The Male-Specific Lethal 2 Homolog (MSL2) gene was recently reported to be responsible for a novel, rather severe neurodevelopmental syndrome including brain abnormalities. We report the first prenatal case of an MSL2-related pathology caused by a de novo MSL2 splice variant (c.142+1G>T). RNA study on amniotic fluid cells showed an intronic inclusion and frameshift, consistent with loss-of-function intolerance. The fetus, who presented with bilateral moderate ventriculomegaly, also carried a paternally inherited 15q13 microduplication. Brain MRI at 2 and 4 months of age showed stable, mildly enlarged lateral ventricles. Clinical evaluation at 11 months revealed only a mild developmental delay. This case illustrates the challenges in predicting the postnatal outcome of recently characterized syndromes with limited documented cases, especially in association with a second independent genetic anomaly. Follow-up will be crucial to better define the developmental impact of this first reported MSL2 splice mutation in combination with the 15q13 microduplication, and characterization of more patients with MSL2 mutations will contribute to expanding the phenotypic spectrum.

Loss of fragile X messenger ribonucleoprotein (FMRP) causes fragile X syndrome (FXS), an inherited neurodevelopmental disorder resulting in intellectual disability and autism spectrum disorder; however, the molecular function of FMRP remains uncertain. Here, using cell lines and fibroblasts and induced pluripotent stem cell-derived neurons from healthy individuals and patients with FXS, we showed that FMRP regulates collided ribosomes by recruiting activating signal cointegrator 1 complex subunit 3 (ASCC3), an early-acting ribosome-associated quality control (RQC) factor to collided ribosomes, and either positively or negatively regulating translation, depending on transcript context. Disease-associated ASCC3 variants that perturbed ASCC3-FMRP interaction were also found to be defective in ribosome association and handling of collided ribosomes. In cells of a patient with FXS and the Fmr1 KO mouse model, ASCC3 abundance was reduced, and overexpression of ASCC3 in the brains of fetal Fmr1 KO mice promoted neuronal migration. In addition, CRISPR-mediated activation of ASCC3 by lateral ventricular injection of adeno-associated virus (AAV) ameliorated synaptic defects and improved locomotor activity, cognitive deficits, obsessive-compulsive-like behavior, and social interaction deficits after 1 month in 2-month-old Fmr1 KO mice compared with untreated Fmr1 KO controls. In conclusion, these data implicated FMRP in the handling of collided ribosomes to maintain protein homeostasis during neurodevelopment and synaptogenesis and demonstrated proof of concept that targeting RQC may offer alternative treatment strategies for FXS.

Recessive mutations in POLR3A exhibit considerable phenotypic diversity, spanning from severe childhood-onset hypomyelinating leukodystrophic syndrome to less severe gait disorders, which may present later in life and may be accompanied by additional non-neurological symptoms. In this study, we report a new case of rare POLR3A variants in a 6-year-old female patient sharing common genetic and neuropsychological profiles of POLR3-related disorders, although without revealing the classic MRI phenotype and severe clinical signs of POLR3-related leukodystrophy, such as diffuse hypomyelination. Our probe was born after full term pregnancy complicated by Intrauterine Growth Restriction and risk of preterm birth treated with tocolytics during the last weeks of pregnancy. On the second day of life, tremors in the lower and upper limbs were detected and lasted until the second month of life. At the age of 6 months, she was diagnosed with hypotonia. The child showed a delay in the stages of psychomotor development and a slowing of the language. Brain MRI performed at the age of 5 years revealed mild and symmetrical ectasia of the lateral ventricles, mild hypoplasia of the cerebellar vermis and brainstem with wide communication between the fourth ventricle and the cisterna magna. Neurological examination revealed dyslalia, mild generalized hypotonia, ataxic gait, motor coordination and balance deficits, while the Wechsler Intelligence Scale for Children revealed the presence of mild intellectual disability. A clinical exome and neurodevelopmental multigenic analysis revealed two variants of the POLR3A gene in compound heterozygosity (c.1795 C > A and c.1289 + 3 A > G) previously described in the literature and a novel and not yet reported CACNA2D2 variant (c.2929 C > T). Beside the shared genetic and neuropsychological findings, the distinctive MRI and classical clinical signs of POLR3-related leukodystrophy have not been revealed in our case. This finding underscores the need to expand the diagnostic approach for POLR3A-related disorders, highlighting the significance of differentiating subtle clinical signs and promoting the use of genetic testing, especially in younger patients who may not yet display the typical clinical and MRI patterns. Further studies are necessary to shed light on different pathogenic mechanisms potentially responsible for the heterogeneous phenotype associated with POLR3-related disorders.

Rett syndrome is a genetic neurodevelopmental disorder that predominantly affects girls. While microcephaly is a common feature, there is limited information on the detailed structural changes in the brain. This study aimed to identify regional brain volume abnormalities and explore the correlation between brain volume and clinical characteristics. We compared the regional brain volumes of 20 female children with Rett syndrome to those of 25 healthy female children. Additionally, we assessed the correlation between regional brain volume, Clinical Severity Scores, and epilepsy status. Significantly smaller volumes were observed in all brain regions, including the cerebral cortex, cerebral white matter, subcortical gray matter, cerebellum, and brainstem. Within the cortical regions, volume reduction was prominent in the left precentral, right lateral occipital, left precuneus, left inferior parietal, and right medial orbitofrontal cortices. After correcting for intracranial volumes, volume reduction was more prominent in the cerebral cortices than in the cerebral white matter. Small volumes were consistently observed, regardless of age. Negative correlations were observed between the volumes of multiple regions and the Clinical Severity Scores. There were no correlations among regional brain volume, seizure control, or duration of epilepsy. The mechanism underlying the cortical-dominant volume reduction remains unclear; however, it may be caused by altered synapse development associated with methyl-CpG-binding protein 2 gene abnormalities. Characteristic impairments in visual recognition and deterioration of motor function in Rett syndrome may be associated with significant volume reduction in specific cortical regions, such as the lateral occipital cortex, precuneus, and precentral gyrus.

O'Donnell-Luria-Rodan (ODLURO) syndrome is an autosomal dominant disorder associated with KMT2E gene variants. ODLURO syndrome is characterized mainly by developmental delay, intellectual disability and macrocephaly or microcephaly; in some patients, it may manifest as autism or epilepsy. Trio whole-exome sequencing was performed on a female infant with unexplained West syndrome and developmental regression. A de novo splicing variant in the KMT2E gene was identified. The effects of this variant were analysed via a minigene splice assay and in vitro reverse transcription PCR. The patient presented with spasmodic seizures and developmental delay at 6 months of age. The video electroencephalogram (EEG) displayed hypsarrhythmia. Brain MRI revealed abnormal signals around the lateral ventricles and decreased white matter volume. A novel splicing variant in the KMT2E gene (NM_182931.3: c.1248_1248+9del) was identified in our proband. Sanger sequencing confirmed that the variant was not inherited from her parents. The in vitro minigene assay confirmed that c.1248_1248+9del resulted in exon 12 skipping. To our knowledge, this is the first definite report of ODLURO syndrome with West syndrome as the original manifestation. The deleterious effects of KMT2E c.1248_1248+9del were demonstrated in our proband. Splicing variants in the KMT2E gene are rare, and our study expands the phenotype and genotype of ODLURO syndrome. Additional studies are needed to explore the genotype-phenotype correlations of this disease.