Baker-Gordon syndrome (BAGOS) is a neurodevelopmental disorder (NDD) linked to a series of de novo mutations in the synaptic vesicle protein, Synaptotagmin-1 (SYT1). SYT1 is the major calcium sensor for synaptic transmission, and therefore a key molecule in neuronal communication. Several approaches have been used to reveal the underlying molecular mechanisms that lead to BAGOS pathology. While the murine genetic deletion, loss-of-function approach has proven valuable for modeling human diseases, human-induced pluripotent stem cells (hiPSCs) offer a powerful new strategy. In this study, we compare the phenotypes of BAGOS-associated SYT1 mutant variants in murine and human neuron models of either sex. In the well-established murine SYT1 knock-out (KO) model, we found that although all SYT1 mutant variants were correctly localized to the synaptic compartment, none could effectively rescue synaptic transmission. To examine the phenotype of BAGOS-associated SYT1 mutations in the context of human neurons, we generated a SYT1 KO hiPSC line via CRISPR/Cas9 gene editing and used this to derive neurons. As in mouse neurons, SYT1 KO in hiPSCs-derived human neurons strongly impairs synchronous release. Surprisingly, fast synaptic transmission could be rescued to varying extents in the human SYT1 KO model using BAGOS SYT1 mutants. However, overexpression of BAGOS SYT1 mutants in either WT mouse neurons or hiPSC-derived human neurons, a condition closer to the heterozygotic genotype of patients, revealed a dominant-negative effect of the mutant proteins. Our findings suggest that impaired neurotransmitter release efficacy caused by mutations in synaptic proteins may contribute to NDD pathophysiology.

Marden-Walker syndrome (MWS; OMIM 248700) is an extremely rare congenital disorder characterized by multiple joint contractures, craniofacial dysmorphism, neurological abnormalities, and multisystem involvement. Although historically diagnosed on clinical grounds, only a few cases have been molecularly confirmed. Here, we describe a Brazilian female infant with classic manifestations of MWS, carrying a heterozygous pathogenic variant in the PIEZO2 gene not previously reported in MWS. To our knowledge, this is the first molecularly confirmed MWS case from Brazil, thus expanding both the genotype-phenotype spectrum and geographic distribution of PIEZO2-related disorders. Comparative analysis of previously reported molecularly confirmed cases reveals shared core features and highlights the prominent neurological involvement observed in our patient. A review of individuals with the same PIEZO2 variant demonstrates marked phenotypic variability-from Gordon syndrome to distal arthrogryposis type 5-underscoring allelic heterogeneity and variable expressivity. This case refines the phenotypic spectrum of PIEZO2-related disorders and illustrates how allelic heterogeneity contributes to wide clinical variability, while also underscoring the importance of including underrepresented populations in variant interpretation.

We describe the clinical manifestations and developmental abilities of individuals with SYT1-associated neurodevelopmental disorder (Baker-Gordon syndrome) from infancy to adulthood. We further describe the neuroradiological and electrophysiological characteristics of the condition at different ages, and explore the associations between these characteristics and clinical symptoms. Participants were recruited to the UK-based Brain and Behavior in Neurodevelopmental Disorders of Genetic Origin project. Caregivers completed a medical history questionnaire and a battery of standardized neurodevelopmental measures. MRI and EEG records were obtained with consent from treating clinicians. Age-related clinical manifestations and neuroimaging records were systematically analyzed. Balanced accuracy testing was used to explore brain-symptom associations. This study describes 40 individuals with 30 distinct de novo SYT1 variants, including 10 novel variants. Qualitative age-related clinical trends included the resolution of hypotonia and worsening of movement disorders, sleep difficulties, and self-injurious behaviors. Social-communicative impairments were prominent, with evidence of progression with age. MRI abnormalities were identified in 45% of individuals, while EEG abnormalities were present in 93%. Epileptiform activity frequently co-occurred with movement disorders, while irregular sleep EEG coincided with sleep difficulties and respiratory problems. This study characterizes the broad spectrum and age-related progression of clinical symptoms and brain-related findings in individuals with SYT1-associated neurodevelopmental disorder. Further research is needed to understand factors contributing to within-individual change, and to develop targeted interventions aimed at improving outcomes and quality of life for affected individuals and their families.

Baker-Gordon syndrome (BAGOS) is an autosomal dominant neurodevelopmental disorder caused by de novo heterozygous missense mutations in SYT1. The precise pathogenic mechanism of BAGOS is still unclear, with preliminary data favoring a dominant-negative effect, although a previous case presenting a reciprocal translocation disrupting SYT1 supports haploinsufficiency as a possible mechanism. We report a child with a syndromic neurodevelopmental disorder compatible with BAGOS and carrying a t(5; 12)(q31; q21) by G-banded karyotype. Optical genome mapping (OGM) is based on ultrahigh molecular weight DNA molecules allowing the combined analyses of numerical and structural chromosome variants. The rearrangement was investigated using OGM, which revealed an additional structural variant, a paracentric inversion in the segment of Chromosome 12 translocated to der(5). The breakpoint of the paracentric inversion is mapped to Intron 9 of the SYT1 gene, interrupting the C2B domain. This is the second BAGOS case reported in the literature caused by SYT1 disruption, supporting that reduced amounts of functional SYT1, either by haploinsufficiency or dominant-negative effect, is responsible for SYT1-associated neurodevelopmental syndrome.

Pseudohypoaldosteronism type II (PHA II) is a rare genetic syndrome caused by mutations in the WNK1, WNK4, KLHL3 and CUL3 genes, leading to hypertension, hyperkalaemia, and hyperchloremic metabolic acidosis. Each mutation confers a different phenotype, with a large spectrum of clinical presentations, which can delay the diagnosis. We report a case of a 31-year-old female with hypertension. She had uncharacteristic facies, average height and no family history of hypertension or hyperkalaemia. Laboratory data showed hyperkalaemia, hyperchloremic metabolic acidosis, hypercalciuria and suppressed renin. Genetic testing revealed a c.478G>T, p.(Asp160Tyr) variant in the KLHL3 gene, in apparent homozygosity. Based on clinical history, laboratory findings, and genetic testing, a diagnosis of PHA II was made. This is a representative case of a mild PHA II phenotype, with a non-previously reported KLHL3 mutation, highlighting the importance of a high level of suspicion for PHA II. We report a case of a young woman with PHA II caused by a novel variant in KLHL3, that highlights the importance of a high level of clinical suspicion for PHA II diagnosis in patients with milder phenotypes and without family history.PHA II should be considered in all patients with low-renin hypertension, hyperkalaemia, hyperchloremic metabolic acidosis and hypercalciuria, regardless of age, clinical features, or family history.Early diagnosis is extremely important because PHA II can be effectively treated with low dose thiazides, avoiding end organ damage onset.