The genetic causes of epilepsies and developmental and epileptic encephalopathies (DEE) with onset in early childhood are increasingly recognized. Their outcomes vary from benign to severe disability. In this paper, we wished to retrospectively review the clinical, genetic, EEG, neuroimaging, and outcome data of patients experiencing the onset of epilepsy in the first three years of life, diagnosed and followed up in four Italian epilepsy centres (Epilepsy Centre of San Paolo University Hospital in Milan, Child Neurology and Psychiatry Unit of AUSL-IRCCS di Reggio Emilia, Pediatric Neurology Unit of Vittore Buzzi Children’s Hospital, Milan, and Child Neurology and Psychiatry Unit, IRCCS Mondino Foundation, Pavia). We included 168 patients (104 with monogenic conditions, 45 with copy number variations (CNVs) or chromosomal abnormalities, and 19 with variants of unknown significance), who had been followed up for a mean of 14.75 years. We found a high occurrence of generalized seizures at onset, drug resistance, abnormal neurological examination, global developmental delay and intellectual disability, and behavioural and psychiatric comorbidities. We also documented differing presentations between monogenic issues versus CNVs and chromosomal conditions, as well as atypical/rare phenotypes. Genetic early-childhood-onset epilepsies and DEE show a very wide phenotypic and genotypic spectrum, with a high risk of complex neurological and neuropsychiatric phenotypes.

Chromatinopathies (CPs) are an expanding group of rare genetic disorders affecting epigenetic machinery. Besides an intricate genotypic spectrum, these conditions share overlapping phenotypes characterized by neurocognitive impairment, growth defects and distinctive, but often convergent, facial features. Although individually rare, the landscape of CPs is increasingly growing and represents an emerging and possibly underestimated cause of disability. Due to their complexity and rarity, accurate diagnosis and management pose significant difficulties. To address these challenges and gain a deeper overview of these diseases' spectrum, we retrospectively collected clinical characteristics of 239 patients diagnosed with CPs and critically analyzed their diagnostic journey, growth charts, neurological and gestaltic features. Starting from the largest collection of CPs to date, our data point to wide sequencing analyses as the best shortcut to diagnosis. We have also demonstrated the importance of growth defects in this group of disorders that require dedicated growth tables, and we have delved into the great variability of neurological and clinical burden in these conditions. This retrospective study provides a significant advance in our understanding of these rare diseases and will help to improve diagnostic, therapeutic, and clinical approaches to CPs and to develop personalized multidisciplinary care plans for affected patients.

Background Neurodevelopmental disorders, hypotonia, microcephaly or macrocephaly, poor growth and distinctive facial traits are some of the most common reasons to refer a child to an expert consultant. But which expert? A priori response might not be always predictable. Clinical experience teaches that it is not unusual to come across a metabolic diagnosis in a patient suspected of a genetic condition and vice versa. Still, although phenotypically convergent, genetic and metabolic disorders strongly diverge on therapeutic availability. In such an entangled scenario, new sequencing technologies may bring to light further uncertainties, detecting variants that often need a clinical confirm to be interpreted. Methods. In order to explore clinical convergence among metabolic and genetic disorders we present a cases’ collection of patients wrongly referred to metabolic disorder clinic or to medical genetic service in a third level Center in the North of Italy. Results. Data gained from this retrospective review demonstrate the striking importance of multi-disciplinary management of complex pediatric cases. Conclusions. In Hub Hospitals and in rare diseases’ Centers, it appears mandatory to promote a side by side collaboration embracing pediatricians, clinical geneticists and laboratory in order to take an all-around point of view of undiagnosed patients. What falls out of our competence might fall out of our view as well.

Background: Defining a genetic diagnosis is a challenging and stepwise process, often limited by current knowledge perspectives. Alterations in non-coding RNAs and in their modulating mechanisms are now emerging as one of the main possible explanations underpinning many unsolved cases of neurodevelopmental disorders. The latest description concerns the PUS7 gene, which encodes a pseudouridine synthase (PUS) enzyme, which has been causatively associated with an extremely rare recessive disease characterized by postnatal microcephaly, neurodevelopmental impairment, and minor dysmorphisms. Here, we report a novel case of this poorly known disorder, which was diagnosed in a young girl referred to our center following a misdiagnosis of Kleefstra Syndrome type 2. Methods: Whole-genome sequencing detected two composite heterozygous deletions in the PUS7 gene, which led us to dismiss the former diagnosis. Guided by the gestaltic evaluation of our case, we reviewed the current knowledge about the PUS7-related disorder and, driven by the biological role of this enzyme, investigated its similarities with a main spliceosomopathy, ReNU syndrome. Results: Data obtained from this exploratory analysis, together with the recent evidence from the literature, support the affinity between these conditions, suggesting that disorders of pseudouridylation might possibly be included among spliceosomopathies. Conclusions: Aside from expanding the current knowledge about the PUS7-related disorder and exploring its nosological classification, one of the main aims of our report is to raise awareness of the impact of genetic labelling and misdiagnoses. The use of whole-genome sequencing technologies requires the effective collaboration between laboratories and physicians to reach the correct diagnosis.

Background: The STAG1 gene has been related to a poorly known form of intellectual disability, known as Intellectual Developmental Disorder, Autosomal Dominant 47 (MRD47). Functionally, MRD47 is part of the Cohesinopathies, a small family of rare genetic disorders caused by defective cohesin complex, whose activity is essential for sister chromatid cohesion and therefore for chromatin organization. Chromatin state modulation is an entangled process finely modulated by a large number of actors that, if altered, give rise to the so-called Chromatinopathies. The clinical and biological overlap among these families of conditions on one hand poses significant challenges during diagnostic definition, and, on the other, may help delineate more accurate management guidelines. Methods: Starting from the report of a novel pathogenic variant in the STAG1 gene, we performed a retrospective clinical and molecular review of all previously reported patients affected by this rare disorder. Once clinical and photographic data of all published patients were collected, we used Face2Gene deep learning technology to analyze STAG1 facial phenotype, comparing it to both Chromatinopathy and Cohesinopathy profiles. Results: Our clinical and molecular re-evaluation of reported cases confirms MRD47 as a mainly neurodevelopmental disorder. Through artificial intelligence technology, we were able to first create the gestaltic profile of MRD47. Face2Gene analyses of this composite phenotype, although limited by the tool’s analysis modalities, demonstrates the strong overlap of STAG1 disorder with Chromatinopathies. Conclusions: The present literature review, together with gestaltic analyses of the STAG1-related phenotype, underscores the strong resemblance of MRD47 to epigenetic machinery disorders. The present case brings to light once more the biological and phenotypical entanglement of Cohesinopathies and Chromatinopathies, hinting at STAG1 as the joining chain.

Background: Neurodevelopmental disorders, hypotonia, microcephaly or macrocephaly, poor growth and distinctive facial traits are some of the most common reasons to refer a child to an expert consultant. But which expert? A priori response might not be always predictable. Clinical experience teaches that it is not unusual to come across a metabolic diagnosis in a patient suspected of a genetic condition and vice versa. Still, although phenotypically convergent, genetic and metabolic disorders strongly diverge on therapeutic availability. In such an entangled scenario, new sequencing technologies may bring to light further uncertainties, detecting variants that often need a clinical confirm to be interpreted. Methods: To explore clinical convergence among metabolic and genetic disorders we present a cases’ collection of patients wrongly referred to metabolic disorder clinic or to medical genetic service in a third level Center in the North of Italy. Results: Data gained from this retrospective review demonstrate the great importance of multi-disciplinary management of complex pediatric cases. Conclusions: In Hub Hospitals and in rare diseases’ Centers, it appears important to promote a side by side collaboration embracing pediatricians, clinical geneticists and laboratory in order to take an all-around point of view of undiagnosed patients. What falls out of our competence might fall out of our view as well.