Publications by authors named "Nicola Brunetti-Pierri"

194 Publications

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

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

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

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

Expanded cardiovascular phenotype of Myhre syndrome includes tetralogy of Fallot suggesting a role for SMAD4 in human neural crest defects.

Am J Med Genet A 2022 Jan 13. Epub 2022 Jan 13.

Genetics Unit, Department of Pediatrics, MassGeneral Hospital for Children, Boston, Massachusetts, USA.

Tetralogy of Fallot (ToF) can be associated with a wide range of extracardiac anomalies, with an underlying etiology identified in approximately 10% of cases. Individuals affected with Myhre syndrome due to recurrent SMAD4 mutations frequently have cardiovascular anomalies, including congenital heart defects. In addition to two patients in the literature with ToF, we describe five additional individuals with Myhre syndrome and classic ToF, ToF with pulmonary atresia and multiple aorto-pulmonary collaterals, and ToF with absent pulmonary valve. Aorta hypoplasia was documented in one patient and suspected in another two. In half of these individuals, postoperative cardiac dysfunction was thought to be more severe than classic postoperative ToF repair. There may be an increase in right ventricular pressure, and right ventricular dysfunction due to free pulmonic regurgitation. Noncardiac developmental abnormalities in our series and the literature, including corectopia, heterochromia iridis, and congenital miosis suggest an underlying defect of neural crest cell migration in Myhre syndrome. We advise clinicians that Myhre syndrome should be considered in the genetic evaluation of a child with ToF, short stature, unusual facial features, and developmental delay, as these children may be at risk for increased postoperative morbidity. Additional research is needed to investigate the hypothesis that postoperative hemodynamics in these patients may be consistent with restrictive myocardial physiology.
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http://dx.doi.org/10.1002/ajmg.a.62645DOI Listing
January 2022

Alpha-1 antitrypsin deficiency: a re-surfacing adult liver disorder.

J Hepatol 2021 Nov 27. Epub 2021 Nov 27.

Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Aachen, Germany. Electronic address:

Alpha-1 antitrypsin deficiency (AATD) arises from mutations in the SERPINA1 gene encoding alpha-1 antitrypsin (AAT) that lead to AAT retention in the endoplasmic reticulum of hepatocytes, causing proteotoxic liver injury and loss-of-function lung disease. The homozygous Pi*Z mutation (Pi*ZZ genotype) is responsible for the majority of severe AATD cases and can precipitate both pediatric and adult liver diseases, while the heterozygous Pi*Z mutation (Pi*MZ genotype) is an established modifier of liver disease. We review genotype-related hepatic phenotypes/disease predispositions. We also describe the mechanisms and factors promoting the development of liver disease, as well as approaches to evaluate the extent of liver fibrosis. We discuss the emerging therapeutic approaches, diagnosis, and clinical management of this neglected disorder.
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http://dx.doi.org/10.1016/j.jhep.2021.11.022DOI Listing
November 2021

Epilepsy in KAT6A syndrome: Description of two individuals and revision of the literature.

Eur J Med Genet 2022 Jan 5;65(1):104380. Epub 2021 Nov 5.

Department of Neuroscience, Reproductive and Odontostomatological Sciences, Federico II University, Naples, Italy.

Pathogenic variants in KAT6A, encoding a histone acetyltransferase, have been identified as a cause of a developmental disorder with a definite clinical spectrum including intellectual disability, speech delay, dysmorphic facial features, microcephaly, cardiac and gastrointestinal defects. Seizures have been described in a minority of patients without a detailed characterization. In this work we focus on epilepsy in KAT6A syndrome, reporting two affected girls with history of seizures, bearing a KAT6A de novo heterozygous variant, of which one is novel. We describe the different epilepsy phenotypes of these two patients and compare them to the other individuals in literature presenting with epilepsy.
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http://dx.doi.org/10.1016/j.ejmg.2021.104380DOI Listing
January 2022

Long-term efficacy of T3 analogue Triac in children and adults with MCT8 deficiency: a real-life retrospective cohort study.

J Clin Endocrinol Metab 2021 Oct 22. Epub 2021 Oct 22.

Department of Pediatrics, Hematology and Oncology, Medical University of Gdańsk, Gdańsk, Poland.

Context: Patients with mutations in thyroid hormone transporter MCT8 have developmental delay and chronic thyrotoxicosis associated with being underweight and having cardiovascular dysfunction. Our previous trial showed improvement of key clinical and biochemical features during one year of treatment with the T3-analogue Triac. Long-term follow-up data are lacking.

Methods: In this real-life retrospective cohort study, we investigated the efficacy of Triac in MCT8 deficient patients in 33 sites. The primary endpoint was the change in serum T3 concentrations from baseline to last-available measurement. Secondary endpoints were changes in other thyroid parameters, anthropometric parameters, heart rate, and biochemical markers of thyroid hormone action.

Results: Between 15-Oct-2014 and 1-Jan-2021, sixty-seven patients with a median baseline age of 4.6 years (range:0.5-66 years) were treated up to 6 years, with a median of 2.2 years (range 0.2-6.2 years). Mean T3 concentrations decreased from 4.58 (SD:1.11) to 1.66 (0.69) nmol/L (mean decrease 2.92 nmol/L, 95%CI:2.61-3.23, p<0.0001; target:1.4-2.5 nmol/L). Body weight-for-age exceeded that of untreated historical controls (mean difference 0.72 SDs, 95%CI:0.36-1.09, p=0.0002). Heart rate-for-age decreased (mean difference 0.64 SDs, 95%CI:0.29-0.98, p=0.0005). SHBG concentrations decreased from 245 (99) to 209 (92) nmol/L (mean decrease 36 nmol/L, 95%CI:16-57, p=0.0008). Mean creatinine concentrations increased from 32 (11) to 39 (13) µmol/L (mean increase 7 µmol/L, 95%CI:6-9, p<0.0001). Mean CK concentrations did not significantly change. No drug-related severe adverse events were reported.

Conclusions: Key features were sustainably alleviated in patients with MCT8 deficiency across all ages and highlight the potential of Triac for MCT8 deficiency in real-life.
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http://dx.doi.org/10.1210/clinem/dgab750DOI Listing
October 2021

Mild Clinical Presentation of Joubert Syndrome in a Male Adult Carrying Biallelic Truncating Variants.

Diagnostics (Basel) 2021 Jul 6;11(7). Epub 2021 Jul 6.

Eye Clinic, Multidisciplinary Department of Medical, Surgical and Dental Sciences, Università degli Studi della Campania 'Luigi Vanvitelli', Via Pansini 5, 80131 Naples, Italy.

Pathogenic variants in the gene are responsible for a ciliopathy with a wide spectrum of clinical manifestations ranging from Meckel and Joubert syndrome (JBTS) to Bardet-Biedl syndrome, and involving the central nervous system, liver, kidney, skeleton, and retina. We report a 39-year-old male individual presenting with isolated Retinitis Pigmentosa (RP), as assessed by full ophthalmological evaluation including Best-Corrected Visual Acuity measurements, fundus examination, Goldmann Visual Field test, and full-field Electroretinography. A clinical exome identified biallelic nonsense variants in that prompted post-genotyping investigations for systemic abnormalities of ciliopathy. Brain magnetic resonance imaging revealed malformations of the posterior cranial fossa with the 'molar tooth sign' and cerebellar folia dysplasia, which are both distinctive features of JBTS. No other organ or skeletal abnormalities were detected. This case illustrates the power of clinical exome for the identification of the mildest forms of a disease spectrum, such as a mild JBTS with RP in the presented case of an individual carrying biallelic truncating variants in .
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http://dx.doi.org/10.3390/diagnostics11071218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8303764PMC
July 2021

ZTTK syndrome: Clinical and molecular findings of 15 cases and a review of the literature.

Am J Med Genet A 2021 12 31;185(12):3740-3753. Epub 2021 Jul 31.

St. George's Genomics Service, St. George's University Hospitals NHS FT, London, UK.

Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome is caused by de novo loss-of-function variants in the SON gene (MIM #617140). This multisystemic disorder is characterized by intellectual disability, seizures, abnormal brain imaging, variable dysmorphic features, and various congenital anomalies. The wide application and increasing accessibility of whole exome sequencing (WES) has helped to identify new cases of ZTTK syndrome over the last few years. To date, there have been approximately 45 cases reported in the literature. Here, we describe 15 additional individuals with variants in the SON gene, including those with missense variants bringing the total number of known cases to 60. We have reviewed the clinical and molecular data of these new cases and all previously reported cases to further delineate the most common as well as emerging clinical findings related to this syndrome. Furthermore, we aim to delineate any genotype-phenotype correlations specifically for a recurring pathogenic four base pair deletion (c.5753_5756del) along with discussing the impact of missense variants seen in the SON gene.
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http://dx.doi.org/10.1002/ajmg.a.62445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8595531PMC
December 2021

Recurrent missense variants in can cause syndromic intellectual disability.

J Med Genet 2021 Jun 28. Epub 2021 Jun 28.

Department of Translational Medicine, Section of Pediatrics, Federico II University Hospital, Naples, Italy.

Purpose: Binding proteins (G-proteins) mediate signalling pathways involved in diverse cellular functions and comprise Gα and Gβγ units. Human diseases have been reported for all five Gβ proteins. A missense variant in was recently reported in one individual with developmental delay/intellectual disability (DD/ID) and dysmorphism. We aim to confirm as a neurodevelopmental disease gene, and elucidate the -associated neurodevelopmental phenotype in a patient cohort.

Methods: We discovered a variant in the index case via exome sequencing and sought individuals with variants via international data-sharing initiatives. modelling of the variants was assessed, along with multiple lines of evidence in keeping with American College of Medical Genetics and Genomics guidelines for interpretation of sequence variants.

Results: We identified 12 unrelated individuals with five missense variants in , four of which are recurrent: p.(Ala73Thr), p.(Gly77Arg), p.(Lys89Glu) and p.(Lys89Thr). All individuals have DD/ID with variable dysmorphism and extraneurologic features. The variants are located at the universally conserved shared interface with the Gα subunit, which modelling suggests weaken this interaction.

Conclusion: Missense variants in cause a congenital neurodevelopmental disorder with variable syndromic features, broadening the spectrum of multisystem phenotypes associated with variants in genes encoding G-proteins.
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http://dx.doi.org/10.1136/jmedgenet-2020-107462DOI Listing
June 2021

Diagnostic issues faced by a rare disease healthcare network during Covid-19 outbreak: data from the Campania Rare Disease Registry.

J Public Health (Oxf) 2021 05 13. Epub 2021 May 13.

Centro di Coordinamento Malattie Rare, Regione Campania Naples 80131, Italy.

Background: The aims of this study were: to investigate the capacity of the rare disease healthcare network in Campania to diagnose patients with rare diseases during the outbreak of Covid-19; and to shed light on problematic diagnoses during this period.

Methods: To describe the impact of the Covid-19 pandemic on the diagnosis of patients with rare diseases, a retrospective analysis of the Campania Region Rare Disease Registry was performed. A tailored questionnaire was sent to rare disease experts to investigate major issues during the emergency period.

Results: Prevalence of new diagnoses of rare disease in March and April 2020 was significantly lower than in 2019 (117 versus 317, P < 0.001 and 37 versus 349, P < 0.001, respectively) and 2018 (117 versus 389, P < 0.001 and 37 versus 282, P < 0.001, respectively). Eighty-two among 98 rare disease experts completed the questionnaire. Diagnostic success (95%), access to diagnosis (80%) and follow-up (72%), lack of Personal Protective Equipment (60%), lack of Covid-19 guidelines (50%) and the need for home therapy (78%) were the most important issues raised during Covid-19 outbreak.

Conclusions: This study describes the effects of the Covid-19 outbreak on the diagnosis of rare disease in a single Italian region and investigates potential issues of diagnosis and management during this period.
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http://dx.doi.org/10.1093/pubmed/fdab137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8194710PMC
May 2021

Variants in the degron of AFF3 are associated with intellectual disability, mesomelic dysplasia, horseshoe kidney, and epileptic encephalopathy.

Am J Hum Genet 2021 05;108(5):857-873

GeneDx, Gaithersburg, MD 20877, USA.

The ALF transcription factor paralogs, AFF1, AFF2, AFF3, and AFF4, are components of the transcriptional super elongation complex that regulates expression of genes involved in neurogenesis and development. We describe an autosomal dominant disorder associated with de novo missense variants in the degron of AFF3, a nine amino acid sequence important for its binding to ubiquitin ligase, or with de novo deletions of this region. The sixteen affected individuals we identified, along with two previously reported individuals, present with a recognizable pattern of anomalies, which we named KINSSHIP syndrome (KI for horseshoe kidney, NS for Nievergelt/Savarirayan type of mesomelic dysplasia, S for seizures, H for hypertrichosis, I for intellectual disability, and P for pulmonary involvement), partially overlapping the AFF4-associated CHOPS syndrome. Whereas homozygous Aff3 knockout mice display skeletal anomalies, kidney defects, brain malformations, and neurological anomalies, knockin animals modeling one of the microdeletions and the most common of the missense variants identified in affected individuals presented with lower mesomelic limb deformities like KINSSHIP-affected individuals and early lethality, respectively. Overexpression of AFF3 in zebrafish resulted in body axis anomalies, providing some support for the pathological effect of increased amount of AFF3. The only partial phenotypic overlap of AFF3- and AFF4-associated syndromes and the previously published transcriptome analyses of ALF transcription factors suggest that these factors are not redundant and each contributes uniquely to proper development.
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http://dx.doi.org/10.1016/j.ajhg.2021.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206167PMC
May 2021

Bi-allelic KARS1 pathogenic variants affecting functions of cytosolic and mitochondrial isoforms are associated with a progressive and multisystem disease.

Hum Mutat 2021 06 11;42(6):745-761. Epub 2021 May 11.

Department of Translational Medicine, Federico II University, Naples, Italy.

KARS1 encodes a lysyl-transfer RNA synthetase (LysRS) that links lysine to its cognate transfer RNA. Two different KARS1 isoforms exert functional effects in cytosol and mitochondria. Bi-allelic pathogenic variants in KARS1 have been associated to sensorineural hearing and visual loss, neuropathy, seizures, and leukodystrophy. We report the clinical, biochemical, and neuroradiological features of nine individuals with KARS1-related disorder carrying 12 different variants with nine of them being novel. The consequences of these variants on the cytosol and/or mitochondrial LysRS were functionally validated in yeast mutants. Most cases presented with severe neurological features including congenital and progressive microcephaly, seizures, developmental delay/intellectual disability, and cerebral atrophy. Oculo-motor dysfunction and immuno-hematological problems were present in six and three cases, respectively. A yeast growth defect of variable severity was detected for most variants on both cytosolic and mitochondrial isoforms. The detrimental effects of two variants on yeast growth were partially rescued by lysine supplementation. Congenital progressive microcephaly, oculo-motor dysfunction, and immuno-hematological problems are emerging phenotypes in KARS1-related disorder. The data in yeast emphasize the role of both mitochondrial and cytosolic isoforms in the pathogenesis of KARS1-related disorder and supports the therapeutic potential of lysine supplementation at least in a subset of patients.
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http://dx.doi.org/10.1002/humu.24210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251883PMC
June 2021

Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism.

Am J Hum Genet 2021 06 27;108(6):1138-1150. Epub 2021 Apr 27.

Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94143, USA.

ANKRD17 is an ankyrin repeat-containing protein thought to play a role in cell cycle progression, whose ortholog in Drosophila functions in the Hippo pathway as a co-factor of Yorkie. Here, we delineate a neurodevelopmental disorder caused by de novo heterozygous ANKRD17 variants. The mutational spectrum of this cohort of 34 individuals from 32 families is highly suggestive of haploinsufficiency as the underlying mechanism of disease, with 21 truncating or essential splice site variants, 9 missense variants, 1 in-frame insertion-deletion, and 1 microdeletion (1.16 Mb). Consequently, our data indicate that loss of ANKRD17 is likely the main cause of phenotypes previously associated with large multi-gene chromosomal aberrations of the 4q13.3 region. Protein modeling suggests that most of the missense variants disrupt the stability of the ankyrin repeats through alteration of core structural residues. The major phenotypic characteristic of our cohort is a variable degree of developmental delay/intellectual disability, particularly affecting speech, while additional features include growth failure, feeding difficulties, non-specific MRI abnormalities, epilepsy and/or abnormal EEG, predisposition to recurrent infections (mostly bacterial), ophthalmological abnormalities, gait/balance disturbance, and joint hypermobility. Moreover, many individuals shared similar dysmorphic facial features. Analysis of single-cell RNA-seq data from the developing human telencephalon indicated ANKRD17 expression at multiple stages of neurogenesis, adding further evidence to the assertion that damaging ANKRD17 variants cause a neurodevelopmental disorder.
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http://dx.doi.org/10.1016/j.ajhg.2021.04.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206162PMC
June 2021

Truncating SRCAP variants outside the Floating-Harbor syndrome locus cause a distinct neurodevelopmental disorder with a specific DNA methylation signature.

Am J Hum Genet 2021 06 27;108(6):1053-1068. Epub 2021 Apr 27.

Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.

Truncating variants in exons 33 and 34 of the SNF2-related CREBBP activator protein (SRCAP) gene cause the neurodevelopmental disorder (NDD) Floating-Harbor syndrome (FLHS), characterized by short stature, speech delay, and facial dysmorphism. Here, we present a cohort of 33 individuals with clinical features distinct from FLHS and truncating (mostly de novo) SRCAP variants either proximal (n = 28) or distal (n = 5) to the FLHS locus. Detailed clinical characterization of the proximal SRCAP individuals identified shared characteristics: developmental delay with or without intellectual disability, behavioral and psychiatric problems, non-specific facial features, musculoskeletal issues, and hypotonia. Because FLHS is known to be associated with a unique set of DNA methylation (DNAm) changes in blood, a DNAm signature, we investigated whether there was a distinct signature associated with our affected individuals. A machine-learning model, based on the FLHS DNAm signature, negatively classified all our tested subjects. Comparing proximal variants with typically developing controls, we identified a DNAm signature distinct from the FLHS signature. Based on the DNAm and clinical data, we refer to the condition as "non-FLHS SRCAP-related NDD." All five distal variants classified negatively using the FLHS DNAm model while two classified positively using the proximal model. This suggests divergent pathogenicity of these variants, though clinically the distal group presented with NDD, similar to the proximal SRCAP group. In summary, for SRCAP, there is a clear relationship between variant location, DNAm profile, and clinical phenotype. These results highlight the power of combined epigenetic, molecular, and clinical studies to identify and characterize genotype-epigenotype-phenotype correlations.
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http://dx.doi.org/10.1016/j.ajhg.2021.04.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206150PMC
June 2021

Peculiar footprints in a child with agenesis of corpus callosum.

J Paediatr Child Health 2021 03;57(3):450-451

Department of Translational Medicine, Section of Paediatrics, Federico II University, Naples, Italy.

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http://dx.doi.org/10.1111/jpc.1_15176DOI Listing
March 2021

Up-regulation of miR-34b/c by JNK and FOXO3 protects from liver fibrosis.

Proc Natl Acad Sci U S A 2021 03;118(10)

Telethon Institute of Genetics and Medicine, Pozzuoli, 80078 Naples, Italy;

α1-Antitrypsin (AAT) deficiency is a common genetic disease presenting with lung and liver diseases. AAT deficiency results from pathogenic variants in the gene encoding AAT and the common mutant Z allele of encodes for Z α1-antitrypsin (ATZ), a protein forming hepatotoxic polymers retained in the endoplasmic reticulum of hepatocytes. PiZ mice express the human ATZ and are a valuable model to investigate the human liver disease of AAT deficiency. In this study, we investigated differential expression of microRNAs (miRNAs) between PiZ and control mice and found that miR-34b/c was up-regulated and its levels correlated with intrahepatic ATZ. Furthermore, in PiZ mouse livers, we found that Forkhead Box O3 (FOXO3) driving microRNA-34b/c (miR-34b/c) expression was activated and miR-34b/c expression was dependent upon c-Jun N-terminal kinase (JNK) phosphorylation on Ser Deletion of miR-34b/c in PiZ mice resulted in early development of liver fibrosis and increased signaling of platelet-derived growth factor (PDGF), a target of miR-34b/c. Activation of FOXO3 and increased miR-34c were confirmed in livers of humans with AAT deficiency. In addition, JNK-activated FOXO3 and miR-34b/c up-regulation were detected in several mouse models of liver fibrosis. This study reveals a pathway involved in liver fibrosis and potentially implicated in both genetic and acquired causes of hepatic fibrosis.
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http://dx.doi.org/10.1073/pnas.2025242118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958360PMC
March 2021

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition).

Autophagy 2021 Jan 8;17(1):1-382. Epub 2021 Feb 8.

University of Crete, School of Medicine, Laboratory of Clinical Microbiology and Microbial Pathogenesis, Voutes, Heraklion, Crete, Greece; Foundation for Research and Technology, Institute of Molecular Biology and Biotechnology (IMBB), Heraklion, Crete, Greece.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
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http://dx.doi.org/10.1080/15548627.2020.1797280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996087PMC
January 2021

Beclin-1-mediated activation of autophagy improves proximal and distal urea cycle disorders.

EMBO Mol Med 2021 02 28;13(2):e13158. Epub 2020 Dec 28.

Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.

Urea cycle disorders (UCD) are inherited defects in clearance of waste nitrogen with high morbidity and mortality. Novel and more effective therapies for UCD are needed. Studies in mice with constitutive activation of autophagy unravelled Beclin-1 as druggable candidate for therapy of hyperammonemia. Next, we investigated efficacy of cell-penetrating autophagy-inducing Tat-Beclin-1 (TB-1) peptide for therapy of the two most common UCD, namely ornithine transcarbamylase (OTC) and argininosuccinate lyase (ASL) deficiencies. TB-1 reduced urinary orotic acid and improved survival under protein-rich diet in spf-ash mice, a model of OTC deficiency (proximal UCD). In Asl mice, a model of ASL deficiency (distal UCD), TB-1 increased ureagenesis, reduced argininosuccinate, and improved survival. Moreover, it alleviated hepatocellular injury and decreased both cytoplasmic and nuclear glycogen accumulation in Asl mice. In conclusion, Beclin-1-dependent activation of autophagy improved biochemical and clinical phenotypes of proximal and distal defects of the urea cycle.
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http://dx.doi.org/10.15252/emmm.202013158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863400PMC
February 2021

A pilot clinical trial with losartan in Myhre syndrome.

Am J Med Genet A 2021 03 24;185(3):702-709. Epub 2020 Dec 24.

Department of Translational Medicine, Section of Pediatrics, Federico II University, Naples, Italy.

Introduction: Myhre syndrome (MS) is an ultra-rare disorder due to pathogenic variants in the SMAD4 gene that encodes a protein regulating the TGF-β pathway and extra-cellular matrix (ECM) homeostasis. Main clinical features of MS include thickening of skin and joint stiffness. Previous studies showed that losartan improved ECM deposition in MS fibroblasts.

Materials And Methods: Four molecularly confirmed MS subjects (mean age 23.8 ± 17 years) were evaluated for: (a) skin thickness by Rodnan score, (b) joint range of motion (ROM) by goniometry, and (c) speckle-tracking echocardiogram. Following baseline evaluations, three MS individuals received losartan for 12 months and pre-defined endpoints were monitored after 6 and 12 months of treatment.

Results: At baseline, Rodnan scores were increased, joint ROM was reduced, and speckle-tracking echocardiogram revealed reduced myocardial strain. In three MS subjects, improvements in skin thickness, joint ROM and to a lesser extent of myocardial strain, were observed after 6 and 12 months of losartan treatment.

Conclusions: Although further long-term controlled clinical trials with a larger number of affected individuals are needed, the present study suggests that losartan might improve skin, joint and heart abnormalities of MS.
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http://dx.doi.org/10.1002/ajmg.a.62019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898344PMC
March 2021

Rare and de novo coding variants in chromodomain genes in Chiari I malformation.

Am J Hum Genet 2021 01 21;108(1):100-114. Epub 2020 Dec 21.

Department of Pediatrics, Washington University, St. Louis, MO 63110, USA; Department of Orthopaedic Surgery, Washington University, St. Louis, MO 63110, USA; Department of Neurology, Washington University, St. Louis, MO 63110, USA.

Chiari I malformation (CM1), the displacement of the cerebellum through the foramen magnum into the spinal canal, is one of the most common pediatric neurological conditions. Individuals with CM1 can present with neurological symptoms, including severe headaches and sensory or motor deficits, often as a consequence of brainstem compression or syringomyelia (SM). We conducted whole-exome sequencing (WES) on 668 CM1 probands and 232 family members and performed gene-burden and de novo enrichment analyses. A significant enrichment of rare and de novo non-synonymous variants in chromodomain (CHD) genes was observed among individuals with CM1 (combined p = 2.4 × 10), including 3 de novo loss-of-function variants in CHD8 (LOF enrichment p = 1.9 × 10) and a significant burden of rare transmitted variants in CHD3 (p = 1.8 × 10). Overall, individuals with CM1 were found to have significantly increased head circumference (p = 2.6 × 10), with many harboring CHD rare variants having macrocephaly. Finally, haploinsufficiency for chd8 in zebrafish led to macrocephaly and posterior hindbrain displacement reminiscent of CM1. These results implicate chromodomain genes and excessive brain growth in CM1 pathogenesis.
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http://dx.doi.org/10.1016/j.ajhg.2020.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820723PMC
January 2021

FBXO28 causes developmental and epileptic encephalopathy with profound intellectual disability.

Epilepsia 2021 01 6;62(1):e13-e21. Epub 2020 Dec 6.

Epilepsy Research Centre, Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia.

Chromosome 1q41-q42 deletion syndrome is a rare cause of intellectual disability, seizures, dysmorphology, and multiple anomalies. Two genes in the 1q41-q42 microdeletion, WDR26 and FBXO28, have been implicated in monogenic disease. Patients with WDR26 encephalopathy overlap clinically with those with 1q41-q42 deletion syndrome, whereas only one patient with FBXO28 encephalopathy has been described. Seizures are a prominent feature of 1q41-q42 deletion syndrome; therefore, we hypothesized that pathogenic FBXO28 variants cause developmental and epileptic encephalopathies (DEEs). We describe nine new patients with FBXO28 pathogenic variants (four missense, including one recurrent, three nonsense, and one frameshift) and analyze all 10 known cases to delineate the phenotypic spectrum. All patients had epilepsy and 9 of 10 had DEE, including infantile spasms (3) and a progressive myoclonic epilepsy (1). Median age at seizure onset was 22.5 months (range 8 months to 5 years). Nine of 10 patients had intellectual disability, which was profound in six of nine and severe in three of nine. Movement disorders occurred in eight of 10 patients, six of 10 had hypotonia, four of 10 had acquired microcephaly, and five of 10 had dysmorphic features, albeit different to those typically seen in 1q41-q42 deletion syndrome and WDR26 encephalopathy. We distinguish FBXO28 encephalopathy from both of these disorders with more severe intellectual impairment, drug-resistant epilepsy, and hyperkinetic movement disorders.
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http://dx.doi.org/10.1111/epi.16784DOI Listing
January 2021

Dual diagnosis in a child with familial SCN8A-related encephalopathy complicated by a 1p13.2 deletion involving NRAS gene.

Neurol Sci 2021 05 17;42(5):2115-2117. Epub 2020 Nov 17.

Department of Translational Medical Sciences, Child Neurology, University of Naples Federico II, Naples, Italy.

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http://dx.doi.org/10.1007/s10072-020-04898-1DOI Listing
May 2021

Corrigendum to "A systematic cross-sectional survey of multiple sulfatase deficiency" [Mol Genet Metab. 2020 Aug;130(4):283-288].

Mol Genet Metab 2020 Sep - Oct;131(1-2):284. Epub 2020 Nov 2.

Department of Translational Medicine, Federico II University, Naples, Italy; Telethon Institute of Genetics and Medicine, Pozzuoli, Naples, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.ymgme.2020.10.012DOI Listing
November 2020

Clinical and Functional Consequences of C-Terminal Variants in MCT8: A Case Series.

J Clin Endocrinol Metab 2021 01;106(2):539-553

Academic Center For Thyroid Disease, Department of Internal Medicine, Erasmus Medical Center, GD Rotterdam, The Netherlands.

Context: Genetic variants in SLC16A2, encoding the thyroid hormone transporter MCT8, can cause intellectual and motor disability and abnormal serum thyroid function tests, known as MCT8 deficiency. The C-terminal domain of MCT8 is poorly conserved, which complicates prediction of the deleteriousness of variants in this region. We studied the functional consequences of 5 novel variants within this domain and their relation to the clinical phenotypes.

Methods: We enrolled male subjects with intellectual disability in whom genetic variants were identified in exon 6 of SLC16A2. The impact of identified variants was evaluated in transiently transfected cell lines and patient-derived fibroblasts.

Results: Seven individuals from 5 families harbored potentially deleterious variants affecting the C-terminal domain of MCT8. Two boys with clinical features considered atypical for MCT8 deficiency had a missense variant [c.1724A>G;p.(His575Arg) or c.1796A>G;p.(Asn599Ser)] that did not affect MCT8 function in transfected cells or patient-derived fibroblasts, challenging a causal relationship. Two brothers with classical MCT8 deficiency had a truncating c.1695delT;p.(Val566*) variant that completely inactivated MCT8 in vitro. The 3 other boys had relatively less-severe clinical features and harbored frameshift variants that elongate the MCT8 protein [c.1805delT;p.(Leu602HisfsTer680) and c.del1826-1835;p.(Pro609GlnfsTer676)] and retained ~50% residual activity. Additional truncating variants within transmembrane domain 12 were fully inactivating, whereas those within the intracellular C-terminal tail were tolerated.

Conclusions: Variants affecting the intracellular C-terminal tail of MCT8 are likely benign unless they cause frameshifts that elongate the MCT8 protein. These findings provide clinical guidance in the assessment of the pathogenicity of variants within the C-terminal domain of MCT8.
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http://dx.doi.org/10.1210/clinem/dgaa795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823235PMC
January 2021

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

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

Oasi Research Institute-IRCCS, Troina, Italy.

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

Rubinstein-Taybi syndrome in diverse populations.

Am J Med Genet A 2020 12 27;182(12):2939-2950. Epub 2020 Sep 27.

Kapi'olani Medical Center and University of Hawai'i, Honolulu, Hawaii, USA.

Rubinstein-Taybi syndrome (RSTS) is an autosomal dominant disorder, caused by loss-of-function variants in CREBBP or EP300. Affected individuals present with distinctive craniofacial features, broad thumbs and/or halluces, and intellectual disability. RSTS phenotype has been well characterized in individuals of European descent but not in other populations. In this study, individuals from diverse populations with RSTS were assessed by clinical examination and facial analysis technology. Clinical data of 38 individuals from 14 different countries were analyzed. The median age was 7 years (age range: 7 months to 47 years), and 63% were females. The most common phenotypic features in all population groups included broad thumbs and/or halluces in 97%, convex nasal ridge in 94%, and arched eyebrows in 92%. Face images of 87 individuals with RSTS (age range: 2 months to 47 years) were collected for evaluation using facial analysis technology. We compared images from 82 individuals with RSTS against 82 age- and sex-matched controls and obtained an area under the receiver operating characteristic curve (AUC) of 0.99 (p < .001), demonstrating excellent discrimination efficacy. The discrimination was, however, poor in the African group (AUC: 0.79; p = .145). Individuals with EP300 variants were more effectively discriminated (AUC: 0.95) compared with those with CREBBP variants (AUC: 0.93). This study shows that clinical examination combined with facial analysis technology may enable earlier and improved diagnosis of RSTS in diverse populations.
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http://dx.doi.org/10.1002/ajmg.a.61888DOI Listing
December 2020
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