Purpose AUTS2-related syndrome is characterized by developmental delay, autism spectrum disorder, and intellectual disability. From alternative promoters, AUTS2 encodes 2 distinct long and short isoforms encoding a putative transcriptional activator. Methods Through a European collaborative study, we collected clinical and genotype data on the largest AUTS2-related syndrome cohort of 58 patients harboring genomic rearrangements or single-nucleotide variants (SNVs). Results Pathogenic SNVs were recurrently found in individuals from different countries, suggesting mutational hotspots. Independent of the underlying defect at the AUTS2 locus, we observed that autistic behavior, hyperactivity, learning difficulties, and speech delay are common features of AUTS2-related syndrome. Among patients with SNVs, individuals carrying pathogenic variants affecting both longer and shorter AUTS2 transcripts showed a recognizable phenotype with microcephaly, brachycephaly, microretrognathia, broad nasal base, and anteverted nares. Behavioral disorders were more common in patients with variants affecting only the longer isoform. Arthrogryposis and stiff movements were only observed in patients with SNVs. Conclusion This study provides a comprehensive clinical characterization of AUTS2-related syndrome, reveals few genotype-phenotype correlations, and suggests that the disruption of the 2 distinct AUTS2 transcripts has a different impact on the clinical phenotype.

Following the publication of the above article, an interested reader drew the authors' attention to the fact that the CTK18 panel in Fig. 2E on p. 1917, showing the results of RT‑PCR analysis of cytokeratin 18 from patient no. 88, appeared to be very similar to the CTK18 panel in Fig. 2F (showing the results from patient no. 93). After having re‑examined their original data, which were also presented to the Editorial Office, and considering that the observed experiment is an end-point RT-PCR performed more than ten years ago, the authors cannot definitively rule out the possibility that Fig. 2E was inadvertently misassembled. Therefore, given the high similarity of the two images, it was decided to publish a revised version of Fig. 2, which now shows data from a different replicate of the experiment for the CTK18 panel in Fig. 2E, shown on the next page. Note that this revision did not affect the overall conclusions reported in the study. The authors are grateful to the Editor of International Journal of Oncology for allowing them this opportunity to publish a Corrigendum, and all the authors agree with its publication. Furthermore, the authors apologize to the readership for any inconvenience caused. [International Journal of Oncology 46: 1913‑1923, 2015; DOI: 10.3892/ijo.2015.2911].

Immunodeficiency, Centromeric instability and Facial anomalies (ICF) syndrome is a rare genetic disorder characterized by variable immunodeficiency. More than half of the affected individuals show mild to severe intellectual disability at early onset. This disorder is genetically heterogeneous and ZBTB24 is the causative gene of the subtype 2, accounting for about 30% of the ICF cases. ZBTB24 is a multifaceted transcription factor belonging to the Zinc-finger and BTB domain-containing protein family, which are key regulators of developmental processes. Aberrant DNA methylation is the main molecular hallmark of ICF syndrome. The functional link between ZBTB24 deficiency and DNA methylation errors is still elusive. Here, we generated a novel ICF2 disease model by deriving induced pluripotent stem cells (iPSCs) from peripheral CD34 + -blood cells of a patient homozygous for the p.Cys408Gly mutation, the most frequent missense mutation in ICF2 patients and which is associated with a broad clinical spectrum. The mutation affects a conserved cysteine of the ZBTB24 zinc-finger domain, perturbing its function as transcriptional activator. ICF2-iPSCs recapitulate the methylation defects associated with ZBTB24 deficiency, including centromeric hypomethylation. We validated that the mutated ZBTB24 protein loses its ability to directly activate expression of CDCA7 and other target genes in the patient-derived iPSCs. Upon hematopoietic differentiation, ICF2-iPSCs showed decreased vitality and a lower percentage of CD34 + /CD43 + /CD45 + progenitors. Overall, the ICF2-iPSC model is highly relevant to explore the role of ZBTB24 in DNA methylation homeostasis and provides a tool to investigate the early molecular events linking ZBTB24 deficiency to the ICF2 clinical phenotype.

Profilin 1—encoded by PFN1— is a small actin-binding protein with a tumour suppressive role in various adenocarcinomas and pagetic osteosarcomas. However, its contribution to tumour development is not fully understood. Using fix and live cell imaging, we report that Profilin 1 inactivation results in multiple mitotic defects, manifested prominently by anaphase bridges, multipolar spindles, misaligned and lagging chromosomes, and cytokinesis failures. Accordingly, next-generation sequencing technologies highlighted that Profilin 1 knock-out cells display extensive copy-number alterations, which are associated with complex genome rearrangements and chromothripsis events in primary pagetic osteosarcomas with Profilin 1 inactivation. Mechanistically, we show that Profilin 1 is recruited to the spindle midzone at anaphase, and its deficiency reduces the supply of actin filaments to the cleavage furrow during cytokinesis. The mitotic defects are also observed in mouse embryonic fibroblasts and mesenchymal cells deriving from a newly generated knock-in mouse model harbouring a Pfn1 loss-of-function mutation. Furthermore, nuclear atypia is also detected in histological sections of mutant femurs. Thus, our results indicate that Profilin 1 has a role in regulating cell division, and its inactivation triggers mitotic defects, one of the major mechanisms through which tumour cells acquire chromosomal instability.

(Abstracted from Prenat Diagn 2022;42:1575–1586 Methods for diagnosis of genetic abnormalities have recently undergone substantial improvement. Noninvasive prenatal testing (NIPT) is performed early in pregnancy, typically at the end of the first trimester using cell-free DNA (cfDNA) to identify 3 commonly occurring trisomies (13, 18, and 21).

Journal of Paediatrics and Child HealthVolume 57, Issue 3 p. 450-451 Images of the Month Peculiar footprints in a child with agenesis of corpus callosum Dr Gerarda Cappuccio, Dr Gerarda Cappuccio orcid.org/0000-0003-3934-2342 Department of Translational Medicine, Section of Paediatrics, Federico II University, Naples, Italy Telethon Institute of Genetics and Medicine, Naples, ItalySearch for more papers by this authorDr Rita Genesio, Dr Rita Genesio Department of Molecular Medicine and Medical Biotechnology, Federico II University, Naples, ItalySearch for more papers by this authorDr Piero Pignataro, Dr Piero Pignataro Department of Molecular Medicine and Medical Biotechnology, Federico II University, Naples, ItalySearch for more papers by this authorProfessor Nicola Brunetti-Pierri, Professor Nicola Brunetti-Pierri Department of Translational Medicine, Section of Paediatrics, Federico II University, Naples, Italy Telethon Institute of Genetics and Medicine, Naples, ItalySearch for more papers by this author Dr Gerarda Cappuccio, Dr Gerarda Cappuccio orcid.org/0000-0003-3934-2342 Department of Translational Medicine, Section of Paediatrics, Federico II University, Naples, Italy Telethon Institute of Genetics and Medicine, Naples, ItalySearch for more papers by this authorDr Rita Genesio, Dr Rita Genesio Department of Molecular Medicine and Medical Biotechnology, Federico II University, Naples, ItalySearch for more papers by this authorDr Piero Pignataro, Dr Piero Pignataro Department of Molecular Medicine and Medical Biotechnology, Federico II University, Naples, ItalySearch for more papers by this authorProfessor Nicola Brunetti-Pierri, Professor Nicola Brunetti-Pierri Department of Translational Medicine, Section of Paediatrics, Federico II University, Naples, Italy Telethon Institute of Genetics and Medicine, Naples, ItalySearch for more papers by this author First published: 17 March 2021 https://doi.org/10.1111/jpc.1_15176Read the full textAboutRelatedInformationPDFPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessClose modalShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume57, Issue3March 2021Pages 450-451 RelatedInformation RecommendedLate-onset Psychosis with Agenesis of the Corpus CallosumMitsuru Suzuki, Satoshi Kawamura, Harutomo Watanabe, Akio Sakai, PsychogeriatricsSonography of fetal agenesis of the corpus callosum: a survey of 35 casesG. Pilu, F. Sandri, A. Perolo, M. C. Pittalis, G. Grisolia, G. Cocchi, M. P. Foschini, G. P. Salvioli, L. Bovicelli, Ultrasound in Obstetrics & GynecologyBi-allelic KARS1 pathogenic variants affecting functions of cytosolic and mitochondrial isoforms are associated with a progressive and multisystem diseaseGerarda Cappuccio, Camilla Ceccatelli Berti, Enrico Baruffini, Jennifer Sullivan, Vandana Shashi, Tamison Jewett, Tara Stamper, Silvia Maitz, Francesco Canonico, Anya Revah-Politi, Gabriel S. Kupchik, Kwame Anyane-Yeboa, Vimla Aggarwal, Andreas Benneche, Eirik Bratland, Siren Berland, Felice D'Arco, Cesar A. Alves, Adeline Vanderver, Daniela Longo, Enrico Bertini, Annalaura Torella, Vincenzo Nigro, Telethon Undiagnosed Diseases Program, Alessandra D'Amico, Marjo S. van der Knaap, Paola Goffrini, Nicola Brunetti-Pierri, Human MutationAgenesis of the corpus callosum and macrocephaly in siblingsI. D. Young, J. Q. Trounce, M. I. Levene, J. S. Fitzsimmons, J. R. Moore, Clinical Genetics

Wolfram syndrome (WFS) is a rare autosomal recessive neurodegenerative disease whose diagnosis requires diabetes mellitus and optic atrophy (OA). WFS includes a wide spectrum of other possible complications such as diabetes insipidus, sensorineural deafness, urinary tract problems, neurological and psychiatric disorders. Most WFS patients show type 1 syndrome (WFS1) caused by mutations in the WFS1 gene, encoding Wolframin protein, while few patients are affected by WFS type 2 (WFS2) due to a pathogenetic variants in the CISD2 gene encoding an endoplasmic reticulum intermembrane small protein. WFS2 is considered a phenotypic and genotypic variant of WFS, from which differs only for the increased risk of bleeding and presence of peptic ulcers. OA and diabetes are considered cardinal features of WFS. We hereby report the ophthalmologic evaluation in a patient, previously described, with WFS2 after 8 years of follow-up. A 20-year-old white woman was referred to our retinal center for the first time in 2012 following a diagnosis of a novel intragenic exon 2 CISD2 homozygous deletion, for the suspicion of an associated bilateral OA. Fundus examination, spectral-domain optical coherence tomography, visual field, visual evoked potentials were performed and confirmed the presence of an optic neuropathy that remained stable over 8 years follow up. A slowly progressive optic neuropathy, rather than OA can characterize patients with WFS2 and CISD2 intragenic deletion.

Background: The presence of mitochondrial alterations in Down syndrome suggests that it might affect neuronal differentiation. We established a model of trisomic iPSCs, differentiating into neural precursor cells (NPCs) to monitor the occurrence of differentiation defects and mitochondrial dysfunction. Methods: Isogenic trisomic and euploid iPSCs were differentiated into NPCs in monolayer cultures using the dual-SMAD inhibition protocol. Expression of pluripotency and neural differentiation genes was assessed by qRT-PCR and immunofluorescence. Meta-analysis of expression data was performed on iPSCs. Mitochondrial Ca2+, reactive oxygen species (ROS) and ATP production were investigated using fluorescent probes. Oxygen consumption rate (OCR) was determined by Seahorse Analyzer. Results: NPCs at day 7 of induction uniformly expressed the differentiation markers PAX6, SOX2 and NESTIN but not the stemness marker OCT4. At day 21, trisomic NPCs expressed higher levels of typical glial differentiation genes. Expression profiles indicated that mitochondrial genes were dysregulated in trisomic iPSCs. Trisomic NPCs showed altered mitochondrial Ca2+, reduced OCR and ATP synthesis, and elevated ROS production. Conclusions: Human trisomic iPSCs can be rapidly and efficiently differentiated into NPC monolayers. The trisomic NPCs obtained exhibit greater glial-like differentiation potential than their euploid counterparts and manifest mitochondrial dysfunction as early as day 7 of neuronal differentiation.

Mitochondrial dysfunction plays a primary role in neurodevelopmental anomalies and neurodegeneration of Down syndrome (DS) subjects. For this reason, targeting mitochondrial key genes, such as PGC-1α/PPARGC1A, is emerging as a good therapeutic approach to attenuate cognitive disability in DS. After demonstrating the efficacy of the biguanide metformin (a PGC-1α activator) in a cell model of DS, we extended the study to other molecules that regulate the PGC-1α pathway acting on PPAR genes. We, therefore, treated trisomic fetal fibroblasts with different doses of pioglitazone (PGZ) and evaluated the effects on mitochondrial dynamics and function. Treatment with PGZ significantly increased mRNA and protein levels of PGC-1α. Mitochondrial network was fully restored by PGZ administration affecting the fission-fusion mitochondrial machinery. Specifically, optic atrophy 1 (OPA1) and mitofusin 1 (MFN1) were upregulated while dynamin-related protein 1 (DRP1) was downregulated. These effects, together with a significant increase of basal ATP content and oxygen consumption rate, and a significant decrease of reactive oxygen species (ROS) production, provide strong evidence of an overall improvement of mitochondria bioenergetics in trisomic cells. In conclusion, we demonstrate that PGZ is able to improve mitochondrial phenotype even at low concentrations (0.5 μM). We also speculate that a combination of drugs that target mitochondrial function might be advantageous, offering potentially higher efficacy and lower individual drug dosage.

We investigated the added value of combining information from direction-encoded color (DEC) maps with high-resolution structural magnetic resonance imaging scans (T1-weighted images [T1WIs]) to improve the identification of regions of interest (ROIs) for fiber tracking during preoperative planning for patients with brain tumors.The dataset included 42 patients with gliomas and 10 healthy subjects from the Human Connectome Project. For identification of the ROIs, we combined the structural information from high-resolution T1WIs and the directional information from DEC maps. To test our hypothesis, we examined the interrater and intrarater agreement.We identified specific ROIs to extract the main white matter bundles. The directional information from the DEC maps combined with the T1WIs (T1WI–DEC maps) had significantly facilitated ROI identification in patients with brain tumors, especially patients in whom the tracts had been displaced by the mass effect of the tumor. Fiber tracking using the combined T1WI–DEC maps showed significantly greater inter- and intrarater agreement compared with using either T1WI or DEC maps alone.Combining the information from diffusion-derived color-encoded maps with high-resolution anatomical details from structural imaging (T1WI–DEC map), especially in patients with brain tumors, could be useful for accurate identification of the ROIs.

Mitochondria are organelles that mainly control energy conversion in the cell. In addition, they also participate in many relevant activities, such as the regulation of apoptosis and calcium levels, and other metabolic tasks, all closely linked to cell viability. Functionality of mitochondria appears to depend upon their network architecture that may dynamically pass from an interconnected structure with long tubular units, to a fragmented one with short separate fragments. A decline in mitochondrial quality, which presents itself as an altered structural organization and a function of mitochondria, has been observed in Down syndrome (DS), as well as in aging and in age-related pathologies. This review provides a basic overview of mitochondrial dynamics, from fission/fusion mechanisms to mitochondrial homeostasis. Molecular mechanisms determining the disruption of the mitochondrial phenotype in DS and aging are discussed. The impaired activity of the transcriptional co-activator PGC-1α/PPARGC1A and the hyperactivation of the mammalian target of rapamycin (mTOR) kinase are emerging as molecular underlying causes of these mitochondrial alterations. It is, therefore, likely that either stimulating the PGC-1α activity or inhibiting mTOR signaling could reverse mitochondrial dysfunction. Evidence is summarized suggesting that drugs targeting either these pathways or other factors affecting the mitochondrial network may represent therapeutic approaches to improve and/or prevent the effects of altered mitochondrial function. Overall, from all these studies it emerges that the implementation of such strategies may exert protective effects in DS and age-related diseases.

A newborn female child was delivered by cesarean after 37 weeks of gestation, complicated by intrauterine growth retardation. Her weight was 1610 g (<3rd percentile), length 42 cm (<3rd percentile), and occipitofrontal circumference 29 cm (<3rd percentile). She was noted to have micrognathia and mild hypotonia. An echocardiogram showed multiple, small ventricular septal defects; no abnormalities were detected by cerebral and abdominal ultrasound examinations. In the first days of life, she was noted to have a high-pitched, monochromatic cry, resembling the sound of a cat [Audio File; available at www.jpeds.com]. Cri-du-chat syndrome (OMIM #123450) was suspected and a karyotype with banding confirmed the terminal deletion of a portion of the short arm of chromosome 5 (Figure). Cri-du-chat syndrome, also known as 5p deletion syndrome, or 5p- syndrome, was first described in 1963 by Lejeune et al1Lejeune J. Lafourcade J. Berger R. Vialatta J. Boeswillwald M. Seringe P. et al.Trois ca de deletion partielle du bras court d'un chromosome 5.C R Hebd Seances Acad Sci. 1963; 257: 3098PubMed Google Scholar and is among the most common chromosomal abnormalities with an incidence ranging from 1 in 15 000 to 50 000 live births.2Niebuhr E. The cri du chat syndrome: epidemiology, cytogenetics, and clinical features.Hum Genet. 1978; 44: 227-275Crossref PubMed Scopus (228) Google Scholar,3Cerruti Mainardi P. Cri du Chat syndrome.Orphanet J Rare Dis. 2006; 1: 33Crossref PubMed Scopus (139) Google Scholar Clinical features are variable and often include microcephaly, round face, hypertelorism, epicanthal folds, micrognathia, low-set ears, hypotonia, developmental delay, intellectual disability, and malformations of brain, heart, and genitourinary system. Although many affected individuals have similar overlapping deletions, there is no common recurring breakpoint. The high pitched cry has been attributed to multiple regions within the short arm of chromosome 5 and likely depends on congenital anomalies of a narrow and diamond-shaped larynx along with a floppy and small epiglottis.2Niebuhr E. The cri du chat syndrome: epidemiology, cytogenetics, and clinical features.Hum Genet. 1978; 44: 227-275Crossref PubMed Scopus (228) Google Scholar,4Nguyen J.M. Qualmann K.J. Okashah R. Reilly A. Alexeyev M.F. Campbell D.J. 5p deletions: current knowledge and future directions.Am J Med Genet C Semin Med Genet. 2015; 169: 224-238Crossref PubMed Scopus (43) Google Scholar Physicians have always used their bodies as an instrument to make a diagnosis: inspection, palpation, percussion, and auscultation, and even smell and hearing. Even with highly technological diagnostic advances, a doctor's senses have not been yet replaced by instruments and tests, as illustrated by this case. Data sharing statement available at www.jpeds.com. Download .xml (.0 MB) Help with xml files Data ProfileeyJraWQiOiI4ZjUxYWNhY2IzYjhiNjNlNzFlYmIzYWFmYTU5NmZmYyIsImFsZyI6IlJTMjU2In0.eyJzdWIiOiI3MzRhNmRlZDJlODUzYzFjNWMxNzY4N2Y5MGFhMDgyZSIsImtpZCI6IjhmNTFhY2FjYjNiOGI2M2U3MWViYjNhYWZhNTk2ZmZjIiwiZXhwIjoxNjQxMTI4NjM3fQ.FUGHYbDmwbSVB1RnLVCeInHwdOqerH3QfQwhHYNQdTBmPJcKORZ8SJ-iJVEF420sYK2L3-nfaeQ2rUVClNG35SgrXbNw02CqYYaDA434kZ1VAdP8y3X-6vyWljxcgBFOTePMn0Y_HdAFFrsv_WoD3MxH-xfKx9oWRFOECQ0L8dnLbMLubASlLzuuWLIqTZkDSHx83Xwwb-CkD8jmAn5NPVAQO1WMXgoOFQOS30SMim1dLyK-DiY3zIXSRPVME34F5ylTvdas0b7h5-_ZanO98DSUl_m6_CkpvQakL4FKfU9hKpir5xUDruyw2cNKT3dlfdp2mJqrLCJ13eLUd7XL0Q Download .mp4 (12.42 MB) Help with .mp4 files Audio File

Interstitial deletions of 16q chromosome including 16q12.1q21 region are very rare, with only three cases reported to date. Main clinical features include dysmorphisms, short stature, microcephaly, eye abnormalities, epilepsy, development delay, intellectual disability, and autism spectrum disorder. We report two independent subjects with 16q12.1q21 deletion syndrome presenting with dysmorphic facial features, developmental delay, strabismus, and aggressive behavior. A minimal region of overlap spanning 1.7 Mb on chromosome 16, including IRX5, GNAO1, and NUDT21 genes was shared among these two cases and those previously reported. This minimal region of overlap suggests the potential pathogenic role of these genes, previously implicated in diseases of the central nervous system.

BACKGROUND: The phenotype of early embryonic fourth branchial arch defects encompasses a wide spectrum of clinical conditions including DiGeorge syndrome (DGS), velocardiofacial syndrome, and conotruncal anomaly face syndrome. The majority of the patients have a 22q11.2 deletion. However, in 6% to 17% of patients, the identification of a genetic cause remains unknown through fluorescence in situ hybridization. In these patients, the clinical features and the immunological abnormalities are not well defined. OBJECTIVE: To describe the main genomic abnormalities, clinical features, and immunological abnormalities of a cohort of patients resembling the 22q11.2 deletion phenotype in the absence of 22q11.2 locus alterations. METHODS: Eleven patients from unrelated nonconsanguineous families with suspected 22q11.2 deletion syndrome (22q11.2DS) according to Tobias criteria were enrolled. Array-comparative genomic hybridization was performed in 10 patients. A phenotypic and immunological assessment was performed in all patients. RESULTS: The majority of patients had a phenotype overlapping with 22q11.2DS and immunological abnormalities suggestive of abnormalities in T-cell development, being severe in 2 of them. Most subjects suffered from recurrent infections. Clinically overt autoimmune manifestations were identified in 2 (18%) subjects. New pathogenic or likely pathogenic genomic regions associated with 22q11.2DS features were identified. CONCLUSION: Patients with a DGS-like phenotype share the same features of the classical 22q11.2DS associated with other rare genomic alterations. Severe forms of immunodeficiency may also be observed in this group. (C) 2020 American Academy of Allergy, Asthma & Immunology