Publications by authors named "Antonio Novelli"

204 Publications

Establishment and Characterization of a Cell Line (S-RMS1) Derived from an Infantile Spindle Cell Rhabdomyosarcoma with Fusion Transcript.

Int J Mol Sci 2021 May 22;22(11). Epub 2021 May 22.

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

: Spindle cell rhabdomyosarcoma (S-RMS) is a rare tumor that was previously considered as an uncommon variant of embryonal RMS (ERMS) and recently reclassified as a distinct RMS subtype with NCOA2, NCOA1, and VGLL2 fusion genes. In this study, we established a cell line (S-RMS1) derived from a four-month-old boy with infantile spindle cell RMS harboring gene fusion. : Morphological and molecular characteristics of S-RMS1 were analyzed and compared with two RMS cell lines, RH30 and RD18. Whole genome sequencing of S-RMS1 and clinical exome sequencing of genomic DNA were performed. : S-RMS1 showed cells small in size, with a fibroblast-like morphology and positivity for MyoD-1, myogenin, desmin, and smooth muscle actin. The population doubling time was 3.7 days. Whole genome sequencing demonstrated that S-RMS1 retained the same genetic profile of the tumor at diagnosis. A Western blot analysis showed downregulation of AKT-p and YAP-p while RT-qPCR showed upregulation of endoglin and GATA6 as well as downregulation of TGFßR1 and Mef2C transcripts. : This is the first report of the establishment of a cell line from an infantile spindle cell RMS with SRF-NCOA2 gene fusion. S-RMS1 should represent a useful tool for the molecular characterization of this rare and almost unknown tumor.
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http://dx.doi.org/10.3390/ijms22115484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196948PMC
May 2021

Cognitive and Adaptive Characterization of Children and Adolescents with KBG Syndrome: An Explorative Study.

J Clin Med 2021 Apr 6;10(7). Epub 2021 Apr 6.

Department of Neuroscience, Child and Adolescent Psychiatry Unit, Bambino Gesù Children's Hospital, IRCCS, 00146 Rome, Italy.

KBG syndrome (KBGS) is a rare Mendelian condition caused by heterozygous mutations in or microdeletions in chromosome 16q24.3 encompassing the gene. KBGS is clinically variable, which makes its diagnosis difficult in a significant proportion of cases. The present study aims at delineating the cognitive profile and adaptive functioning of children and adolescents with KBGS. Twenty-four Italian KBGS with a confirmed diagnosis by molecular testing of the causative gene were recruited to define both cognitive profile as measured by the Wechsler Intelligence Scale and adaptive functioning as measured by Vineland Adaptive Behavior Scales-II Edition or the Adaptive Behavior Assessment System-II Edition. Among children and adolescents, 17 showed intellectual disability, six presented borderline intellectual functioning and only one child did not show cognitive defects. Concerning cognitive profile, results revealed significant differences between the four indexes of Wechsler Intelligence Scale. Namely, the verbal comprehension index was significantly higher than the perceptual reasoning index, working memory index and the processing speed index. Concerning adaptive functioning, no difference between the domains was found. In conclusion, in our cohort, a heterogeneous profile has been documented in cognitive profiles, with a spike on verbal comprehension, while a flat-trend has emerged in adaptive functioning. Our cognitive and adaptive characterization drives professionals to set the best clinical supports, capturing the complexity and heterogeneity of this rare condition.
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http://dx.doi.org/10.3390/jcm10071523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038739PMC
April 2021

Severe herpes virus 6 interstitial pneumonia in an infant with three variants in genes predisposing to lung disease.

J Med Virol 2021 Apr 14. Epub 2021 Apr 14.

Neonatal Intensive Care Unit, Department of Medical and Surgical Neonatology, "Bambino Gesù" Children's Hospital IRCCS, Rome, Italy.

Infections due to human herpesvirus 6 (HHV-6) are frequent during early childhood. Usually, they have a favorable clinical course. Conversely, HHV-6 congenital infections occur in about 1% of neonates and may present with more severe clinical pictures. HHV-6 can be found in lung tissues and bronchoalveolar lavage (BAL) samples from patients with pneumonia and in immunocompromised patients can cause mild to severe pneumonia. In neonates, the role of HHV-6 in the genesis of severe pneumonia is poorly defined still now. We describe a healthy infant with a late-onset (15 days of life) severe interstitial pneumonia and heavy HHV-6 genome load, persistently detected in its BAL fluid. The baby underwent high-frequency oscillatory ventilation, hydroxychloroquine, steroids, and ganciclovir for 6 weeks and at 9 months she died. Next-generation sequencing of genes known to cause neonatal respiratory insufficiency revealed the presence of a "probably pathogenetic" heterozygous variant in the autosomal recessive DRC1 gene, a heterozygous variant of unknown significance (VUS) in the autosomal recessive RSPH9 gene, and a heterozygous VUS in the autosomal recessive MUC5B gene. HHV-6 infection should be considered in the differential diagnosis of late-onset severe respiratory distress in neonates and the co-occurrence of genetic predisposing factors or modifiers should be tested by specific molecular techniques. The intensity of HHV-6 genome load in BAL fluid could be an indicator of the response to antiviral therapy.
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http://dx.doi.org/10.1002/jmv.27016DOI Listing
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

Remember friedreich ataxia even in a toddler with apparently isolated dilated (not hypertrophic!) cardiomyopathy: revisited.

Minerva Pediatr (Torino) 2021 Apr 2. Epub 2021 Apr 2.

European Reference Network for rare, low prevalence and complex diseases of the heart - ERN GUARD-Heart HCP, Pediatric Cardiology and Arrhythmia/Syncope Units, Bambino Gesù Children Hospital and Research Institute, Rome, Italy -

Background: Friedreich Ataxia (FRDA) is the most common form of ataxia in late childhood. Neurological manifestations often precede cardiac involvement, presenting mainly as hypertrophic cardiomyopathy.

Methods: We describe a toddler with apparently isolated severe heart failure, successfully managed with heart transplant (HT). Although well described in adolescents and adults, onset of FRDA is very uncommon in toddlers and neurological ataxic features are predominant. The presenting symptom of cardiomyopathy is very rare. Similar history is rarely reported in literature, that we described, including an aggressive cardiomyopathy in children younger than 5years-old.

Results: Our patient was diagnosed with FRDA at a postoperative stage due to minimal neurological manifestations. Moreover, the novelty of this study lies in demonstrating a major DNA triplet repeat expansion in skeletal muscle compared to DNA from peripheral blood leukocytes. These results support the concept that triplet repeat expansion is variable among different tissues in FRDA, and in our case it was more expanded in the post mitotic muscular tissue than in blood cells.

Conclusions: We believe on the importance of taking in consideration this rare condition even in a toddler with apparently isolated cardiomyopathy and especially when conventional investigations give negative results. We discuss potential trigger effect of heart transplant as a precipitating factor in manifesting neurological symptoms. This observation corresponds to our experience and relates to three patients described so far (the third patient died suddenly). Early onset cardiomyopathy with FRDA should increase awareness of this rare condition and we highlight HT successful outcome. Further reports are needed to delineate this rare condition in youngsters.
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http://dx.doi.org/10.23736/S2724-5276.21.05969-3DOI Listing
April 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

First prenatal case of Noonan syndrome with SOS2 mutation: Implications of early diagnosis for genetic counseling.

Am J Med Genet A 2021 06 22;185(6):1897-1902. Epub 2021 Mar 22.

Medical Genetics Unit, Department of Human Reproductive Medicine, ASL Bari, Bari, Italy.

RASopathies are a group of syndromes with partially overlapping clinical features caused by germline mutations of the RAS/MAPK signaling pathway genes. The most common disorder is Noonan syndrome (NS; MIM 163950). We report the first prenatal case of NS with SOS2 (NM_006939.4) mutation in a euploid fetus with a severe increase in nuchal translucency (NT > 12 mm). Trio-based custom next-generation sequencing detected a de novo heterozygous missense mutation in the SOS2 gene: c.800 T > A (p.Met267Lys). Owing to the marked variable expressivity of NS and the scarcity of SOS2 mutation-related NS cases reported in the literature, it is difficult to provide appropriate genetic counseling. Several issues such as the best management technique and optimal NT cutoff have been discussed. In addition, in general, the fine balance between the advantages of an early prenatal diagnosis and the challenge of determining if the detected gene variant is pathogenic and, primarily, the stress of the counselees when providing a genetic counseling with limited information on the prenatal phenotype have been discussed. A prenatal path comprising examinations and multidisciplinary counseling is essential to support couples in a shared decision-making process.
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http://dx.doi.org/10.1002/ajmg.a.62180DOI Listing
June 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

Gene Set Enrichment Analysis of Interaction Networks Weighted by Node Centrality.

Front Genet 2021 24;12:577623. Epub 2021 Feb 24.

Department of Science and High Technology, Center of Bioinformatics, University of Insubria, Busto Arsizio, Italy.

Gene set enrichment analysis (GSEA) is a powerful tool to associate a disease phenotype to a group of genes/proteins. GSEA attributes a specific weight to each gene/protein in the input list that depends on a metric of choice, which is usually represented by quantitative expression data. However, expression data are not always available. Here, GSEA based on betweenness centrality of a protein-protein interaction (PPI) network is described and applied to two cases, where an expression metric is missing. First, personalized PPI networks were generated from genes displaying alterations (assessed by array comparative genomic hybridization and whole exome sequencing) in four probands bearing a 16p13.11 microdeletion in common and several other point variants. Patients showed disease phenotypes linked to neurodevelopment. All networks were assembled around a cluster of first interactors of altered genes with high betweenness centrality. All four clusters included genes known to be involved in neurodevelopmental disorders with different centrality. Moreover, the GSEA results pointed out to the evidence of "cell cycle" among enriched pathways. Second, a large interaction network obtained by merging proteomics studies on three neurodegenerative disorders was analyzed from the topological point of view. We observed that most central proteins are often linked to Parkinson's disease. The selection of these proteins improved the specificity of GSEA, with "Metabolism of amino acids and derivatives" and "Cellular response to stress or external stimuli" as top-ranked enriched pathways. In conclusion, betweenness centrality revealed to be a suitable metric for GSEA. Thus, centrality-based GSEA represents an opportunity for precision medicine and network medicine.
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http://dx.doi.org/10.3389/fgene.2021.577623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943873PMC
February 2021

A New Intronic Variant in ECEL1 in Two Patients with Distal Arthrogryposis Type 5D.

Int J Mol Sci 2021 Feb 20;22(4). Epub 2021 Feb 20.

Department of Medical Sciences and Public Health, University of Cagliari, 09124 Cagliari, Italy.

Distal Arthrogryposis type 5D (DA5D) is characterized by congenital contractures involving the distal joints, short stature, scoliosis, ptosis, astigmatism, and dysmorphic features. It is inherited in an autosomal recessive manner, and it is a result of homozygous or compound heterozygous variants in the ECEL1 gene. Here, we report two patients of Sardinian origin harboring a new intronic homozygous variant in ECEL1 (c.1507-9G>A), which was predicted to affect mRNA splicing by activating a cryptic acceptor site. The frequency of the variant is very low in the general human population, and its presence in our families can be attributed to a founder effect. This study provides an updated review of the known causative mutations of the ECEL1 gene, enriching the allelic spectrum to include the noncoding sequence.
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http://dx.doi.org/10.3390/ijms22042106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924324PMC
February 2021

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

Genet Med 2021 Jun 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

Differences between transient neonatal diabetes mellitus subtypes can guide diagnosis and therapy.

Eur J Endocrinol 2021 Apr;184(4):575-585

Department of Pediatrics, University of Rome Sapienza, Rome, Italy.

Objective: Transient neonatal diabetes mellitus (TNDM) is caused by activating mutations in ABCC8 and KCNJ11 genes (KATP/TNDM) or by chromosome 6q24 abnormalities (6q24/TNDM). We wanted to assess whether these different genetic aetiologies result in distinct clinical features.

Design: Retrospective analysis of the Italian data set of patients with TNDM.

Methods: Clinical features and treatment of 22 KATP/TNDM patients and 12 6q24/TNDM patients were compared.

Results: Fourteen KATP/TNDM probands had a carrier parent with abnormal glucose values, four patients with 6q24 showed macroglossia and/or umbilical hernia. Median age at diabetes onset and birth weight were lower in patients with 6q24 (1 week; -2.27 SD) than those with KATP mutations (4.0 weeks; -1.04 SD) (P = 0.009 and P = 0.007, respectively). Median time to remission was longer in KATP/TNDM than 6q24/TNDM (21.5 weeks vs 12 weeks) (P = 0.002). Two KATP/TNDM patients entered diabetes remission without pharmacological therapy. A proband with the ABCC8/L225P variant previously associated with permanent neonatal diabetes entered 7-year long remission after 1 year of sulfonylurea therapy. Seven diabetic individuals with KATP mutations were successfully treated with sulfonylurea monotherapy; four cases with relapsing 6q24/TNDM were treated with insulin, metformin or combination therapy.

Conclusions: If TNDM is suspected, KATP genes should be analyzed first with the exception of patients with macroglossia and/or umbilical hernia. Remission of diabetes without pharmacological therapy should not preclude genetic analysis. Early treatment with sulfonylurea may induce long-lasting remission of diabetes in patients with KATP mutations associated with PNDM. Adult patients carrying KATP/TNDM mutations respond favourably to sulfonylurea monotherapy.
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http://dx.doi.org/10.1530/EJE-20-1030DOI 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

Facial Dysmorphisms, Macrodontia, Focal Epilepsy, and Thinning of the Corpus Callosum: A Rare Mild Form of Kabuki Syndrome.

J Pediatr Genet 2021 Mar 17;10(1):49-52. Epub 2020 Feb 17.

Pediatric Unit, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy.

Kabuki syndrome (KS) is a rare genetic condition with multiple congenital abnormalities and developmental delay. The cardinal manifestations of KS include characteristic facial features, intellectual disability, skeletal defects, dermatoglyphic abnormalities, and postnatal growth deficiencies. Cardiac and urological malformations are commonly present in patient with KS, as well as language deficits and immunological abnormalities. Here, we reported a case of a child with an atypical form of KS, associated with macrodontia, corpus callosum dysmorphism, focal epilepsy responsive to antiepileptic treatment, and a novel gene missense variant, c.2413C > T, never reported to date.
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http://dx.doi.org/10.1055/s-0040-1701645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7853907PMC
March 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

Autism and severe clinical phenotype in a patient with 8p21.2p11.21 deletion: Case report and literature review.

Clin Case Rep 2021 Jan 12;9(1):314-321. Epub 2020 Nov 12.

Victor Babes National Institute of Pathology Bucharest Romania.

Interstitial 8p deletions were previously described, in literature and databases, in approximately 30 patients with neurodevelopmental disorders. We report on a novel patient with a 8p21.2p11.21 deletion presenting a clinical phenotype that includes severe intellectual disability, microcephaly, epilepsy, and autism, the latter having been rarely associated with this genetic defect.
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http://dx.doi.org/10.1002/ccr3.3523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7813129PMC
January 2021

Cytogenetics and Molecular Investigations detect a Mosaic Variant of Turner Syndrome only Suspected by Non-Invasive Prenatal Testing: Two Case Reports with Negative Ultrasound Examinations.

J Med Life 2020 Oct-Dec;13(4):624-628

Department of Prenatal Diagnosis, Altamedica Fetal Medical Centre, Rome, Italy.

Prenatal testing has been moving towards non-invasive methods to determine fetal risk for genetic disorders. Numerous studies have focused the attention on common trisomies; although the detection rate (DR) for trisomy 21 is high (over 95%), the accuracy regarding the DR for trisomies 13 and 18 has come under scrutiny. The testing has been applied to sex chromosome aneuploidies, but many studies have shown that it is not as effective as it is for common trisomies. Although non-invasive prenatal test (NIPT) has become a standard screening procedure for all pregnant women, invasive sampling procedures remain important in confirming NIPT-positive findings. In the present study, we report discordant results of Turner syndrome (TS) mosaicism between NIPT and karyotyping. A 35-year-old pregnant woman underwent NIPT, and a probable risk for Xp deletion was indicated. Subsequently, amniocentesis was performed. The karyotype was identified as mos 45,X [28]/46,X,i(X)(q1.0)[5]. In the second case, a 33-year-old woman underwent amniocentesis after a positive NIPT that indicated a probable risk for monosomy X. The result was mos 45,X [8]/46,XY[8]. Since NIPT is a screening test, the possibility of false-positive or false-negative results should always be considered. We underline the importance of pre/post detailed counseling. Furthermore, women with abnormal NIPT results should undergo immediate amniocentesis that remains the only tool for a correct diagnosis of sex chromosome aneuploidies.
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http://dx.doi.org/10.25122/jml-2020-0092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803325PMC
January 2021

Homozygous and Gene Variants in a Boy with Growth Hormone Deficiency and Early Onset Osteoporosis.

Int J Mol Sci 2021 Jan 13;22(2). Epub 2021 Jan 13.

Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children Hospital, IRCCS, 00146 Rome, Italy.

We report on a patient born to consanguineous parents, presenting with Growth Hormone Deficiency (GHD) and osteoporosis. SNP-array analysis and exome sequencing disclosed long contiguous stretches of homozygosity and two distinct homozygous variants in (Q6H) and (E1361K) genes. The variant was described as causative in a few subjects with an incompletely penetrant dominant form of combined pituitary hormone deficiency (CPHD). The variant is rare, and so far it has never been found in a homozygous form. Segregation analysis showed that both variants were inherited from heterozygous unaffected parents. Present results further elucidate the inheritance pattern of variants and recommend assessing the clinical impact of variants located in C-terminal propeptide of gene for their potential association with rare recessive and early onset forms of osteoporosis.
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http://dx.doi.org/10.3390/ijms22020750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828579PMC
January 2021

Clinical and molecular characterizations of 11 new patients with type 1 Feingold syndrome: Proposal for selecting diagnostic criteria and further genetic testing in patients with severe phenotype.

Am J Med Genet A 2021 04 14;185(4):1204-1210. Epub 2021 Jan 14.

Medical Genetics Unit, Santa Maria della Misericordia Hospital and University of Perugia, Perugia, Italy.

Feingold Syndrome type 1 (FS1) is an autosomal dominant disorder due to a loss of function mutations in the MYCN gene. FS1 is generally clinically characterized by mild learning disability, microcephaly, short palpebral fissures, short stature, brachymesophalangy, hypoplastic thumbs, as well as syndactyly of toes, variably associated with organ abnormalities, the most common being gastrointestinal atresia. In current literature, more than 120 FS1 patients have been described, but diagnostic criteria are not well agreed upon, likewise the genotype-phenotype correlations are not well understood. Here, we describe 11 FS1 patients, belonging to six distinct families, where we have identified three novel MYCN mutations along with three pathogenetic variants, the latter which have already been reported. Several patients presented a mild phenotype of the condition and they have been diagnosed as being affected only after segregation analyses of the MYCN mutation identified in the propositus. We also describe here the first ever FS1 patient with severe intellectual disability having a maternally inherited MYCN variant together with an additional GNAO1 mutation inherited paternally. Mutations in the GNAO1 gene are associated with a specific form of intellectual disability and epilepsy, thus the finding of two different rare diseases in the same patient could explain his severe phenotype. Therein, a thorough investigation is merited into the possibility that additional variants in patients with a MYCN mutation and severe phenotype do exist. Finally, in order to guarantee a more reliable diagnosis of FS1, we suggest using both major and minor clinical-molecular diagnostic criteria.
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http://dx.doi.org/10.1002/ajmg.a.62068DOI Listing
April 2021

Clinical Application of Easychip 8x15K Platform in 4106 Pregnancies Without Ultrasound Anomalies.

Reprod Sci 2021 04 6;28(4):1142-1149. Epub 2021 Jan 6.

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

Clinical utility of Array-CGH Easychip 8x15K platform can be assessed by testing its ability to detect the occurrence of pathogenic copy number variants (CNVs), and occurrence of variants of uncertain significance (VoUS) in pregnancies without structural fetal malformations. The demand of chromosomal microarray analysis in prenatal diagnosis is progressively increasing in uneventful pregnancies. However, depending on such platform resolution, a genome-wide approach also provides a high risk of detecting VoUS and incidental finding (IF) also defined as "toxic findings." In this context, novel alternative strategies in probe design and data filtering are required to balance the detection of disease causing CNVs and the occurrence of unwanted findings. In a cohort of consecutive pregnancies without ultrasound anomalies, a total of 4106 DNA samples from cultured and uncultured amniotic fluid or chorionic villi were collected and analyzed by a previously designed Array-CGH mixed-resolution custom platform, which is able to detect pathogenic CNVs and structural imbalanced rearrangements limiting the identification of VoUS and IF. Pathogenic CNVs were identified in 88 samples (2.1%), 19 of which (0.5%) were undetectable by standard karyotype. VoUS accounted for 0.6% of cases. Our data confirm that a mixed-resolution and targeted array CGH platform, as Easychip 8x15K, yields a similar detection rate of higher resolution CMA platforms and reduces the occurrence of "toxic findings," hence making it eligible for a first-tier genetic test in pregnancies without ultrasound anomalies.
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http://dx.doi.org/10.1007/s43032-020-00419-9DOI Listing
April 2021

Biallelic variants in cause a severe neurodevelopmental disorder with microcephaly, bilateral cataract, epilepsy and simplified gyration.

J Med Genet 2021 Jan 4. Epub 2021 Jan 4.

Medical Genetics Laboratory, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Background: Next-generation sequencing, combined with international pooling of cases, has impressively enhanced the discovery of genes responsible for Mendelian neurodevelopmental disorders, particularly in individuals affected by clinically undiagnosed diseases. To date, biallelic missense variants in gene, encoding a Krüppel-type zinc-finger protein, have been reported in three families with non-syndromic intellectual disability.

Methods: Here, we describe five individuals from four unrelated families with an undiagnosed neurodevelopmental disorder in which we performed exome sequencing, on a combination of trio-based (4 subjects) or single probands (1 subject).

Results: We identified five patients from four unrelated families with homozygous variants by whole exome sequencing. Four had variants resulting in truncation of ZNF526; they were affected by severe prenatal and postnatal microcephaly (ranging from -4 SD to -8 SD), profound psychomotor delay, hypertonic-dystonic movements, epilepsy and simplified gyral pattern on MRI. All of them also displayed bilateral progressive cataracts. A fifth patient had a homozygous missense variant and a slightly less severe disorder, with postnatal microcephaly (-2 SD), progressive bilateral cataracts, severe intellectual disability and unremarkable brain MRI.Mutant zebrafish larvae had notable malformations of the eye and central nervous system, resembling findings seen in the human holoprosencephaly spectrum.

Conclusion: Our findings support the role of biallelic variants in a complex neurodevelopmental disorder, primarily affecting brain and eyes, resulting in severe microcephaly, simplified gyral pattern, epileptic encephalopathy and bilateral cataracts.
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http://dx.doi.org/10.1136/jmedgenet-2020-107430DOI Listing
January 2021

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

Clin Genet 2021 Apr 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

When embryology meets genetics: the definition of developmentally incompetent preimplantation embryos (DIPE)-the consensus of two Italian scientific societies.

J Assist Reprod Genet 2021 Feb 24;38(2):319-331. Epub 2020 Nov 24.

Clinical Genetics Units, University Hospital of Padova, Padova, Italy.

A clear definition of developmentally incompetent preimplantation embryo (DIPE) in literature is still missing, while several scientific societies are discussing this challenging topic. From both a clinical and scientific perspective, the identification of embryos unfit for reproductive purpose is crucial. This aim should be pursued in light of all diagnostic technologies for embryo evaluation, encompassing also genetic analyses, of recent implementation in IVF. The Italian context is characterized by an unusual scenario: embryos can be discarded only if not viable and cannot be used for research purposes either. Therefore, thousands of embryos, diagnosed as affected and/or aneuploid as resulting from preimplantation genetic testing (PGT) and clinically not utilizable, are cryopreserved and stored indefinitely, with important psychological, legal, and financial implications. With the aim of updating the definition of DIPE, also on the basis of the embryo genetic status, the Italian Society of Embryology, Reproduction and Research (SIERR) and the Italian Society of Human Genetic (SIGU) reviewed the literature on this topic, found a consensus, and produced a list of relevant criteria.
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http://dx.doi.org/10.1007/s10815-020-02015-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884494PMC
February 2021

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

Recurrent prenatal PIEZO1-related lymphatic dysplasia: Expanding molecular and ultrasound findings.

Eur J Med Genet 2021 Jan 20;64(1):104106. Epub 2020 Nov 20.

Department of Experimental Medicine, Sapienza University of Rome, Policlinico Umberto I Hospital, Rome, Italy.

Generalized lymphatic dysplasia (GLD), characterized by lymphedema, lymphangiectasias, chylothorax, effusions, represents a recognized cause of fetal hydrops. We describe for the first time recurrent pregnancies showing different ultrasound presentations of lymphatic dysplasia. The first fetus displayed diffuse subcutaneous cysts and septations while the second one presented fetal hydrops. Exome sequencing results at 18 gestational weeks in the second pregnancy showed compound heterozygosity for two novel PIEZO1 variants, afterwards detected also in the first fetus and in the heterozygous parents. Both ultrasound and genetic findings expand the current knowledge of PIEZO1-related GLD. We suggest exome sequencing in hydropic fetuses with normal cytogenetics and in pregnancies with recurrent hydrops/lymphatic dysplasia.
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http://dx.doi.org/10.1016/j.ejmg.2020.104106DOI Listing
January 2021

Deficiency Causing Dysregulation of NK Cell Functions and Presenting With Hemophagocytic Lymphohistiocytosis.

Front Genet 2020 18;11:937. Epub 2020 Sep 18.

Division of Rheumatology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

We describe a 2 year old boy with two previously undescribed frameshift mutations in the interferon (IFN)α/β receptor 2 () gene presenting with hemophagocytic lymphohistiocytosis (HLH) following measles-mumps-rubella vaccination. Functional analyses show the absence of response to type I IFN in the patient's cells, as revealed by the lack of phosphorylation of STAT1 and the lack of induction of interferon-stimulated genes upon stimulation with IFNα. HLH has been reported in patients with inborn errors of type I IFN-mediated immune responses following vaccination with live-attenuated viruses. The relation between HLH and defective type I IFN-mediated responses is unclear. We show that in patient's natural killer (NK) cells stimulated with IFNα the expected increase in degranulation and inhibition of IFNγ production were affected. These data support a role for NK cell function dysregulation and lack of inhibition of IFNγ production as contributors to the development of HLH in patients with impaired type I IFN signaling.
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http://dx.doi.org/10.3389/fgene.2020.00937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7531586PMC
September 2020

7q11.23 Microduplication Syndrome: Clinical and Neurobehavioral Profiling.

Brain Sci 2020 Nov 11;10(11). Epub 2020 Nov 11.

Child and Adolescent Neuropsychiatry Unit, Department of Neurological and Psychiatric Science, Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy.

7q11.23 Microduplication (dup7q11.23) syndrome is a rare autosomal dominant disorder due to a recurring 1.5 to 1.8 Mb duplication of the Williams-Beuren Syndrome critical region. Dup7q11.23 has been associated with several neuro-behavioral characteristics such as low cognitive and adaptive functioning, expressive language impairment, anxiety problems and autistic features. In the present study, we analyze the clinical features of ten individuals in which array-CGH detected dup7q11.23, spanning from 1.4 to 2.1 Mb. The clinical characteristics associated with dup7q11.23 are discussed with respect to its reciprocal deletion. Consistent with previous studies, we confirm that individuals with dup7q11.23 syndrome do not have a homogeneous clinical profile, although some recurring dysmorphic features were found, including macrocephaly, prominent forehead, elongated palpebral fissures, thin lip vermilion and microstomia. Minor congenital malformations include patent ductus arteriosus, cryptorchidism and pes planus. A common finding is hypotonia and joint laxity, resulting in mild motor delay. Neuropsychological and psychodiagnostic assessment confirm that mild cognitive impairment, expressive language deficits and anxiety are recurring neurobehavioral features. New insights into adaptive, psychopathological and neurodevelopmental profiles are discussed.
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http://dx.doi.org/10.3390/brainsci10110839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7697259PMC
November 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