Pinto E Vairo, Filippo

AbstractBackgroundMucopolysaccharidoses (MPS) is a group of hereditary multisystemic lysosomal disorders. Most neuroimaging studies in MPS have focused on the supratentorial compartment and craniocervical junction abnormalities, and data regarding posterior fossa findings are scarce in the literature. Thus, our purpose is to describe posterior fossa findings on magnetic resonance imaging (MRI) of MPS patients.MethodsWe reviewed routine MRI scans of MPS patients being followed up at our institution (types I, II, III, IV, and VI), focusing on posterior fossa structures.ResultsForty‐seven MPS patients were included. MRI‐visible perivascular spaces were commonly found in the midbrain and adjacent to the dentate nuclei (85% and 55% of patients, respectively). White‐matter lesion was not identified in most cases. Its most frequent localizations were in the pons and cerebellum (34% and 30% of patients, respectively). Enlargement of cerebrospinal fluid (CSF) spaces in the posterior fossa was present in 55% of individuals and was more frequent in neuronopathic patients (73% vs 40%; P = .02). Cerebellar volume was classified as normal, apparent macrocerebellum, atrophic, and hypoplastic in 38%, 38%, 21%, and 3% of patients, respectively. A depression of the posterior fossa floor in the midline sagittal plane was found in 22 patients (47%), which was statistical significantly associated with enlargement of CSF spaces (P = .02) and with apparent macrocerebellum (P = .03).ConclusionThe present study compiled the main posterior fossa findings in MPS patients. Classically described in the supratentorial compartment, MRI‐visible perivascular spaces, white matter lesions, and enlarged perivascular spaces were also found in the posterior fossa. However, atrophy, which commonly affects cerebral hemispheres, was not the most frequent cerebellar morphology found in our study. Moreover, potential findings for future research were described.

Abstract Background GNB1 encodes a subunit of a heterotrimeric G‐protein complex that transduces intracellular signaling cascades. Disruptions to the gene have previously been shown to be embryonic lethal in knockout mice and to cause complex neurodevelopmental disorders in humans. To date, the majority of variants associated with disease in humans have been missense variants in exons 5‐7. Methods Genetic sequencing was performed on two patients presenting with complex neurological phenotypes including intellectual disability, hypotonia, and in one patient seizures. Reported variants were assessed using RNA sequencing and functional BRET/BiFC assays. Results A splice variant reported in patient 1 was confirmed to cause usage of a cryptic splice site leading to a truncated protein product. Patient 2 was reported to have a truncating variant. BRET and BiFC assays of both patient variants confirmed both were deficient in inducing GPCR‐induced G protein activation due to lack of dimer formation with the Gγ subunit. Conclusion Here, we report two patients with functionally confirmed loss of function variants in GNB1 and neurodevelopmental phenotypes including intellectual disability, hypotonia, and seizures in one patient. These results suggest haploinsufficiency of GNB1 is a mechanism for neurodevelopmental disorders in humans.

AbstractBackgroundWe describe a patient presenting with pachygyria, epilepsy, developmental delay, short stature, failure to thrive, facial dysmorphisms, and multiple osteochondromas.MethodsThe patient underwent extensive genetic testing and analysis in an attempt to diagnose the cause of his condition. Clinical testing included metaphase karyotyping, array comparative genomic hybridization, direct sequencing and multiplex ligation‐dependent probe amplification and trio‐based exome sequencing. Subsequently, research‐based whole transcriptome sequencing was conducted to determine whether it might shed light on the undiagnosed phenotype.ResultsClinical exome sequencing of patient and parent samples revealed a maternally inherited splice‐site variant in the doublecortin (DCX) gene that was classified as likely pathogenic and diagnostic of the patient's neurological phenotype. Clinical array comparative genome hybridization analysis revealed a 16p13.3 deletion that could not be linked to the patient phenotype based on affected genes. Further clinical testing to determine the cause of the patient's multiple osteochondromas was unrevealing despite extensive profiling of the most likely causative genes, EXT1 and EXT2, including mutation screening by direct sequence analysis and multiplex ligation‐dependent probe amplification. Whole transcriptome sequencing identified a SAMD12‐EXT1 fusion transcript that could have resulted from a chromosomal deletion, leading to the loss of EXT1 function. Re‐review of the clinical array comparative genomic hybridization results indicated a possible unreported mosaic deletion affecting the SAMD12 and EXT1 genes that corresponded precisely to the introns predicted to be affected by a fusion‐causing deletion. The existence of the mosaic deletion was subsequently confirmed clinically by an increased density copy number array and orthogonal methodologiesConclusionsWhile mosaic mutations and deletions of EXT1 and EXT2 have been reported in the context of multiple osteochondromas, to our knowledge, this is the first time that transcriptomics technologies have been used to diagnose a patient via fusion transcript analysis in the congenital disease setting.