Marcello Scala - Independent Researcher (original) (raw)

Papers by Marcello Scala

Genotype–phenotype spectrum and correlations in Xia‐Gibbs syndrome: Report of five novel cases and literature review

Birth Defects Research, Jun 18, 2022

BackgroundXia‐Gibbs syndrome (XGS) is a rare neurodevelopmental disorder caused by pathogenic var... more BackgroundXia‐Gibbs syndrome (XGS) is a rare neurodevelopmental disorder caused by pathogenic variants in the AT‐hook DNA‐binding motif‐containing 1 gene (AHDC1), encoding a protein with a crucial role in transcription and epigenetic regulation, axonogenesis, brain function, and neurodevelopment. AHDC1 variants possibly act through a dominant‐negative mechanism and may interfere with DNA repair processes, leading to genome instability and impaired DNA translesion repair. Variants affecting residues closer to the N‐terminal are thought to determine a milder phenotype with better cognitive performances. However, clean‐cut genotype–phenotype correlations are still lacking.CasesIn this study, we investigated five subjects with XGS in whom exome sequencing led to the identification of five novel de novo pathogenic variants in AHDC1. All variants were extremely rare and predicted to cause a loss of protein function. The phenotype of the reported patients included developmental delay, hypotonia, and distinctive facial dysmorphisms. Additionally, uncommon clinical features were observed, including congenital hypothyroidism and peculiar skeletal abnormalities.ConclusionsIn this study, we report uncommon XGS features associated with five novel truncating variants in AHDC, thus expanding the genotype and phenotypic spectrum of this complex condition. We also compared our cases to previously reported cases, discussing the current status of genotype–phenotype correlations in XGS.

Pelizaeus–Merzbacher Disease due to PLP1 Frameshift Mutation in a Female with Nonrandom Skewed X-Chromosome Inactivation

Neuropediatrics, May 28, 2019

The identification of the genetic causes and the underlying pathogenic mechanisms in early-onset ... more The identification of the genetic causes and the underlying pathogenic mechanisms in early-onset epilepsies has proved to be essential in improving the efficacy of therapeutic decisions and the overall patient management, especially in the era of precision medicine. We report an infant presenting with a cluster of focal motor seizures with autonomic manifestations at day 3 of life. Electroencephalograms showed multifocal epileptic abnormalities and a burst-suppression pattern. Neurological examination showed poor visual fixation and hypotonia. Neuroimaging was normal. Seizures remitted with phenytoin and were well-controlled after the switch to oral carbamazepine. In the hypothesis of a genetic etiology, next-generation sequencing panel for epileptic encephalopathies was performed and identified a de novo missense mutation in KCNQ2 : c.1742G>A; p.(Arg581Gln) (NM_172107.2). This case report highlights the importance of the early recognition of the electroclinical phenotype and the detection of the underlying genetic cause in the implementation of "tailored" therapies in early-onset genetic epilepsies.

Frontiers in Neuroscience, Jun 11, 2020

We acknowledge the support from Enea-Eroi in ricerca onlus (www.eneaonlus.org). We also gratefull... more We acknowledge the support from Enea-Eroi in ricerca onlus (www.eneaonlus.org). We also gratefully acknowledge the family for their participation to this study.

European Journal of Human Genetics, Mar 28, 2023

Ciliopathies are disorders of the primary cilium that can affect almost all organs and that are c... more Ciliopathies are disorders of the primary cilium that can affect almost all organs and that are characterized by pleiotropy and extensive intra-and interfamilial phenotypic variability. Accordingly, mutations in the same gene can cause different ciliopathy phenotypes of varying severity. WDR60 encodes a protein thought to play a role in the primary cilium's intraflagellar transport machinery. Mutations in this gene are a rare cause of Jeune asphyxiating thoracic dystrophy (JATD) and short-rib polydactyly syndrome (SRPS). Here we report on a milder and distinct phenotype in a consanguineous Pakistani pedigree with two adolescent sisters affected by retinal degeneration and postaxial polydactyly, but lack of any further skeletal or chondrodysplasia features. By targeted high-throughput sequencing of genes known or suspected to be involved in ciliogenesis, we detected a novel homozygous N-terminal truncating WDR60 mutation (c.44delC/p. Ala15Glufs*90) that co-segregated with the disease in the family. Our finding broadens the spectrum of WDR60-related phenotypes and shows the utility of broad multigene panels during the genetic work-up of patients with ciliopathies.

Congenital myopathy associated with a novel mutation in MEGF10 gene, myofibrillar alteration and progressive course

PubMed, 2022

Early-onset myopathy, areflexia, respiratory distress, and dysphagia (EMARDD) is caused by homozy... more Early-onset myopathy, areflexia, respiratory distress, and dysphagia (EMARDD) is caused by homozygous or compound heterozygous mutation in the MEGF10 gene (OMIM #614399). Phenotypic spectrum of EMARDD is variable, ranging from severe infantile forms in which patients are ventilator-dependent and die in childhood, to milder chronic disorders with a more favorable course (mild variant, mvEMARDD). Here we describe a 22 years old boy, offspring of consanguineous parents, presenting a congenital myopathic phenotype since infancy with elbow contractures and scoliosis. The patient developed a slowly progressive muscle weakness with impaired walking, rhinolalia, dysphagia, and respiratory involvement, which required noninvasive ventilation therapy since the age of 16 years. First muscle biopsy revealed unspecific muscle damage, with fiber size variation, internal nuclei and fibrosis. Myofibrillar alterations were noted at a second muscle biopsy including whorled fibres, cytoplasmic inclusion and minicores. Exome sequencing identified a homozygous mutation in MEGF10 gene, c.2096G > C (p.Cys699Ser), inherited by both parents. This variant, not reported in public databases of mutations, is expected to alter the structure of the protein and is therefore predicted to be probably damaging according to ACMG classification. In conclusion, we found a new likely pathogenic mutation in MEGF10, which is responsible for a progressive form of mvEMARDD with myofibrillar alterations at muscle biopsy. Interestingly, the presence of MEGF10 mutations has not been reported in Italian population. Early diagnosis of MEGF10 myopathy is essential in light of recent results from in vivo testing demonstrating a potential therapeutic effect of SSRIs compounds.

Letter to the Editor Regarding “Primary Aneurysmal Bone Cyst of the Thoracic Spine: A Pediatric Case Report”

World Neurosurgery, Dec 1, 2020

European Journal of Paediatric Neurology, Jul 1, 2019

GRIN1 encodes the obligate subunit (GluN1) of glutamate N-methyl-D-aspartate receptor (NMDAr). Pa... more GRIN1 encodes the obligate subunit (GluN1) of glutamate N-methyl-D-aspartate receptor (NMDAr). Pathogenic variants in GRIN1 are a well-known cause of infantile encephalopathy characterized by profound developmental delay (DD), variable epileptic phenotypes, and distinctive behavioral abnormalities. Recently, GRIN1 has also been implicated in the pathogenesis of polymicrogyria (PMG). We investigated two patients presenting with severe intellectual disability (ID), epilepsy, stereotyped movements, and abnormal ocular movements. They showed distinctive circadian rhythm alterations and sleep-wake patterns anomalies characterized by recurrent cyclic crying or laughing spells. Genetic analysis led to the identification of two distinct de novo variants in GRIN1 affecting the same amino acid residue of an important functional protein domain. Recent advances in circadian rhythm and sleep regulation suggest that abnormal GluN1 function might play a relevant pathogenetic role for the peculiar behavioral abnormalities observed in GRIN1 patients. Our cases highlight the relevance of circadian rhythm abnormalities in epileptic children as a clue toward GRIN1 encephalopathy and expand the complex phenotypic spectrum of this severe genetic disorder.

Journal of Genetics, Jun 1, 2019

The 16p12.2 chromosome band contains three large segmental duplications: BP1, BP2 and BP3, provid... more The 16p12.2 chromosome band contains three large segmental duplications: BP1, BP2 and BP3, providing a substrate for recombination and recurrent chromosomal rearrangements. The '16p12.2 microdeletion' is a recurrent deletion comprised between BP2 and BP3, associated with variable clinical findings. We identified a heterozygous 16p12.2 microdeletion spanning between BP1 and BP2 in a child evaluated for short stature and mild dyslexia. Unexpectedly, the mother carried the same deletion in the homozygous state and suffered from severe hearing loss. Detailed family history revealed consanguinity of the maternal grandparents. The 16p12.2 microdeletion is a rare condition and contains only three genes: METTL9, IGSF6 and OTOA of which the OTOA is considered responsible for DFNB22 hearing loss (MIM: 607039) under its homozygous condition. A number of OTOA mutations have been described, whereas very few cases of a 16p12.2 microdeletion similar to that observed in our family have been reported. In conclusion, we describe a rare 'distal 16p12.2 microdeletion' widening the phenotypic spectrum associated with the recurrent 16p12.2 microdeletion and support the causative role of OTOA microdeletion in hearing impairment.

Gain-of-function p.F28S variant inRAC3disrupts neuronal differentiation, migration and axonogenesis during cortical development, leading to neurodevelopmental disorder

Journal of Medical Genetics, May 20, 2022

BackgroundRAC3encodes a Rho family small GTPase that regulates the behaviour and organisation of ... more BackgroundRAC3encodes a Rho family small GTPase that regulates the behaviour and organisation of actin cytoskeleton and intracellular signal transduction. Variants inRAC3can cause a phenotypically heterogeneous neurodevelopmental disorder with structural brain anomalies and dysmorphic facies. The pathomechanism of this recently discovered genetic disorder remains unclear.MethodsWe investigated an early adolescent female with intellectual disability, drug-responsive epilepsy and white matter abnormalities. Through exome sequencing, we identified the novel de novo variant (NM_005052.3): c.83T>C (p.Phe28Ser) inRAC3. We then examined the pathophysiological significance of the p.F28S variant in comparison with the recently reported disease-causing p.Q61L variant, which results in a constitutively activated version of RAC3.ResultsIn vitro analyses revealed that the p.F28S variant was spontaneously activated by substantially increased intrinsic GTP/GDP-exchange activity and bound to downstream effectors tested, such as PAK1 and MLK2. The variant suppressed the differentiation of primary cultured hippocampal neurons and caused cell rounding with lamellipodia. In vivo analyses using in utero electroporation showed that acute expression of the p.F28S variant caused migration defects of excitatory neurons and axon growth delay during corticogenesis. Notably, defective migration was rescued by a dominant negative version of PAK1 but not MLK2.ConclusionOur results indicate that RAC3 is critical for brain development and the p.F28S variant causes morphological and functional defects in cortical neurons, likely due to the hyperactivation of PAK1.

medRxiv (Cold Spring Harbor Laboratory), Sep 15, 2021

doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by pee... more doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.

Italian Journal of Pediatrics, Oct 12, 2021

Background: Heterozygous variants in CNTNAP2 have been implicated in a wide range of neurological... more Background: Heterozygous variants in CNTNAP2 have been implicated in a wide range of neurological phenotypes, including intellectual disability (ID), epilepsy, autistic spectrum disorder (ASD), and impaired language. However, heterozygous variants can also be found in unaffected individuals. Biallelic CNTNAP2 variants are rarer and cause a well-defined genetic syndrome known as CASPR2 deficiency disorder, a condition characterised by ID, early-onset refractory epilepsy, language impairment, and autistic features. Case-report: A 7-year-old boy presented with hyperkinetic stereotyped movements that started during early infancy and persisted over childhood. Abnormal movements consisted of rhythmic and repetitive shaking of the four limbs, with evident stereotypic features. Additional clinical features included ID, attention deficit-hyperactivity disorder (ADHD), ASD, and speech impairment, consistent with CASPR2 deficiency disorder. Whole-genome array comparative genomic hybridization detected a maternally inherited 0.402 Mb duplication, which involved intron 1, exon 2, and intron 2 of CNTNAP2 (c.97 +?_209-?dup). The affected region in intron 1 contains a binding site for the transcription factor FOXP2, potentially leading to abnormal CNTNAP2 expression regulation. Sanger sequencing of the coding region of CNTNAP2 also identified a paternally-inherited missense variant c.2752C > T, p.(Leu918Phe). Conclusion: This case expands the molecular and phenotypic spectrum of CASPR2 deficiency disorder, suggesting that Hyperkinetic stereotyped movements may be a rare, yet significant, clinical feature of this complex neurological disorder. Furthermore, the identification of an in-frame, largely non-coding duplication in CNTNAP2 points to a sophisticated underlying molecular mechanism, likely involving impaired FOXP2 binding.

Homozygous SCN1B variants causing early infantile epileptic encephalopathy 52 affect voltage‐gated sodium channel function

Epilepsia, Apr 26, 2021

We identified nine patients from four unrelated families harboring three biallelic variants in SC... more We identified nine patients from four unrelated families harboring three biallelic variants in SCN1B ({"type":"entrez-nucleotide","attrs":{"text":"NM_001037.5","term_id":"1519245880"}}NM_001037.5: c.136C>T; p.[Arg46Cys], c.178C>T; p.[Arg60Cys], and c.472G>A; p.[Val158Met]). All subjects presented with early infantile epileptic encephalopathy 52 (EIEE52), a rare, severe developmental and epileptic encephalopathy featuring infantile onset refractory seizures followed by developmental stagnation or regression. Because SCN1B influences neuronal excitability through modulation of voltage-gated sodium (NaV) channel function, we examined the effects of human SCN1BR46C (β1R46C), SCN1BR60C (β1R60C), and SCN1BV158M (β1V158M) on the three predominant brain NaV channel subtypes NaV1.1 (SCN1A), NaV1.2 (SCN2A), and NaV1.6 (SCN8A). We observed a shift toward more depolarizing potentials of conductance–voltage relationships (NaV1.2/β1R46C, NaV1.2/β1R60C, NaV1.6/β1R46C, NaV1.6/β1R60C, and NaV1.6/β1V158M) and channel availability (NaV1.1/β1R46C, NaV1.1/β1V158M, NaV1.2/β1R46C, NaV1.2/β1R60C, and NaV1.6/β1V158M), and detected a slower recovery from fast inactivation for NaV1.1/β1V158M. Combined with modeling data indicating perturbation-induced structural changes in β1, these results suggest that the SCN1B variants reported here can disrupt normal NaV channel function in the brain, which may contribute to EIEE52.

Frontiers in Genetics, Mar 29, 2022

Reelin is a secreted extracellular matrix protein playing pivotal roles in neuronal migration and... more Reelin is a secreted extracellular matrix protein playing pivotal roles in neuronal migration and cortical stratification during embryonal brain development. In the adult brain, its activity is crucial for synaptic plasticity, memory processing, and cognition. Genetic alterations in RELN have been variably reported as possible contributors to the pathogenesis of autism spectrum disorders (ASD). In particular, GCCs repeats in the 5′UTR, and single nucleotide polymorphysms (SNPs) in RELN have been suggested to affect brain development and predispose to autism. We reviewed pertinent literature on RELN expression and haplotypes transmission in children with ASD, critically analyzing available evidence in support of the pathophysiological association between Reelin deficiency and ASD.

Frontiers in Pediatrics, Feb 27, 2023

De novo POLR2A p.(Ile457Thr) variant associated with early-onset encephalopathy and cerebellar atrophy: expanding the phenotypic spectrum

Brain & Development, Aug 1, 2022

BACKGROUND Heterozygous POLR2A variants have been recently reported in patients with a neurodevel... more BACKGROUND Heterozygous POLR2A variants have been recently reported in patients with a neurodevelopmental syndrome characterized by profound infantile-onset hypotonia. POLR2A encodes the highly conserved RBP1 protein, an essential subunit of the DNA-dependent RNA polymerase II. CASE PRESENTATION We investigated a 12-year-old girl presenting with an early-onset encephalopathy characterized by psychomotor delay, facial dysmorphism, refractory epilepsy with variable seizure types, behavioural abnormalities, and sleep disorder. Brain MRI showed a slowly progressive cerebellar atrophy. Trio-exome sequencing (Trio-ES) revealed the de novo germline variant NM_000937.5:c.1370T>C; p.(Ile457Thr) in POLR2A. This variant was previously reported in a subject with profound generalized hypotonia and muscular atrophy by Haijes et al. Our patient displayed instead a severe epileptic phenotype with refractory hypotonic seizures with impaired consciousness, myoclonic jerks, and drop attacks. CONCLUSION This case expands the clinical spectrum of POLR2A-related syndrome, highlighting its phenotypic variability and supporting the relevance of epilepsy as a core feature of this emerging condition.

International Journal of Molecular Sciences, Apr 25, 2021

This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

Journal of Genetics, May 30, 2019

Neuronal migration disorders (NMDs) are a heterogeneous group of conditions caused by the abnorma... more Neuronal migration disorders (NMDs) are a heterogeneous group of conditions caused by the abnormal migration of neuroblasts in the developing brain and nervous system, resulting in severe developmental impairment, intractable epilepsy and intellectual disability (Spalice et al. 2009). To date, many genes have been identified as the leading cause of migration defects, i.e. agyria/pachygyria, polymicrogyria, heterotopias, agenesis of the corpus callosum and agenesis of the cranial nerves (Spalice et al. 2009). Here, we present a patient with early infantile epileptic encephalopathy (Ohtahara syndrome) with seizure onset on the first day of life, severe developmental delay and an abnormal brain MRI with excessive folding of small, fused gyri and bilateral perisylvian polymicrogyria, suggestive of neuronal migration disorder. To clarify the unknown aetiology, we conducted whole-exome sequencing, which detected a de novo missense variant (c.5308A>T; p.(Met1770Leu)) in the SCN2A gene. This is a report of SCN2A gene variant identified in a patient with neuronal migration disorder which could further expand the phenotypic spectrum of these genetic disorders.

Frontiers in Pediatrics, Jan 14, 2022

American Journal of Medical Genetics, Jul 31, 2021

This is the author manuscript accepted for publication and has undergone full peer review but has... more This is the author manuscript accepted for publication and has undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as