Publications by authors named "Annalaura Torella"

63 Publications

INPP5K and SIL1 associated pathologies with overlapping clinical phenotypes converge through dysregulation of PHGDH.

Brain 2021 Apr 1. Epub 2021 Apr 1.

Guy's and St Thomas' NHS Trust and King's College London, London, UK.

Marinesco-Sjögren syndrome (MSS) is a rare human disorder caused by biallelic mutations in SIL1 characterized by cataracts in infancy, myopathy and ataxia, symptoms that are also associated with a novel disorder caused by mutations in INPP5K. While these phenotypic similarities may suggest commonalties at a molecular level, an overlapping pathomechanism has not been established yet. In this study, we present six new INPP5K patients and expand the current mutational and phenotypical spectrum of the disease showing the clinical overlap between MSS and the INPP5K-phenotype. We applied unbiased proteomic profiling on cells derived from MSS- and INPP5K-patients and identified alterations in D-3-phosphoglycerate dehydrogenase as a common molecular feature. D-3-phosphoglycerate dehydrogenase modulates the production of L-serine and mutations in this enzyme were previously associated with a neurological phenotype, which clinically overlaps with MSS and INPP5K-disease. As, L-serine administration represents a promising therapeutic strategy for D-3-phosphoglycerate dehydrogenase patients, we tested the effect of L-serine in generated sil1, phgdh and inpp5k a + b zebrafish models which showed an improvement in their neuronal phenotype. Thus our study defines a core phenotypical feature underpinning a key common molecular mechanism in three rare diseases and reveals a common and novel therapeutic target for these patients.
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http://dx.doi.org/10.1093/brain/awab133DOI Listing
April 2021

Performance of cell-free DNA sequencing-based non-invasive prenatal testing: experience on 36,456 singleton and multiple pregnancies.

BMC Med Genomics 2021 Mar 30;14(1):93. Epub 2021 Mar 30.

AMES, Centro Polidiagnostico Strumentale, Srl, Naples, Italy.

Background: This paper describes the clinical practice and performance of cell-free DNA sequencing-based non-invasive prenatal testing (NIPT) as a screening method for fetal trisomy 21, 18, and 13 (T21, T18, and T13) and sex chromosome aneuploidies (SCA) in a general Italian pregnancy population.

Methods: The AMES-accredited laboratory offers NIPT in maternal blood as a screening test for fetal T21, T18, T13 and SCA. Samples were sequenced on a NextSeq 550 (Illumina) using the VeriSeq NIPT Solution v1 assay.

Results: A retrospective analysis was performed on 36,456 consecutive maternal blood samples, including 35,650 singleton pregnancies, 800 twin pregnancies, and 6 triplet pregnancies. Samples were tested between April 2017 and September 2019. The cohort included 46% elevated-risk and 54% low-risk patients. A result indicative of a classic trisomy was found in 356 (1%) of singleton or twin samples: 254 T21, 69 T18, and 33 T13. In addition, 145 results (0.4%) were indicative of a SCA. Of the combined 501 screen-positive cases, 484 had confirmatory diagnostic testing. NIPT results were confirmed in 99.2% (247/249) of T21 cases, 91.2% (62/68) of T18 cases, 84.4% (27/32) of T13 cases, and 86.7% (117/135) of SCA cases. In the 35,955 cases reported as unaffected by a classic trisomy or SCA, no false negative cases were reported. Assuming that false negative results would be reported, the sensitivity of NIPT was 100.00% for T21 (95% Cl 98.47-100.0), T18 (95% Cl 94.17-100.0), and T13 (95% Cl 87.54-100.0). The specificities were 99.99% (95% Cl 99.98-100.0), 99.98% (95% Cl 99.96-100.0), 99.99% (95% Cl 99.97-100.0), and 99.95% (95% Cl 99.92-99.97) for T21, T18, T13, and SCA, respectively.

Conclusion: This retrospective analysis of a large cohort of consecutive patients who had whole-genome sequencing-based NIPT for classic trisomies and SCA shows excellent detection rates and low false positive rates.
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http://dx.doi.org/10.1186/s12920-021-00941-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011149PMC
March 2021

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

Genes (Basel) 2021 Jan 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

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.

Folkhälsan Research Center, Helsinki, Finland.

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 Translational Medicine, Federico II University, Naples, Italy.

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
January 2020

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 Aug;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.

Unit of Medical Genetics, Department of Medical Sciences, University of Ferrara, Ferrara, 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

Clinical and Genetic Analysis of a European Cohort with Pericentral Retinitis Pigmentosa.

Int J Mol Sci 2019 Dec 20;21(1). Epub 2019 Dec 20.

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

Retinitis pigmentosa (RP) is a clinically heterogenous disease that comprises a wide range of phenotypic and genetic subtypes. Pericentral RP is an atypical form of RP characterized by bone-spicule pigmentation and/or atrophy confined in the near mid-periphery of the retina. In contrast to classic RP, the far periphery is better preserved in pericentral RP. The aim of this study was to perform the first detailed clinical and genetic analysis of a cohort of European subjects with pericentral RP to determine the phenotypic features and the genetic bases of the disease. A total of 54 subjects from 48 independent families with pericentral RP, non-syndromic and syndromic, were evaluated through a full ophthalmological examination and underwent clinical exome or retinopathy gene panel sequencing. Disease-causative variants were identified in 22 of the 35 families (63%) in 10 different genes, four of which are also responsible for syndromic RP. Thirteen of the 34 likely pathogenic variants were novel. Intra-familiar variability was also observed. The current study confirms the mild phenotype of pericentral RP and extends the spectrum of genes associated with this condition.
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http://dx.doi.org/10.3390/ijms21010086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6982348PMC
December 2019

Clinical and Genetic Findings in Children with Neurofibromatosis Type 1, Legius Syndrome, and Other Related Neurocutaneous Disorders.

Genes (Basel) 2019 07 31;10(8). Epub 2019 Jul 31.

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

Pigmentary manifestations can represent an early clinical sign in children affected by Neurofibromatosis type 1 (NF1), Legius syndrome, and other neurocutaneous disorders. The differential molecular diagnosis of these pathologies is a challenge that can now be met by combining next generation sequencing of target genes with concurrent second-level tests, such as multiplex ligation-dependent probe amplification and RNA analysis. We clinically and genetically investigated 281 patients, almost all pediatric cases, presenting with either NF1 ( = 150), only pigmentary features (café au lait macules with or without freckling; ( = 95), or clinical suspicion of other RASopathies or neurocutaneous disorders ( = 36). The causative variant was identified in 239 out of the 281 patients analyzed (85.1%), while 42 patients remained undiagnosed (14.9%). The and genes were mutated in 73.3% and 2.8% of cases, respectively. The remaining 8.9% carried mutations in different genes associated with other disorders. We achieved a molecular diagnosis in 69.5% of cases with only pigmentary manifestations, allowing a more appropriate clinical management of these patients. Our findings, together with the increasing availability and sharing of clinical and genetic data, will help to identify further novel genotype-phenotype associations that may have a positive impact on patient follow-up.
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http://dx.doi.org/10.3390/genes10080580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6722641PMC
July 2019

Cardiac diseases as a predictor warning of hereditary muscle diseases. The case of laminopathies.

Acta Myol 2019 Jun 1;38(2):33-36. Epub 2019 Jun 1.

Cardiomiology and Medical Genetics, Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy.

Mutations in the gene are associated with a wide spectrum of disease phenotypes, ranging from neuromuscular, cardiac and metabolic disorders to premature aging syndromes. Skeletal muscle involvement may present with different phenotypes: limb-girdle muscular dystrophy type 1B or -related dystrophy; autosomal dominant Emery-Dreifuss muscular dystrophy; and a congenital form of muscular dystrophy, frequently associated with early onset of arrhythmias. Heart involvement may occur as part of the muscle involvement or independently, regardless of the presence of the myopathy. Notably conduction defects and dilated cardiomyopathy may exist without a muscle disease. This paper will focus on cardiac diseases presenting as the first manifestation of skeletal muscle hereditary disorders such as laminopathies, inspired by two large families with cardiovascular problems long followed by conventional cardiologists who did not suspect a genetic muscle disorder underlying these events. Furthermore it underlines the need for a multidisciplinary approach in these disorders and how the figure of the may play a key role in facilitating the diagnostic process, and addressing the adoption of appropriate prevention measures.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6598412PMC
June 2019

A new family with transportinopathy: increased clinical heterogeneity.

Ther Adv Neurol Disord 2019 9;12:1756286419850433. Epub 2019 Jun 9.

TIGEM (Telethon Institute of Genetics and Medicine), University at Campania, Naples, Italy.

We describe a family with a novel TNPO3 mutation of limb-girdle muscular dystrophy D2 (or LGMD 1F), a rare muscle disorder with autosomal dominant inheritance, first identified in an Italo-Spanish family where the causative defect has been found to be due to TNPO3 gene mutation, encoding transportin-3 protein (TNPO3). We present the clinical, histopathological and muscle magnetic resonance imaging (MRI) features in two patients, mother and son Hungarian origin, affected by LGMD D2 and correlate their clinical, MRI and histopathological data found in this condition. The affected son presented early pelvic girdle muscle weakness and thin muscles similar to a congenital myopathy; the mother was less compromised and had an LGMD phenotype. Muscle MRI showed a very pronounced lower limb muscle atrophy in both patients. The most relevant change obtained in the child muscle biopsy was a generalized type 1 fibre atrophy. The two patients presented the same mutation, but a different phenotype has been observed in mother and son.
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http://dx.doi.org/10.1177/1756286419850433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6558532PMC
June 2019

Congenital myopathy with hanging big toe due to homozygous myopalladin (MYPN) mutation.

Skelet Muscle 2019 05 27;9(1):14. Epub 2019 May 27.

Dipartimento di Medicina di Precisione, Università della Campania "Luigi Vanvitelli", Naples, Italy.

Background: Myopalladin (MYPN) is a component of the sarcomere that tethers nebulin in skeletal muscle and nebulette in cardiac muscle to alpha-actinin at the Z lines. Autosomal dominant MYPN mutations cause hypertrophic, dilated, or restrictive cardiomyopathy. Autosomal recessive MYPN mutations have been reported in only six families showing a mildly progressive nemaline or cap myopathy with cardiomyopathy in some patients.

Case Presentation: A consanguineous family with congenital to adult-onset muscle weakness and hanging big toe was reported. Muscle biopsy showed minimal changes with internal nuclei, type 1 fiber predominance, and ultrastructural defects of Z line. Muscle CT imaging showed marked hypodensity of the sartorius bilaterally and MRI scattered abnormal high-intensity areas in the internal tongue muscle and in the posterior cervical muscles. Cardiac involvement was demonstrated by magnetic resonance imaging and late gadolinium enhancement. Whole exome sequencing analysis identified a homozygous loss of function single nucleotide deletion in the exon 11 of the MYPN gene in two siblings. Full-length MYPN protein was undetectable on immunoblotting, and on immunofluorescence, its localization at the Z line was missed.

Conclusions: This report extends the phenotypic spectrum of recessive MYPN-related myopathies showing: (1) the two patients had hanging big toe and the oldest one developed spine and hand contractures, none of these signs observed in the previously reported patients, (2) specific ultrastructural changes consisting in Z line fragmentation, but (3) no nemaline or caps on muscle pathology.
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http://dx.doi.org/10.1186/s13395-019-0199-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6535860PMC
May 2019

Retinal dystrophy in an individual carrying a de novo missense variant of SMARCA4.

Mol Genet Genomic Med 2019 06 11;7(6):e682. Epub 2019 Apr 11.

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

Background: Coffin-Siris syndrome (CSS) is characterized by intellectual disability, dysmorphic facial features, growth deficiency, microcephaly, and abnormalities of the fifth fingers/toes. CSS is caused by mutations in several genes of the BRG1-associated factor pathway including SMARCA4.

Methods: Whole-exome sequencing was performed on a 14-year-old female individual who presented with mild intellectual disability and dysmorphic features, tooth abnormalities, and short stature. She had brachydactyly but no aplasia or hypoplasia of the distal phalanx or nail of the fifth digit. She was also found to have retinal dystrophy that has not been previously reported in CSS.

Results: The individual presented herein was found to harbor a previously unreported de novo variant in SMARCA4.

Conclusion: This case expands the phenotypic spectrum of CSS manifestations.
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http://dx.doi.org/10.1002/mgg3.682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6565552PMC
June 2019

Three de novo DDX3X variants associated with distinctive brain developmental abnormalities and brain tumor in intellectually disabled females.

Eur J Hum Genet 2019 08 1;27(8):1254-1259. Epub 2019 Apr 1.

Department of Neurosurgery, IRCCS Istituto Giannina Gaslini, Via Gerolamo Gaslini, 5, 16147, Genoa, Italy.

De novo DDX3X variants account for 1-3% of syndromic intellectual disability (ID) in females and have been occasionally reported in males. Furthermore, somatic DDX3X variants occur in several aggressive cancers, including medulloblastoma. We report three unrelated females with severe ID, dysmorphic features, and a common brain malformative pattern characterized by malformations of cortical development, callosal dysgenesis, basal ganglia anomalies, and midbrain-hindbrain malformations. A pilocytic astrocytoma was incidentally diagnosed in Patient 1 and trigonocephaly was found in Patient 2. With the use of family based whole exome sequencing (WES), we identified three distinct de novo variants in DDX3X. These findings expand the phenotypic spectrum of DDX3X-related disorders, demonstrating unique neuroradiological features resembling those of the tubulinopathies, and support a role for DDX3X in neuronal development. Our observations further suggest a possible link between germline DDX3X variants and cancer development.
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http://dx.doi.org/10.1038/s41431-019-0392-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777618PMC
August 2019

Correction: Biallelic sequence and structural variants in RAX2 are a novel cause for autosomal recessive inherited retinal disease.

Genet Med 2019 04;21(4):1028

Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent, Belgium.

The original version of this Article contained an incorrect version of Fig. 3, which included two variants initially shown in black text in Fig. 3a that the authors removed from the final manuscript. The correct version of Fig. 3 without the two variants now appears in the PDF and HTML versions of the Article.
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http://dx.doi.org/10.1038/s41436-018-0392-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752296PMC
April 2019

AP1S2-truncating variant in a patient with severe neurodevelopmental disorder and cerebral folate deficiency.

Acta Paediatr 2019 03 27;108(3):564-565. Epub 2018 Nov 27.

Department of Human Neurosciences, Unit of Infantile Neurology and Psychiatry, University of Rome 'La Sapienza', Rome, Italy.

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http://dx.doi.org/10.1111/apa.14633DOI Listing
March 2019

Biallelic sequence and structural variants in RAX2 are a novel cause for autosomal recessive inherited retinal disease.

Genet Med 2019 06 31;21(6):1319-1329. Epub 2018 Oct 31.

Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent, Belgium.

Purpose: RAX2 encodes a homeobox-containing transcription factor, in which four monoallelic pathogenic variants have been described in autosomal dominant cone-dominated retinal disease.

Methods: Exome sequencing in a European cohort with inherited retinal disease (IRD) (n = 2086) was combined with protein structure modeling of RAX2 missense variants, bioinformatics analysis of deletion breakpoints, haplotyping of RAX2 variant c.335dup, and clinical assessment of biallelic RAX2-positive cases and carrier family members.

Results: Biallelic RAX2 sequence and structural variants were found in five unrelated European index cases, displaying nonsyndromic autosomal recessive retinitis pigmentosa (ARRP) with an age of onset ranging from childhood to the mid-40s (average mid-30s). Protein structure modeling points to loss of function of the novel recessive missense variants and to a dominant-negative effect of the reported dominant RAX2 alleles. Structural variants were fine-mapped to disentangle their underlying mechanisms. Haplotyping of c.335dup in two cases suggests a common ancestry.

Conclusion: This study supports a role for RAX2 as a novel disease gene for recessive IRD, broadening the mutation spectrum from sequence to structural variants and revealing a founder effect. The identification of biallelic RAX2 pathogenic variants in five unrelated families shows that RAX2 loss of function may be a nonnegligible cause of IRD in unsolved ARRP cases.
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http://dx.doi.org/10.1038/s41436-018-0345-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752271PMC
June 2019

Copy Number Variants Account for a Tiny Fraction of Undiagnosed Myopathic Patients.

Genes (Basel) 2018 Oct 26;9(11). Epub 2018 Oct 26.

Dipartimento di Medicina di Precisione, Università degli Studi della Campania "Luigi Vanvitelli", 80138 Napoli, Italy.

Next-generation sequencing (NGS) technologies have led to an increase in the diagnosis of heterogeneous genetic conditions. However, over 50% of patients with a genetically inherited disease are still without a diagnosis. In these cases, different hypotheses are usually postulated, including variants in novel genes or elusive mutations. Although the impact of copy number variants (CNVs) in neuromuscular disorders has been largely ignored to date, missed CNVs are predicted to have a major role in disease causation as some very large genes, such as the dystrophin gene, have prone-to-deletion regions. Since muscle tissues express several large disease genes, the presence of elusive CNVs needs to be comprehensively assessed following an accurate and systematic approach. In this multicenter cohort study, we analyzed 234 undiagnosed myopathy patients using a custom array comparative genomic hybridization (CGH) that covers all muscle disease genes at high resolution. Twenty-two patients (9.4%) showed non-polymorphic CNVs. In 12 patients (5.1%), the identified CNVs were considered responsible for the observed phenotype. An additional ten patients (4.3%) presented candidate CNVs not yet proven to be causative. Our study indicates that deletions and duplications may account for 5⁻9% of genetically unsolved patients. This strongly suggests that other mechanisms of disease are yet to be discovered.
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http://dx.doi.org/10.3390/genes9110524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6267442PMC
October 2018