Publications by authors named "Vincenzo Nigro"

137 Publications

Early Findings in Neonatal Cases of -Related Congenital Myopathies.

Front Neurol 2021 28;12:664618. Epub 2021 Jun 28.

Neurology Unit, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Ryanodine receptor type 1-related congenital myopathies are the most represented subgroup among congenital myopathies (CMs), typically presenting a central core or multiminicore muscle histopathology and high clinical heterogeneity. We evaluated a cohort of patients affected with Ryanodine receptor type 1-related congenital myopathy (-RCM), focusing on four patients who showed a severe congenital phenotype and underwent a comprehensive characterization at few months of life. To date there are few reports on precocious instrumental assessment. In two out of the four patients, a muscle biopsy was performed in the first days of life (day 5 and 37, respectively) and electron microscopy was carried out in two patients detecting typical features of congenital myopathy. Two patients underwent brain MRI in the first months of life (15 days and 2 months, respectively), one also a fetal brain MRI. In three children electromyography was performed in the first week of life and neurogenic signs were excluded. Muscle MRI obtained within the first years of life showed a typical pattern of -CM. The diagnosis was confirmed through genetic analysis in three out of four cases using Next Generation Sequencing (NGS) panels. The development of a correct and rapid diagnosis is a priority and may lead to prompt medical management and helps optimize inclusion in future clinical trials.
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http://dx.doi.org/10.3389/fneur.2021.664618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8273285PMC
June 2021

Urine concentrating defect as presenting sign of progressive renal failure in Bardet-Biedl syndrome patients.

Clin Kidney J 2021 Jun 6;14(6):1545-1551. Epub 2020 Dec 6.

Department of Translational Medical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy.

Background: Urine concentrating defect is a common dysfunction in ciliopathies, even though its underlying mechanism and its prognostic meaning are largely unknown. This study assesses renal function in a cohort of 54 Bardet-Biedl syndrome (BBS) individuals and analyses whether renal hyposthenuria is the result of specific tubule dysfunction and predicts renal disease progression.

Methods: The estimated glomerular filtration rate (eGFR), urine albumin:creatinine ratio (ACR) and maximum urine osmolality (max-Uosm) were measured in all patients. Genetic analysis was conducted in 43 patients. Annual eGFR decline (ΔeGFR) was measured in patients with a median follow-up period of 6.5 years. Urine aquaporin-2 (uAQP2) excretion was measured and the furosemide test was performed in patients and controls.

Results: At baseline, 33 (61.1%), 12 (22.2%) and 9 (16.7%) patients showed an eGFR >90, 60-90 and <60 mL/min/1.73 m, respectively; 27.3% showed an ACR >30 mg/g and 55.8% of patients showed urine concentrating defect in the absence of renal insufficiency. Baseline eGFR, but not max-Uosm, correlated negatively with age. Conversely, truncating mutations affected max-Uosm and showed a trend towards a reduction in eGFR. Max-Uosm correlated with ΔeGFR (P < 0.005), suggesting that urine concentrating defect may predict disease progression. uAQP2 excretion and Na and Cl fractional excretion after furosemide did not differ between hyposthenuric patients and controls, suggesting that specific collecting duct and thick ascending limb dysfunctions are unlikely to play a central role in the pathogenesis of hyposthenuria.

Conclusions: Hyposthenuria is a warning sign predicting poor renal outcome in BBS. The pathophysiology of this defect is most likely beyond defective tubular function.
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http://dx.doi.org/10.1093/ckj/sfaa182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8162863PMC
June 2021

Direct repression of Nanog and Oct4 by OTX2 modulates the contribution of epiblast-derived cells to germline and somatic lineage.

Development 2021 May 13;148(10). Epub 2021 May 13.

Institute of Genetics and Biophysics 'Adriano Buzzati-Traverso', CNR, Via P. Castellino, 111, 80131 Naples, Italy.

In mammals, the pre-gastrula proximal epiblast gives rise to primordial germ cells (PGCs) or somatic precursors in response to BMP4 and WNT signaling. Entry into the germline requires activation of a naïve-like pluripotency gene regulatory network (GRN). Recent work has shown that suppression of OTX2 expression in the epiblast by BMP4 allows cells to develop a PGC fate in a precise temporal window. However, the mechanisms by which OTX2 suppresses PGC fate are unknown. Here, we show that, in mice, OTX2 prevents epiblast cells from activating the pluripotency GRN by direct repression of Oct4 and Nanog. Loss of this control during PGC differentiation in vitro causes widespread activation of the pluripotency GRN and a deregulated response to LIF, BMP4 and WNT signaling. These abnormalities, in specific cell culture conditions, result in massive germline entry at the expense of somatic mesoderm differentiation. Increased generation of PGCs also occurs in mutant embryos. We propose that the OTX2-mediated repressive control of Oct4 and Nanog is the basis of the mechanism that determines epiblast contribution to germline and somatic lineage.
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http://dx.doi.org/10.1242/dev.199166DOI Listing
May 2021

Missense mutations in small muscle protein X-linked (SMPX) cause distal myopathy with protein inclusions.

Acta Neuropathol 2021 Aug 11;142(2):375-393. Epub 2021 May 11.

Folkhälsan Research Center, Helsinki, Finland.

Using deep phenotyping and high-throughput sequencing, we have identified a novel type of distal myopathy caused by mutations in the Small muscle protein X-linked (SMPX) gene. Four different missense mutations were identified in ten patients from nine families in five different countries, suggesting that this disease could be prevalent in other populations as well. Haplotype analysis of patients with similar ancestry revealed two different founder mutations in Southern Europe and France, indicating that the prevalence in these populations may be higher. In our study all patients presented with highly similar clinical features: adult-onset, usually distal more than proximal limb muscle weakness, slowly progressing over decades with preserved walking. Lower limb muscle imaging showed a characteristic pattern of muscle involvement and fatty degeneration. Histopathological and electron microscopic analysis of patient muscle biopsies revealed myopathic findings with rimmed vacuoles and the presence of sarcoplasmic inclusions, some with amyloid-like characteristics. In silico predictions and subsequent cell culture studies showed that the missense mutations increase aggregation propensity of the SMPX protein. In cell culture studies, overexpressed SMPX localized to stress granules and slowed down their clearance.
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http://dx.doi.org/10.1007/s00401-021-02319-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270885PMC
August 2021

Nephroplex: a kidney-focused NGS panel highlights the challenges of PKD1 sequencing and identifies a founder BBS4 mutation.

J Nephrol 2021 May 8. Epub 2021 May 8.

Department of Translational Medical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy.

Background: Genetic testing of patients with inherited kidney diseases has emerged as a tool of clinical utility by improving the patients' diagnosis, prognosis, surveillance and therapy.

Methods: The present study applied a Next Generation Sequencing (NGS)-based panel, named NephroPlex, testing 115 genes causing renal diseases, to 119 individuals, including 107 probands and 12 relatives. Thirty-five (poly)cystic and 72 non (poly)cystic individuals were enrolled. The latter subgroup of patients included Bardet-Biedl syndrome (BBS) patients, as major components.

Results: Disease-causing mutations were identified in 51.5 and 40% of polycystic and non-polycystic individuals, respectively. Autosomal dominant polycystic kidney disease (ADPKD) patients with truncating PKD1 variants showed a trend towards a greater slope of the age-estimated glomerular filtration rate (eGFR) regression line than patients with (i) missense variants, (ii) any PKD2 mutations and (iii) no detected mutations, according to previous findings. The analysis of BBS individuals showed a similar frequency of BBS4,9,10 and 12 mutations. Of note, all BBS4-mutated patients harbored the novel c.332+1G>GTT variant, which was absent in public databases, however, in our internal database, an additional heterozygote carrier was found. All BBS4-mutated individuals originated from the same geographical area encompassing the coastal provinces of Naples.

Discussion: In conclusion, these findings indicate the potential for a genetic panel to provide useful information at both clinical and epidemiological levels.
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http://dx.doi.org/10.1007/s40620-021-01048-4DOI Listing
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 Jun 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

A novel MEIS2 mutation explains the complex phenotype in a boy with a typical NF1 microdeletion syndrome.

Eur J Med Genet 2021 May 17;64(5):104190. Epub 2021 Mar 17.

Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy. Electronic address:

Concurrence of distinct genetic conditions in the same patient is not rare. Several cases involving neurofibromatosis type 1 (NF1) have recently been reported, indicating the need for more extensive molecular analysis when phenotypic features cannot be explained by a single gene mutation. Here, we describe the clinical presentation of a boy with a typical NF1 microdeletion syndrome complicated by cleft palate and other dysmorphic features, hypoplasia of corpus callosum, and partial bicoronal craniosynostosis caused by a novel 2bp deletion in exon 2 of Meis homeobox 2 gene (MEIS2) inherited from the mildly affected father. This is only the second case of an inherited MEIS2 intragenic mutation reported to date. MEIS2 is known to be associated with cleft palate, intellectual disability, heart defects, and dysmorphic features. Our clinical report suggests that this gene may also have a role in cranial morphogenesis in humans, as previously observed in animal models.
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http://dx.doi.org/10.1016/j.ejmg.2021.104190DOI Listing
May 2021

Novel unconventional variants expand the allelic spectrum of OPHN1 gene.

Am J Med Genet A 2021 05 27;185(5):1575-1581. Epub 2021 Feb 27.

Department of Molecular Medicine, University of Pavia, Pavia, Italy.

Mutations in the OPHN1 gene cause a rare X-linked recessive neurodevelopmental disorder characterized by intellectual disability, variably associated with cerebellar hypoplasia and distinctive facial appearance. In most of cases so far reported, the identified genomic variants involve the region encoding the central RhoGAP domain of the oligophrenin-1 protein, and are predicted to result in a complete loss of function. By using a NGS-based diagnostic approach, we identified three male and a female patients from two unrelated families carrying novel non-disruptive OPHN1 variants (the in-frame c.116_127 deletion and the missense c.2129C>T change, respectively), affecting either the BAR domain or the C-terminus proline-rich domain of the protein. Clinical and neuroimaging findings in the patients recapitulated the main features of OPHN1-related syndrome, including developmental delay, intellectual disability, behavioral disorder, dysmorphic features, seizures, cerebellar hypoplasia, and ventriculomegaly. Yet, we observed a wide variability even among affected siblings, confirming the lack of clear genotype-phenotype correlation. Our results expand the allelic spectrum of OPHN1 and illustrate the challenges for clinical interpretation of non-disruptive variants affecting X-linked genes.
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http://dx.doi.org/10.1002/ajmg.a.62144DOI Listing
May 2021

Linked-Read Whole Genome Sequencing Solves a Double Gene Rearrangement.

Genes (Basel) 2021 01 21;12(2). Epub 2021 Jan 21.

UOSID Genetica Medica e Cardiomiologia, Dipartimento di Medicina di Precisione, Università degli Studi della Campania "Luigi Vanvitelli", 80138 Napoli, Italy.

Next generation sequencing (NGS) has changed our approach to diagnosis of genetic disorders. Nowadays, the most comprehensive application of NGS is whole genome sequencing (WGS) that is able to detect virtually all DNA variations. However, even after accurate WGS, many genetic conditions remain unsolved. This may be due to the current NGS protocols, based on DNA fragmentation and short reads. To overcome these limitations, we applied a linked-read sequencing technology that combines single-molecule barcoding with short-read WGS. We were able to assemble haplotypes and distinguish between alleles along the genome. As an exemplary case, we studied the case of a female carrier of X-linked muscular dystrophy with an unsolved genetic status. A deletion of exons 16-29 in gene was responsible for the disease in her family, but she showed a normal dosage of these exons by Multiplex Ligation-dependent Probe Amplification (MLPA) and array CGH. This situation is usually considered compatible with a "non-carrier" status. Unexpectedly, the girl also showed an increased dosage of flanking exons 1-15 and 30-34. Using linked-read WGS, we were able to distinguish between the two X chromosomes. In the first allele, we found the 16-29 deletion, while the second allele showed a 1-34 duplication: in both cases, linked-read WGS correctly mapped the borders at single-nucleotide resolution. This duplication in trans apparently restored the normal dosage of exons 16-29 seen by quantitative assays. This had a dramatic impact in genetic counselling, by converting a non-carrier into a double carrier status prediction. We conclude that linked-read WGS should be considered as a valuable option to improve our understanding of unsolved genetic conditions.
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http://dx.doi.org/10.3390/genes12020133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909759PMC
January 2021

Identification of an Identical SCAMP5 Missense Variant in Four Unrelated Patients With Seizures and Severe Neurodevelopmental Delay.

Front Pharmacol 2020 18;11:599191. Epub 2020 Dec 18.

Department of Pediatrics, Peking University First Hospital, Beijing, China.

To establish and broaden the phenotypic spectrum of secretory carrier membrane protein ( associated with epilepsy and neurodevelopmental delay. A Chinese patient was identified at the First Hospital of Peking University, and the three unrelated patients were recruited from two different countries (Italy and United States) through GeneMatcher. pathogenic variants were identified by whole exome sequencing; clinical data of the patients were retrospectively collected and analyzed. The onset age of seizures was ranged from 6 to 15 months. Patients had different types of seizures, including focal seizures, generalized tonic-clonic seizures and tonic seizure. One patient showed typical autism spectrum disorder (ASD) symptoms. Electroencephalogram (EEG) findings presented as focal or multifocal discharges, sometimes spreading to generalization. Brain magnetic resonance imaging (MRI) abnormalities were present in each patient. Severe intellectual disability and language and motor developmental disorders were found in our patients, with all patients having poor language development and were nonverbal at last follow-up. All but one of the patients could walk independently in childhood, but the ability to walk independently in one patient had deteriorated with age. All patients had abnormal neurological exam findings, mostly signs of extrapyramidal system involvement. Dysmorphic features were found in 2/4 patients, mainly in the face and trunk. All four unrelated patients were found to have the same heterozygous pathogenic variant (p. Gly180Trp). Epilepsy, severe developmental delay, abnormal neurological exam findings, with or without ASD or variably dysmorphic features and were common in patients with variant. The onset time and type of seizure varied greatly. The EEG and brain MRI findings were not consistent, but diverse and nonspecific. The motor ability of patients with heterozygous variant might have a regressive course; language development was more severely affected.
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http://dx.doi.org/10.3389/fphar.2020.599191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775611PMC
December 2020

The Human Microbiota in Endocrinology: Implications for Pathophysiology, Treatment, and Prognosis in Thyroid Diseases.

Front Endocrinol (Lausanne) 2020 4;11:586529. Epub 2020 Dec 4.

Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy.

The human microbiota is an integral component in the maintenance of health and of the immune system. Microbiome-wide association studies have found numerous diseases associated to dysbiosis. Studies are needed to move beyond correlations and begin to address causation. Autoimmune thyroid diseases (ATD) are one of the most common organ-specific autoimmune disorders with an increasing prevalence, higher than 5% worldwide. Most frequent manifestations of ATD are Hashimoto's thyroiditis and Graves' disease. The exact etiology of ATD remains unknown. Until now it is not clear whether bacterial infections can trigger ATD or modulate the efficacy of treatment and prognosis. The aim of our review is to characterize the microbiota and in ATD and to evaluate the impact of dysbiosis on treatment and prognosis. Moreover, variation of gut microbiome has been associated with thyroid cancer and benign nodules. Here we will characterize the microbioma in benign thyroid nodules, and papillary thyroid cancer to evaluate their implications in the pathophysiology and progression.
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http://dx.doi.org/10.3389/fendo.2020.586529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746874PMC
May 2021

Milder presentation of TELO2-related syndrome in two sisters homozygous for the p.Arg609His pathogenic variant.

Eur J Med Genet 2021 Jan 8;64(1):104116. Epub 2020 Dec 8.

Developmental Neurology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.

Biallelic loss of function of TELO2 gene cause a severe syndromic disease mainly characterized by global developmental delay with poor motor and language acquisitions, microcephaly, short stature, minor facial and limbs anomalies, sleep disorder, spasticity, and balance impairment up to ataxia. TELO2-related syndrome, also known as You-Hoover-Fong Syndrome, is extremely rare and since its first description in 2016 only 8 individuals have been reported, all showing a severe disability. The causative gene is member of the big molecular family of genes responsible for cells proliferation and DNA stability. We describe the case of two sisters, carrying the homozygous p. Arg609His variant of the gene, who present a milder phenotype of TELO2-related syndrome. Such variant has been reported once in a more severely affected patient, in compound heterozygous state associated with the p. Pro260Leu variant, suggesting a possible role of the p. Arg609His variant in determining milder phenotypes. Comparing the siblings with all previously reported cases, we offer an overview on the condition and discuss TELO2 genetic interactions, in order to further explore the molecular bases of this recently described disorder.
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http://dx.doi.org/10.1016/j.ejmg.2020.104116DOI Listing
January 2021

Estimating the impact of COVID-19 pandemic on services provided by Italian Neuromuscular Centers: an Italian Association of Myology survey of the acute phase.

Acta Myol 2020 Jun 1;39(2):57-66. Epub 2020 Jun 1.

Child and Adolescent Unit, IRCCS Mondino Foundation, Pavia, Italy.

Introduction: Since February 2020, the outbreak of COVID-19 in Italy has forced the health care system to undergo profound rearrangements in its services and facilities, especially in the worst-hit areas in Northern Italy. In this setting, inpatient and outpatient services had to rethink and reorganize their activities to meet the needs of patients during the "lockdown". The Italian Association of Myology developed a survey to estimate the impact of these changes on patients affected by neuromuscular disorders and on specialized neuromuscular centers during the acute phase of COVID-19 pandemic.

Methods: We developed an electronic survey that was sent to neuromuscular centers affiliated with the Italian Association of Myology, assessing changes in pharmacological therapies provision, outpatient clinical and instrumental services, support services (physiotherapy, nursing care, psychological support) and clinical trials.

Results: 40% of surveyed neuromuscular centers reported a reduction in outpatient visit and examinations (44.5% of centers in Northern regions; 25% of centers in Central regions; 50% of centers in Southern regions). Twenty-two% of centers postponed in-hospital administration of therapies for neuromuscular diseases (23.4% in Northern regions; 13.0% in Central regions; 20% in Southern regions). Diagnostic and support services (physiotherapy, nursing care, psychological support) were suspended in 57% of centers (66/43/44% in Northern, Central and Southern centers respectively) Overall, the most affected services were rehabilitative services and on-site outpatient visits, which were suspended in 93% of centers. Strategies adopted by neuromuscular centers to overcome these changes included maintaining urgent on-site visits, addressing patients to available services and promoting remote contact and telemedicine.

Conclusions: Overall, COVID-19 pandemic resulted in a significant disruption of clinical and support services for patients with neuromuscular diseases. Despite the efforts to provide telemedicine consults to patients, this option could be promoted and improved further. A close collaboration between the different neuromuscular centers and service providers as well as further implementation of telehealth platforms are necessary to ensure quality care to NMD patients in the near future and in case of recurrent pandemic waves.
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http://dx.doi.org/10.36185/2532-1900-008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460733PMC
June 2020

New genotype-phenotype correlations in a large European cohort of patients with sarcoglycanopathy.

Brain 2020 09;143(9):2696-2708

Center of Translational and Experimental Myology, IRCCS Istituto Giannina Gaslini, Genova, Italy.

Sarcoglycanopathies comprise four subtypes of autosomal recessive limb-girdle muscular dystrophies (LGMDR3, LGMDR4, LGMDR5 and LGMDR6) that are caused, respectively, by mutations in the SGCA, SGCB, SGCG and SGCD genes. In 2016, several clinicians involved in the diagnosis, management and care of patients with LGMDR3-6 created a European Sarcoglycanopathy Consortium. The aim of the present study was to determine the clinical and genetic spectrum of a large cohort of patients with sarcoglycanopathy in Europe. This was an observational retrospective study. A total of 33 neuromuscular centres from 13 different European countries collected data of the genetically confirmed patients with sarcoglycanopathy followed-up at their centres. Demographic, genetic and clinical data were collected for this study. Data from 439 patients from 13 different countries were collected. Forty-three patients were not included in the analysis because of insufficient clinical information available. A total of 159 patients had a confirmed diagnosis of LGMDR3, 73 of LGMDR4, 157 of LGMDR5 and seven of LGMDR6. Patients with LGMDR3 had a later onset and slower progression of the disease. Cardiac involvement was most frequent in LGMDR4. Sixty per cent of LGMDR3 patients carried one of the following mutations, either in a homozygous or heterozygous state: c.229C>T, c.739G>A or c.850C>T. Similarly, the most common mutations in LMGDR5 patients were c.525delT or c.848G>A. In LGMDR4 patients the most frequent mutation was c.341C>T. We identified onset of symptoms before 10 years of age and residual protein expression lower than 30% as independent risk factors for losing ambulation before 18 years of age, in LGMDR3, LGMDR4 and LGMDR5 patients. This study reports clinical, genetic and protein data of a large European cohort of patients with sarcoglycanopathy. Improving our knowledge about these extremely rare autosomal recessive forms of LGMD was helped by a collaborative effort of neuromuscular centres across Europe. Our study provides important data on the genotype-phenotype correlation that is relevant for the design of natural history studies and upcoming interventional trials in sarcoglycanopathies.
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http://dx.doi.org/10.1093/brain/awaa228DOI Listing
September 2020

A novel RAB39B mutation and concurrent de novo NF1 mutation in a boy with neurofibromatosis type 1, intellectual disability, and autism: a case report.

BMC Neurol 2020 Sep 1;20(1):327. Epub 2020 Sep 1.

Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Via Luigi De Crecchio,7 -, 80138, Naples, Italy.

Background: Mutations in RAB39B at Xq28 causes a rare form of X-linked intellectual disability (ID) and Parkinson's disease. Neurofibromatosis type 1 (NF1) is caused by heterozygous mutations in NF1 occurring de novo in about 50% of cases, usually due to paternal gonadal mutations. This case report describes clinical and genetic findings in a boy with the occurrence of two distinct causative mutations in NF1 and RAB39B explaining the observed phenotype.

Case Presentation: Here we report a 7-year-old boy with multiple café-au-lait macules (CALMs) and freckling, severe macrocephaly, peculiar facial gestalt, severe ID with absent speech, epilepsy, autistic traits, self-harming, and aggressiveness. Proband is an only child born to a father aged 47. Parents did not present signs of NF1, while a maternal uncle showed severe ID, epilepsy, and tremors.By RNA analysis of NF1, we identified a de novo splicing variant (NM_000267.3:c.6579+2T>C) in proband, which explained NF1 clinical features but not the severe ID, behavioral problems, and aggressiveness. Family history suggested an X-linked condition and massively parallel sequencing of X-exome identified a novel RAB39B mutation (NM_171998.2:c.436_447del) in proband, his mother, and affected maternal uncle, subsequently validated by Sanger sequencing in these and other family members.

Conclusions: The case presented here highlights how concurrent genetic defects should be considered in NF1 patients when NF1 mutations cannot reasonably explain all the observed clinical features.
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http://dx.doi.org/10.1186/s12883-020-01911-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460788PMC
September 2020

The position of nonsense mutations can predict the phenotype severity: A survey on the DMD gene.

PLoS One 2020 19;15(8):e0237803. Epub 2020 Aug 19.

Dipartimento di Medicina di Precisione, Università degli Studi della Campania "Luigi Vanvitelli", Napoli, Italy.

A nonsense mutation adds a premature stop signal that hinders any further translation of a protein-coding gene, usually resulting in a null allele. To investigate the possible exceptions, we used the DMD gene as an ideal model. First, because dystrophin absence causes Duchenne muscular dystrophy (DMD), while its reduction causes Becker muscular dystrophy (BMD). Second, the DMD gene is X-linked and there is no second allele that can interfere in males. Third, databases are accumulating reports on many mutations and phenotypic data. Finally, because DMD mutations may have important therapeutic implications. For our study, we analyzed large databases (LOVD, HGMD and ClinVar) and literature and revised critically all data, together with data from our internal patients. We totally collected 2593 patients. Positioning these mutations along the dystrophin transcript, we observed a nonrandom distribution of BMD-associated mutations within selected exons and concluded that the position can be predictive of the phenotype. Nonsense mutations always cause DMD when occurring at any point in fifty-one exons. In the remaining exons, we found milder BMD cases due to early 5' nonsense mutations, if reinitiation can occur, or due to late 3' nonsense when the shortened product retains functionality. In the central part of the gene, all mutations in some in-frame exons, such as in exons 25, 31, 37 and 38 cause BMD, while mutations in exons 30, 32, 34 and 36 cause DMD. This may have important implication in predicting the natural history and the efficacy of therapeutic use of drug-stimulated translational readthrough of premature termination codons, also considering the action of internal natural rescuers. More in general, our survey confirm that a nonsense mutation should be not necessarily classified as a null allele and this should be considered in genetic counselling.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0237803PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7437896PMC
October 2020

Genotype-phenotype correlations in recessive titinopathies.

Genet Med 2020 12 11;22(12):2029-2040. Epub 2020 Aug 11.

Department of Neurosciences, Nerve-Muscle Unit, Lausanne University Hospital (CHUV), 1011, Lausanne, Switzerland.

Purpose: High throughput sequencing analysis has facilitated the rapid analysis of the entire titin (TTN) coding sequence. This has resulted in the identification of a growing number of recessive titinopathy patients. The aim of this study was to (1) characterize the causative genetic variants and clinical features of the largest cohort of recessive titinopathy patients reported to date and (2) to evaluate genotype-phenotype correlations in this cohort.

Methods: We analyzed clinical and genetic data in a cohort of patients with biallelic pathogenic or likely pathogenic TTN variants. The cohort included both previously reported cases (100 patients from 81 unrelated families) and unreported cases (23 patients from 20 unrelated families).

Results: Overall, 132 causative variants were identified in cohort members. More than half of the cases had hypotonia at birth or muscle weakness and a delayed motor development within the first 12 months of life (congenital myopathy) with causative variants located along the entire gene. The remaining patients had a distal or proximal phenotype and a childhood or later (noncongenital) onset. All noncongenital cases had at least one pathogenic variant in one of the final three TTN exons (362-364).

Conclusion: Our findings suggest a novel association between the location of nonsense variants and the clinical severity of the disease.
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http://dx.doi.org/10.1038/s41436-020-0914-2DOI Listing
December 2020

De novo SMARCA2 variants clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability and blepharophimosis distinct from Nicolaides-Baraitser syndrome.

Genet Med 2020 11 22;22(11):1838-1850. Epub 2020 Jul 22.

Department of Genetics, Robert Debré Hospital, AP-HP, Paris, France.

Purpose: Nontruncating variants in SMARCA2, encoding a catalytic subunit of SWI/SNF chromatin remodeling complex, cause Nicolaides-Baraitser syndrome (NCBRS), a condition with intellectual disability and multiple congenital anomalies. Other disorders due to SMARCA2 are unknown.

Methods: By next-generation sequencing, we identified candidate variants in SMARCA2 in 20 individuals from 18 families with a syndromic neurodevelopmental disorder not consistent with NCBRS. To stratify variant interpretation, we functionally analyzed SMARCA2 variants in yeasts and performed transcriptomic and genome methylation analyses on blood leukocytes.

Results: Of 20 individuals, 14 showed a recognizable phenotype with recurrent features including epicanthal folds, blepharophimosis, and downturned nasal tip along with variable degree of intellectual disability (or blepharophimosis intellectual disability syndrome [BIS]). In contrast to most NCBRS variants, all SMARCA2 variants associated with BIS are localized outside the helicase domains. Yeast phenotype assays differentiated NCBRS from non-NCBRS SMARCA2 variants. Transcriptomic and DNA methylation signatures differentiated NCBRS from BIS and those with nonspecific phenotype. In the remaining six individuals with nonspecific dysmorphic features, clinical and molecular data did not permit variant reclassification.

Conclusion: We identified a novel recognizable syndrome named BIS associated with clustered de novo SMARCA2 variants outside the helicase domains, phenotypically and molecularly distinct from NCBRS.
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http://dx.doi.org/10.1038/s41436-020-0898-yDOI Listing
November 2020

ACE2 gene variants may underlie interindividual variability and susceptibility to COVID-19 in the Italian population.

Eur J Hum Genet 2020 11 17;28(11):1602-1614. Epub 2020 Jul 17.

Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy.

In December 2019, an initial cluster of interstitial bilateral pneumonia emerged in Wuhan, China. A human-to-human transmission was assumed and a previously unrecognized entity, termed coronavirus disease-19 (COVID-19) due to a novel coronavirus (SARS-CoV-2) was described. The infection has rapidly spread out all over the world and Italy has been the first European country experiencing the endemic wave with unexpected clinical severity in comparison with Asian countries. It has been shown that SARS-CoV-2 utilizes angiotensin converting enzyme 2 (ACE2) as host receptor and host proteases for cell surface binding and internalization. Thus, a predisposing genetic background can give reason for interindividual disease susceptibility and/or severity. Taking advantage of the Network of Italian Genomes (NIG), here we mined whole-exome sequencing data of 6930 Italian control individuals from five different centers looking for ACE2 variants. A number of variants with a potential impact on protein stability were identified. Among these, three more common missense changes, p.(Asn720Asp), p.(Lys26Arg), and p.(Gly211Arg) were predicted to interfere with protein structure and stabilization. Rare variants likely interfering with the internalization process, namely p.(Leu351Val) and p.(Pro389His), predicted to interfere with SARS-CoV-2 spike protein binding, were also observed. Comparison of ACE2 WES data between a cohort of 131 patients and 258 controls allowed identifying a statistically significant (P value < 0.029) higher allelic variability in controls compared with patients. These findings suggest that a predisposing genetic background may contribute to the observed interindividual clinical variability associated with COVID-19, allowing an evidence-based risk assessment leading to personalized preventive measures and therapeutic options.
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http://dx.doi.org/10.1038/s41431-020-0691-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7366459PMC
November 2020

Expansion of the phenotypic spectrum of de novo missense variants in kinesin family member 1A (KIF1A).

Hum Mutat 2020 Jul 11. Epub 2020 Jul 11.

Brain and Mitochondrial Research Group, Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia.

Defects in the motor domain of kinesin family member 1A (KIF1A), a neuron-specific ATP-dependent anterograde axonal transporter of synaptic cargo, are well-recognized to cause a spectrum of neurological conditions, commonly known as KIF1A-associated neurological disorders (KAND). Here, we report one mutation-negative female with classic Rett syndrome (RTT) harboring a de novo heterozygous novel variant [NP_001230937.1:p.(Asp248Glu)] in the highly conserved motor domain of KIF1A. In addition, three individuals with severe neurodevelopmental disorder along with clinical features overlapping with KAND are also reported carrying de novo heterozygous novel [NP_001230937.1:p.(Cys92Arg) and p.(Pro305Leu)] or previously reported [NP_001230937.1:p.(Thr99Met)] variants in KIF1A. In silico tools predicted these variants to be likely pathogenic, and 3D molecular modeling predicted defective ATP hydrolysis and/or microtubule binding. Using the neurite tip accumulation assay, we demonstrated that all novel KIF1A variants significantly reduced the ability of the motor domain of KIF1A to accumulate along the neurite lengths of differentiated SH-SY5Y cells. In vitro microtubule gliding assays showed significantly reduced velocities for the variant p.(Asp248Glu) and reduced microtubule binding for the p.(Cys92Arg) and p.(Pro305Leu) variants, suggesting a decreased ability of KIF1A to move along microtubules. Thus, this study further expanded the phenotypic characteristics of KAND individuals with pathogenic variants in the KIF1A motor domain to include clinical features commonly seen in RTT individuals.
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http://dx.doi.org/10.1002/humu.24079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7908811PMC
July 2020

Identification and Characterization of Splicing Defects by Single-Molecule Real-Time Sequencing Technology (PacBio).

J Neuromuscul Dis 2020 ;7(4):477-481

Folkhälsan Research Center, Helsinki, Finland.

Although DNA-sequencing is the most effective procedure to achieve a molecular diagnosis in genetic diseases, complementary RNA analyses are often required.Reverse-Transcription polymerase chain reaction (RT-PCR) is still a valuable option when the clinical phenotype and/or available DNA-test results address the diagnosis toward a gene of interest or when the splicing effect of a single variant needs to be assessed.We use Single-Molecule Real-Time sequencing to detect and characterize splicing defects and single nucleotide variants in well-known disease genes (DMD, NF1, TTN). After proper optimization, the procedure could be used in the diagnostic setting, simplifying the workflow of cDNA analysis.
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http://dx.doi.org/10.3233/JND-200523DOI Listing
July 2021

Loss of Wwox Perturbs Neuronal Migration and Impairs Early Cortical Development.

Front Neurosci 2020 11;14:644. Epub 2020 Jun 11.

Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto "Giannina Gaslini", Genoa, Italy.

Mutations in the gene cause a broad range of ultra-rare neurodevelopmental and brain degenerative disorders, associated with a high likelihood of premature death in animal models as well as in humans. The encoded Wwox protein is a WW domain-containing oxidoreductase that participates in crucial biological processes including tumor suppression, cell growth/differentiation and regulation of steroid metabolism, while its role in neural development is less understood. We analyzed the exomes of a family affected with multiple pre- and postnatal anomalies, including cerebellar vermis hypoplasia, severe neurodevelopmental impairment and refractory epilepsy, and identified a segregating homozygous mutation leading to a premature stop codon. Abnormal cerebral cortex development due to a defective architecture of granular and molecular cell layers was found in the developing brain of a -deficient human fetus from this family. A similar disorganization of cortical layers was identified in rats (carrying a homozygous truncating mutation which disrupts the active Wwox C-terminal domain) investigated at perinatal stages. Transcriptomic analyses of Wwox-depleted human neural progenitor cells showed an impaired expression of a number of neuronal migration-related genes encoding for tubulins, kinesins and associated proteins. These findings indicate that loss of Wwox may affect different cytoskeleton components and alter prenatal cortical development, highlighting a regulatory role of the gene in migrating neurons across different species.
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http://dx.doi.org/10.3389/fnins.2020.00644DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7300205PMC
June 2020

An Alu-mediated duplication in NMNAT1, involved in NAD biosynthesis, causes a novel syndrome, SHILCA, affecting multiple tissues and organs.

Hum Mol Genet 2020 08;29(13):2250-2260

Department of Genetics and Genome Biology, University of LE1 7RH Leicester, Leicester, UK.

We investigated the genetic origin of the phenotype displayed by three children from two unrelated Italian families, presenting with a previously unrecognized autosomal recessive disorder that included a severe form of spondylo-epiphyseal dysplasia, sensorineural hearing loss, intellectual disability and Leber congenital amaurosis (SHILCA), as well as some brain anomalies that were visible at the MRI. Autozygome-based analysis showed that these children shared a 4.76 Mb region of homozygosity on chromosome 1, with an identical haplotype. Nonetheless, whole-exome sequencing failed to identify any shared rare coding variants, in this region or elsewhere. We then determined the transcriptome of patients' fibroblasts by RNA sequencing, followed by additional whole-genome sequencing experiments. Gene expression analysis revealed a 4-fold downregulation of the gene NMNAT1, residing indeed in the shared autozygous interval. Short- and long-read whole-genome sequencing highlighted a duplication involving 2 out of the 5 exons of NMNAT1 main isoform (NM_022787.3), leading to the production of aberrant mRNAs. Pathogenic variants in NMNAT1 have been previously shown to cause non-syndromic Leber congenital amaurosis (LCA). However, no patient with null biallelic mutations has ever been described, and murine Nmnat1 knockouts show embryonic lethality, indicating that complete absence of NMNAT1 activity is probably not compatible with life. The rearrangement found in our cases, presumably causing a strong but not complete reduction of enzymatic activity, may therefore result in an intermediate syndromic phenotype with respect to LCA and lethality.
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http://dx.doi.org/10.1093/hmg/ddaa112DOI Listing
August 2020

Sinus pericranii, skull defects, and structural brain anomalies in TRAF7-related disorder.

Birth Defects Res 2020 08 27;112(14):1085-1092. Epub 2020 May 27.

UOC Neurosurgery, IRCCS Istituto Giannina Gaslini, Genoa, Italy.

Background: Several somatic mutations in TRAF7 have been reported in cancers, whereas a few germline heterozygous mutations have been recently linked to a neurodevelopmental disorder, characterized by craniofacial dysmorphisms, congenital heart defects, and digital anomalies.

Cases: We report two subjects harboring de novo heterozygous missense variants in TRAF7, namely the recurrent 1964G>A(p.Arg655Gln) and the novel missense c.1204C>G(p.Leu402Val) variants. In addition to the typical hallmarks of the TRAF7-related disorder, both subjects presented with a recognizable "pear-shaped" skull due to multiple craniosynostosis, sinus pericranii, skull base/cranio-cervical junction anomalies, dysgyria, and inferior cerebellar vermis hypoplasia.

Conclusions: Hence, we expand the genotypic and phenotypic spectrum of this neurodevelopmental disorder, discussing possible implications for clinical management of subjects with germline TRAF7 mutations.
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http://dx.doi.org/10.1002/bdr2.1711DOI Listing
August 2020

Congenital posterior cervical spine malformation due to biallelic c.240-4T>G RIPPLY2 variant: A discrete entity.

Am J Med Genet A 2020 06 25;182(6):1466-1472. Epub 2020 Mar 25.

Centre de génétique humaine, Université de Franche Comté, Besançon, France.

The clinical and radiological spectrum of spondylocostal dysostosis syndromes encompasses distinctive costo-vertebral anomalies. RIPPLY2 biallelic pathogenic variants were described in two distinct cervical spine malformation syndromes: Klippel-Feil syndrome and posterior cervical spine malformation. RIPPLY2 is involved in the determination of rostro-caudal polarity and somite patterning during development. To date, only four cases have been reported. The current report aims at further delineating the posterior malformation in three new patients. Three patients from two unrelated families underwent clinical and radiological examination through X-ray, 3D computed tomography and brain magnetic resonance imaging. After informed consent was obtained, family-based whole exome sequencing (WES) was performed. Complex vertebral segmentation defects in the cervico-thoracic spine were observed in all patients. WES led to the identification of the homozygous splicing variant c.240-4T>G in all subjects. This variant is predicted to result in aberrant splicing of Exon 4. The current report highlights a subtype of cervical spine malformation with major atlo-axoidal malformation compromising spinal cord integrity. This distinctive mutation-specific pattern of malformation differs from Klippel-Feil syndrome and broadens the current classification, defining a sub-type of RIPPLY2-related skeletal disorder. Of note, the phenotype of one patient overlaps with oculo-auriculo-vertebral spectrum disorder.
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http://dx.doi.org/10.1002/ajmg.a.61549DOI Listing
June 2020

The Genetic Landscape of Dystrophin Mutations in Italy: A Nationwide Study.

Front Genet 2020 3;11:131. Epub 2020 Mar 3.

Neuromuscular Diseases and Neuroimmunology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.

Dystrophinopathies are inherited diseases caused by mutations in the dystrophin () gene for which testing is mandatory for genetic diagnosis, reproductive choices and eligibility for personalized trials. We genotyped the gene in our Italian cohort of 1902 patients (BMD n = 740, 39%; DMD n =1162, 61%) within a nationwide study involving 11 diagnostic centers in a 10-year window (2008-2017). In DMD patients, we found deletions in 57%, duplications in 11% and small mutations in 32%. In BMD, we found deletions in 78%, duplications in 9% and small mutations in 13%. In BMD, there are a higher number of deletions, and small mutations are more frequent than duplications. Among small mutations that are generally frequent in both phenotypes, 44% of DMD and 36% of BMD are nonsense, thus, eligible for stop codon read-through therapy; 63% of all out-of-frame deletions are eligible for single exon skipping. Patients were also assigned to Italian regions and showed interesting regional differences in mutation distribution. The full genetic characterization in this large, nationwide cohort has allowed us to draw several correlations between DMD/BMD genotype landscapes and mutation frequency, mutation types, mutation locations along the gene, exon/intron architecture, and relevant protein domain, with effects on population genetic characteristics and new personalized therapies.
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http://dx.doi.org/10.3389/fgene.2020.00131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063120PMC
March 2020

Cavitating and tigroid-like leukoencephalopathy in a case of -related disorder.

JIMD Rep 2020 Mar 6;52(1):11-16. Epub 2020 Feb 6.

Department of Translational Medicine Federico II University Naples Italy.

Biallelic variants in nuclear gene have been reported so far in only three children with variable presentations including Leigh syndrome or leukoencephalopathy. Herein, we report a further female child affected by -related disorder presenting with cavitating and tigroid-like pattern of leukodystrophy and without systemic biochemical abnormalities of mitochondrial disorders.
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http://dx.doi.org/10.1002/jmd2.12094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052689PMC
March 2020

Expansion of the phenotype of lateral meningocele syndrome.

Am J Med Genet A 2020 05 6;182(5):1259-1262. Epub 2020 Mar 6.

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

Lateral meningocele syndrome (LMS) is due to specific pathogenic variants in the last exon of NOTCH3 gene. Besides the lateral meningoceles, this condition presents with dysmorphic features, short stature, congenital heart defects, and feeding difficulties. Here, we report a girl with neurosensorial hearing loss, severe gastroesophageal reflux disease, congenital heart defects, multiple renal cysts, kyphosis and left-convex scoliosis, dysmorphic features, and mild developmental delay. Exome sequencing detected the previously unreported de novo loss-of-function variant in exon 33 of NOTCH3 p.(Lys2137fs). Following the identification of the gene defect, MRI of the brain and spine revealed temporal encephaloceles, inner ears anomalies, multiple spinal lateral meningoceles, and intra- and extra-dural arachnoid spinal cysts. This case illustrates the power of reverse phenotyping to establish clinical diagnosis and expands the spectrum of clinical manifestations related to LMS to include inner ear abnormalities and multi-cystic kidney disease.
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http://dx.doi.org/10.1002/ajmg.a.61536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217177PMC
May 2020

Improved Criteria for the Classification of Titin Variants in Inherited Skeletal Myopathies.

J Neuromuscul Dis 2020 ;7(2):153-166

Folkhälsan Research Center, Helsinki, Finland.

Background: Extensive genetic screening results in the identification of thousands of rare variants that are difficult to interpret. Because of its sheer size, rare variants in the titin gene (TTN) are detected frequently in any individual. Unambiguous interpretation of molecular findings is almost impossible in many patients with myopathies or cardiomyopathies.

Objective: To refine the current classification framework for TTN-associated skeletal muscle disorders and standardize the interpretation of TTN variants.

Methods: We used the guidelines issued by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) to re-analyze TTN genetic findings from our patient cohort.

Results: We identified in the classification guidelines three rules that are not applicable to titin-related skeletal muscle disorders; six rules that require disease-/gene-specific adjustments and four rules requiring quantitative thresholds for a proper use. In three cases, the rule strength need to be modified.

Conclusions: We suggest adjustments are made to the guidelines. We provide frequency thresholds to facilitate filtering of candidate causative variants and guidance for the use and interpretation of functional data and co-segregation evidence. We expect that the variant classification framework for TTN-related skeletal muscle disorders will be further improved along with a better understanding of these diseases.
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http://dx.doi.org/10.3233/JND-190423DOI Listing
November 2020

Parkinsonism, Intellectual Disability, and Catatonia in a Young Male With Variant.

Mov Disord Clin Pract 2020 Jan 21;7(1):118-119. Epub 2019 Nov 21.

Department of Human Neuroscience Sapienza University of Rome Rome Italy.

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http://dx.doi.org/10.1002/mdc3.12865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962672PMC
January 2020
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