IQSEC2 disorder : a new disease entity or a Rett spectrum continuum?

IQSEC2 mutations are associated with IQSEC2-related intellectual disability (ID). Phenotypic spectrum has been better defined in the last few years by the increasing number of reported cases although the genotype-phenotype relationship for IQSEC2 remains overall complex. As for IQSEC2-related ID a wide phenotypic diversity has been described in Rett syndrome (RTT). Several patients harboring IQSEC2 mutations present with clinical symptoms similar to RTT and some cases meet most of the criteria for classic RTT. With the aim of establishing a genotype-phenotype correlation, we collected data of 16 patients harboring IQSEC2 point mutations (15 of them previously unreported) and of five novel patients carrying CNVs encompassing IQSEC2. Most of our patients surprisingly shared a moderate-to-mild phenotype. The similarities in the clinical course between our mild cases and patients with milder forms of atypical RTT reinforce the hypothesis that also IQSEC2 mutated patients may lay under the wide clinical spectrum of RTT and thus IQSEC2 should be considered in the differential diagnosis. Our data confirm that position, type of variant and gender are crucial for IQSEC2-associated phenotype delineation

Encephalopathies with intracranial calcification in children: Clinical and genetic characterization

none42noBackground: We present a group of patients affected by a paediatric onset genetic encephalopathy with cerebral calcification of unknown aetiology studied with Next Generation Sequencing (NGS) genetic analyses. Methods: We collected all clinical and radiological data. DNA samples were tested by means of a customized gene panel including fifty-nine genes associated with known genetic diseases with cerebral calcification. Results: We collected a series of fifty patients. All patients displayed complex and heterogeneous phenotypes mostly including developmental delay and pyramidal signs and less frequently movement disorder and epilepsy. Signs of cerebellar and peripheral nervous system involvement were occasionally present. The most frequent MRI abnormality, beside calcification, was the presence of white matter alterations; calcification was localized in basal ganglia and cerebral white matter in the majority of cases. Sixteen out of fifty patients tested positive for mutations in one of the fifty-nine genes analyzed. In fourteen cases the analyses led to a definite genetic diagnosis while results were controversial in the remaining two. Conclusions: Genetic encephalopathies with cerebral calcification are usually associated to complex phenotypes. In our series, a molecular diagnosis was achieved in 32% of cases, suggesting that the molecular bases of a large number of disorders are still to be elucidated. Our results confirm that cerebral calcification is a good criterion to collect homogeneous groups of patients to be studied by exome or whole genome sequencing; only a very close collaboration between clinicians, neuroradiologists and geneticists can provide better results from these new generation molecular techniques.noneTonduti D.; Panteghini C.; Pichiecchio A.; Decio A.; Carecchio M.; Reale C.; Moroni I.; Nardocci N.; Campistol J.; Garcia-Cazorla A.; Perez Duenas B.; Zorzi G.; Ardissone A.; Granata T.; Freri E.; Zibordi F.; Ragona F.; D'Arrigo S.; Saletti V.; Esposito S.; Pantaleoni C.; Riva D.; De Giorgis V.; Cereda C.; Valente M.L.; Sproviero D.; Poo Arguelles M.P.; Estupina C.F.; Sans Fito A.M.; Martorell Sampol L.; Del Mar O'Callaghan Gordo M.; Ortez Gonzalez C.I.; Gonzalez Alvarez V.; Garcia-Segarra N.; Fusco C.; Bertini E.; Diodato D.; Fazzi E.; Galli J.; Chiapparini L.; Garavaglia B.; Orcesi S.Tonduti, D.; Panteghini, C.; Pichiecchio, A.; Decio, A.; Carecchio, M.; Reale, C.; Moroni, I.; Nardocci, N.; Campistol, J.; Garcia-Cazorla, A.; Perez Duenas, B.; Zorzi, G.; Ardissone, A.; Granata, T.; Freri, E.; Zibordi, F.; Ragona, F.; D'Arrigo, S.; Saletti, V.; Esposito, S.; Pantaleoni, C.; Riva, D.; De Giorgis, V.; Cereda, C.; Valente, M. L.; Sproviero, D.; Poo Arguelles, M. P.; Estupina, C. F.; Sans Fito, A. M.; Martorell Sampol, L.; Del Mar O'Callaghan Gordo, M.; Ortez Gonzalez, C. I.; Gonzalez Alvarez, V.; Garcia-Segarra, N.; Fusco, C.; Bertini, E.; Diodato, D.; Fazzi, E.; Galli, J.; Chiapparini, L.; Garavaglia, B.; Orcesi, S