that new genetic findings contribute to the fading of classification borders.
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http://dx.doi.org/10.1002/ajmg.a.61771DOI Listing
October 2020
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