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Introduction
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January 2005 - present
January 1996 - December 2012
January 1992 - December 2008
Publications
Publications (346)
Purpose
We investigated the natural history of retinal dystrophy owing to variants in the MYO7A gene.
Methods
Fifty-three patients (mean age, 33.6 ± 16.7 years) with Usher syndrome owing to biallelic, mostly pathogenic, variants in MYO7A underwent baseline and two annual follow-up visits. Best-corrected visual acuity (BCVA), semiautomatic kinetic...
ABCA4 is the most frequently mutated gene leading to inherited retinal disease (IRD) with over 2200 pathogenic variants reported to date. Of these, ~1% are copy number variants (CNVs) involving the deletion or duplication of genomic regions, typically >50 nucleotides in length. An in-depth assessment of the current literature based on the public da...
Inherited retinal diseases (IRDs) are a group of rare monogenic diseases with high genetic heterogeneity (pathogenic variants identified in over 280 causative genes). The genetic diagnostic rate for IRDs is around 60%, mainly thanks to the routine application of next-generation sequencing (NGS) approaches such as extensive gene panels or whole exom...
Inherited macular dystrophies (iMDs) are a group of genetic disorders, which affect the central region of the retina. To investigate the genetic basis of iMDs, we used single-molecule Molecular Inversion Probes to sequence 105 maculopathy-associated genes in 1352 patients diagnosed with iMDs. Within this cohort, 39.8% of patients were considered ge...
Mucopolysaccharidosis type IIIA (MPS IIIA or Sanfilippo syndrome type A) is an autosomal recessive lysosomal storage disorder caused by pathogenic variants in the SGSH gene encoding N ‐sulfoglucosamine sulfohydrolase, an enzyme involved in the degradation of heparan sulfate. MPS IIIA is typically characterized by neurocognitive decline and hepatosp...
Objective: To determine the profile of inflammation-related proteins and complement system factors in serum of CRB1-associated inherited retinal dystrophies (CRB1-IRDs).
Design: A case-control study.
Subjects, Participants, and/or Controls: A cohort of 30 Dutch CRB1-IRD patients and 29 Dutch healthy controls (HC) (Cohort I), and a second cohort of...
The ABCA4 gene is the most frequently mutated Mendelian retinopathy-associated gene. Biallelic variants lead to a variety of phenotypes, however, for thousands of cases the underlying variants remain unknown. Here, we aim to shed further light on the missing heritability of ABCA4-associated retinopathy by analyzing a large cohort of macular dystrop...
Background
Non-syndromic inherited retinal dystrophies (IRDs) such as retinitis pigmentosa or Leber congenital amaurosis generally manifest between early childhood and late adolescence, imposing profound long-term impacts as a result of vision impairment or blindness. IRDs are highly heterogeneous, with often overlapping symptoms among different IR...
BACKGROUND: Conversion of adenosine in RNA to inosine by ADAR enzymes, termed 'RNA editing', occurs at thousands of sites across the transcriptome, and is required for healthy development of the central nervous system. RNA editing can modify protein sequences, and dampen the innate immune response. RNA editing is tissue-specific and partly genetica...
Objectives:
VPS35 and VPS13 have been associated with Parkinson's disease (PD), and their shared phenotype in yeast when reduced in function is abnormal vacuolar transport. We aim to test if additional potentially deleterious variants in other genes that share this phenotype can modify the risk for PD.
Methods:
77 VPS and VPS-related genes were...
Background
Inherited retinal diseases (IRD) are genetically heterogeneous disorders that cause the dysfunction or loss of photoreceptor cells and ultimately lead to blindness. To date, next-generation sequencing procedures fail to detect pathogenic sequence variants in coding regions of known IRD disease genes in about 30–40% of patients. One of th...
Introduction: Retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) are two groups of inherited retinal diseases (IRDs) where the rod photoreceptors degenerate followed by the cone photoreceptors of the retina. A genetic diagnosis for IRDs is challenging since >280 genes are associated with these conditions. While whole exome sequencing (W...
Loss-of-function variants in CHAMP1 were recently described as cause of a neurodevelopmental disorder characterized by intellectual disability (ID), autism, and distinctive facial characteristics. By exome sequencing (ES), we identified a truncating variant in CHAMP1, c.1858A > T (p.Lys620*), in a patient who exhibited a similar phenotype of severe...
Inherited retinal diseases (IRDs) are the leading cause of vision loss in the working-age population. We performed a retrospective epidemiological study to determine the genetic basis of IRDs in a large Italian cohort (n = 2790) followed at a single referral center. We provided, mainly by next generation sequencing, potentially conclusive molecular...
Retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) are two groups of inherited retinal diseases (IRDs) where the rod photoreceptors degenerate followed by the cone photoreceptors of the retina. A genetic diagnosis for IRDs is challenging since >280 genes are associated with these conditions. While whole exome sequencing (WES) is commonl...
Here we describe three patients with neurodevelopmental disorders characterized by mild-to-moderate intellectual disability, mildly dysmorphic features, and hirsutism, all of which carry de novo sequence variants in the WW domain-containing adaptor of the coiled-coil (WAC) gene; two of these-c.167delA, p.(Asn56I1efs*136) and c.1746G>C, p.(Gln582His...
To report quantitative retinal changes assessed by spectral-domain optical coherence tomography (SD-OCT) in children treated with voretigene neparvovec (VN) at a single center in Italy. Retrospective review of six consecutive pediatric patients with biallelic RPE65 -related dystrophy treated bilaterally with VN. SD-OCT scans were analyzed to extrac...
Inherited retinal diseases (IRDs) are a group of diseases whose common landmark is progressive photoreceptor loss. The development of gene-specific therapies for IRDs is hampered by their wide genetic heterogeneity. Mitochondrial dysfunction is proving to constitute one of the key pathogenic events in IRDs; hence, approaches that enhance mitochondr...
Retinal photoreceptors have a distinct transcriptomic profile compared to other neuronal subtypes, likely reflecting their unique cellular morphology and function in the detection of light stimuli by way of the ciliary outer segment. We discovered a layer of this molecular specialization by revealing that the vertebrate retina expresses the largest...
Variants in RAC3, encoding a small GTPase RAC3 which is critical for the regulation of actin cytoskeleton and intracellular signal transduction, are associated with a rare neurodevelopmental disorder with structural brain anomalies and facial dysmorphism.
We investigated a cohort of 10 unrelated participants presenting with global psychomotor delay...
Purpose:
To investigate the course of inherited retinal degenerations (IRD) due to mutations in the RPE65 gene.
Methods:
This longitudinal multicentric retrospective chart-review study was designed to collect best corrected visual acuity (BCVA), Goldman visual field, optical coherence tomography (OCT), and electroretinography (ERG) measurements....
Homozygous deletions (HDs) may be the cause of rare diseases and cancer, and their discovery in targeted sequencing is a challenging task. Different tools have been developed to disentangle HD discovery but a sensitive caller is still lacking. We present VarGenius-HZD, a sensitive and scalable algorithm that leverages breadth-of-coverage for the de...
Background
This research aimed to establish recommendations on the clinical and genetic characteristics necessary to confirm patient eligibility for gene supplementation with voretigene neparvovec.
Methods
An expert steering committee comprising an interdisciplinary panel of Italian experts in the three fields of medical specialisation involved in...
Purpose:
To present visual outcomes of the first two Italian patients with RPE65-related inherited retinal dystrophy (RPE65-IRD) treated with voretigene neparvovec (VN).
Methods:
Two pediatric patients with RPE65-IRD were treated with VN in both eyes. Patients were evaluated by best-corrected visual acuity (BCVA), full-field stimulus threshold (...
Retinal photoreceptors differ in their transcriptomic profiles from other neuronal subtypes, likely as a reflection of their unique cellular morphology and function in the detection of light thorough the ciliary outer segment. We discovered a new layer of this molecular specialization by revealing that the vertebrate retina expresses the largest nu...
Die hereditären Netzhautdystrophien (IRD; inherited retinal diseases) sind eine heterogene Gruppe von Krankheiten – unter anderem Retinitis pigmentosa (RP), Lebersche kongenitale Amaurose (LCA) und Netzhautdystrophie mit frühem Krankheitsbeginn (EO[S]RD; early-onset [severe] retinal dystrophy) –, die sich hinsichtlich der Schwere der Krankheit und...
Pathogenic variants in the MKS1 gene are responsible for a ciliopathy with a wide spectrum of clinical manifestations ranging from Meckel and Joubert syndrome (JBTS) to Bardet-Biedl syndrome, and involving the central nervous system, liver, kidney, skeleton, and retina. We report a 39-year-old male individual presenting with isolated Retinitis Pigm...
Inherited retinal diseases (IRDs) are a heterogeneous group of conditions that include retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) and early-onset severe retinal dystrophy (EO[S]RD), which differ in severity and age of onset. IRDs are caused by mutations in >250 genes. Variants in the RPE65 gene account for 0.6–6% of RP and 3–16%...
Purpose:
The purpose of this study was to perform a detailed longitudinal phenotyping and genetic characterization of 32 Italian patients with a nonsyndromic retinal dystrophy and mutations in the CEP290 gene.
Methods:
We reviewed the clinical history and examinations of 32 patients with a nonsyndromic retinal dystrophy due to mutations in the C...
Motivation
Homozygous deletions (HDs) may be the cause of rare diseases and cancer and their discovery in targeted sequencing is a challenging task. Different tools have been developed to disentangle HD discovery but a sensitive caller is still lacking.
Results
We present VarGenius-HZD, a sensitive and scalable algorithm that leverages breadth-of-...
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Achromatopsia (ACHM) is a rare genetic disorder of infantile onset affecting cone photoreceptors. To determine the extent of progressive retinal changes in achromatopsia, we performed a detailed longitudinal phenotyping and genetic characterization of an Italian cohort comprising 21 ACHM patients (17 unrelated families). Molecular genetic testing i...
Photoreceptors (PRs) are specialized neuroepithelial cells of the retina responsible for sensory transduction of light stimuli. In the highly structured vertebrate retina, PRs have a highly polarized modular structure to accommodate the demanding processes of phototransduction and the visual cycle. Because of their function, PRs are exposed to cont...
Purpose:
The purpose of this study was to perform a detailed longitudinal phenotyping of X-linked retinitis pigmentosa (RP) caused by mutations in the RPGR gene during a long follow-up period.
Methods:
An Italian cohort of 48 male patients (from 31 unrelated families) with RPGR-associated RP was clinically assessed at a single center (mean follo...
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...
Importance
Treatment trials require sound knowledge on the natural course of disease.
Objective
To assess clinical features, genetic findings, and genotype-phenotype correlations in patients with retinitis pigmentosa (RP) associated with biallelic sequence variations in the PDE6A gene in preparation for a gene supplementation trial.
Design, Setti...
Gene therapy is proving to be an effective approach to treat or prevent ocular diseases ensuring a targeted, stable, and regulated introduction of exogenous genetic material with therapeutic action. Retinal diseases can be broadly categorized into two groups, namely monogenic and complex (multifactorial) forms. The high genetic heterogeneity of mon...
Peroxisomal biogenesis disorders (PBD) are rare autosomal recessive disorders with various degrees of severity caused by hypomorphic mutations in 13 different peroxin (PEX) genes. In this study, we report the clinical and molecular characterization of a 9-years-old female presenting an apparently isolated pre-lingual sensorineural hearing loss (SNH...
Background
Inherited retinal disorders are a clinically and genetically heterogeneous group of conditions and a major cause of visual impairment. Common disease subtypes include vitelliform macular dystrophy (VMD) and retinitis pigmentosa (RP). Despite the identification of over 90 genes associated with RP, conventional genetic testing fails to det...
Purpose : Inherited retinal diseases (IRDs), characterized by progressive photoreceptor (PRs) cell death, represent a significant cause of visual impairment in the Western population. Their broad genetic heterogeneity constitutes an important limitation to the development of gene-specific therapies. Therefore, there is a strong need for the impleme...
We investigated the genetic origin of the phenotype of three children from two unrelated Italian families presenting with a previously-unrecognized, seemingly autosomal recessive disorder that included a severe form of spondylo-epiphyseal dysplasia, sensorineural hearing loss, intellectual disability, and Leber congenital amaurosis (SHILCA), as wel...
Missing heritability in human diseases represents a major challenge, and this is particularly true for ABCA4-associated Stargardt disease (STGD1). We aimed to elucidate the genomic and transcriptomic variation in 1054 unsolved STGD and STGD-like probands.
Sequencing of the complete 128-kb ABCA4 gene was performed using single-molecule molecular inv...
MicroRNAs (miRNAs) are small noncoding RNAs playing a fundamental role in the regulation of gene expression. Evidence accumulating in the past decades indicate that they are capable of simultaneously modulating diverse signaling pathways involved in a variety of pathophysiological processes. In the present review, we provide a comprehensive overvie...
Vertebrate vision relies on the daily phagocytosis and lysosomal degradation of photoreceptor outer segments (POS) within the retinal pigment epithelium (RPE). However, how these events are controlled by light is largely unknown. Here, we show that the light-responsive miR-211 controls lysosomal biogenesis at the beginning of light-dark transitions...
Inherited retinal diseases (IRDs) represent a frequent cause of genetic blindness. Their high genetic heterogeneity hinders the application of gene-specific therapies to the vast majority of patients. We recently demonstrated that the microRNA miR-204 is essential for retinal function, although the underlying molecular mechanisms remain poorly unde...
Missing heritability in human diseases represents a major challenge. Although whole-genome sequencing enables the analysis of coding and non-coding sequences, substantial costs and data storage requirements hamper its large-scale use to (re)sequence genes in genetically unsolved cases. The ABCA4 gene implicated in Stargardt disease (STGD1) has been...
Accumulating evidence on the role of non-protein-coding RNA sequences in the regulation of gene expression is greatly expanding our understanding of the flow of genetic information within biological systems. The interplay between protein-coding and non-coding RNAs (ncRNAs) is essential for tissue development, homeostasis, and function. NcRNAs can b...
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We identified a 14q21.2 microdeletion in a 16-year-old boy with autism spectrum disorder (ASD), IQ in the lower part of normal range but high-functioning memory skills. The deletion affects a gene desert, and the non-deleted gene closest to the microdeletion boundaries is LRFN5, which encodes a protein involved in synaptic plasticity and implicated...
Mitochondrial diseases (MDs) are a heterogeneous group of devastating and often fatal disorders due to defective oxidative phosphorylation. Despite the recent advances in mitochondrial medicine, effective therapies are still not available for these conditions. Here, we demonstrate that the microRNAs miR-181a and miR-181b (miR-181a/b) regulate key g...
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‐...
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.
Background
Targeted resequencing has become the most used and cost-effective approach for identifying causative mutations of Mendelian diseases both for diagnostics and research purposes. Due to very rapid technological progress, NGS laboratories are expanding their capabilities to address the increasing number of analyses. Several open source tool...
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 vari...
Purpose:
We studied microRNAs as potential biomarkers for Pompe disease.
Methods:
We analyzed microRNA expression by small RNA-seq in tissues from the disease murine model at two different ages (3 and 9 months), and in plasma from Pompe patients.
Results:
In the mouse model we found 211 microRNAs that were differentially expressed in gastrocne...
MicroRNAs (miRNAs) are key post-transcriptional regulators of gene expression that play an important role in the control of fundamental biological processes in both physiological and pathological conditions. Their function in retinal cells is just beginning to be elucidated, and a few have been found to play a role in photoreceptor maintenance and...
The gene DST encodes for the large protein BPAG1 involved in hemidesmosomes. Its alternative splicing gives rise to tissue-enriched isoforms in brain, muscle, and skin. The few patients described so far with bi-allelic mutations in the DST gene have either a skin phenotype of epidermolysis bullosa simplex or a neurological phenotype. Here, we repor...
Fundus Autofluorescence analysis of patients A322, A333a and A333b. The analysis revealed mild macular hypoautofluorescence in A322 (A) and more evident hypoautofluorescence in A333a (B) and A333b (C). Note the absence of autofluorescence in the macula of patients A333a and A333b, as also highlighted by the corresponding increased RPE dystrophy in...