Nobuhiko Okamoto

Pathogenic variants in AGO1 and AGO2, core components of the Argonaute family, have emerged as causes of rare neurodevelopmental disorders characterized by intellectual disability, marked language impairment, behavioral abnormalities, and distinctive craniofacial features. Reported variants cluster at the L1–PAZ boundary, a structurally sensitive region essential for guide‐RNA engagement. We describe two unrelated Japanese individuals carrying de novo variants in AGO1 (NM_012199.5):c.569T>C p.(Leu190Pro) or AGO2 (NM_012154.6):c.544_546del p.(Phe182del), affecting structurally corresponding residues within this boundary. Both individuals exhibited global developmental delay, hypotonia, midface hypoplasia, thin upper lip, elongated facial shape, and reduced cerebral white matter volume, aligning with previously reported AGO1‐ and AGO2‐related phenotypes. Structural assessment using AlphaFold2‐based AGO1 models and the AGO2 crystal structure confirmed positional equivalence of the affected residues, supporting the concept of a shared structural vulnerability across Argonaute paralogs. These observations expand the phenotypic spectrum of Argonaute‐related neurodevelopmental disorders in the Japanese population and highlight RNA‐regulatory dysfunction as a coherent pathogenic axis. Recognition of this clinical gestalt may assist clinicians in prioritizing AGO1 and AGO2 during genomic evaluation of unexplained neurodevelopmental disorders.

The online version contains supplementary material available at 10.1007/s13730-026-01105-6.

DeSanto–Shinawi syndrome is a rare genetic disorder caused by pathogenic variants or deletions involving the WAC gene, located on chromosome 10p12.1, and is characterized by developmental delay, intellectual disability, and distinctive dysmorphic features. In addition to deletions encompassing WAC , several proximal deletions on chromosome 10 that exclude WAC have also been reported. Here, we describe a patient with a microdeletion of chromosome 10p11.23–p11.21 spanning approximately 4.2 Mb. The patient exhibited intellectual disability, agenesis of the corpus callosum, and congenital heart disease. The deleted region includes the following protein‐coding genes: ZNF438 , ZEB1 , ARHGAP12 , KIF5B , EPC1 , CCDC7 , ITGB1 , NRP1 , and PARD3 , while WAC was preserved. Pathogenic variants or deletions of ZEB1 are known to cause corneal abnormalities and agenesis of the corpus callosum, whereas loss of NRP1 has been implicated in the pathogenesis of congenital heart disease. We therefore hypothesize that haploinsufficiency of multiple genes within the deleted region—particularly ZEB1 , EPC1 , KIF5B , and NRP1 —may collectively contribute to the observed clinical phenotype. These findings suggest that microdeletions involving chromosome 10p11.2 are associated with a phenotype distinct from that of DeSanto–Shinawi syndrome.

WDR83 (WD Repeat Domain 83), also known as MORG1 (Mitogen-activated protein kinase Organizer 1), functions as a scaffold protein regulating diverse cellular processes, including cell signaling, proliferation, protein degradation, cell polarity, and autophagy. Through whole-exome sequencing, we identified a novel de novo WDR83 variant [NM_001099737; c.653 T > C,p.(L218P)] in a Japanese female patient presenting with global developmental delay, intellectual disability, and dysmorphic features. As the p.L218P variant was suspected to exert a dominant-negative effect, we investigated its impact on neuronal development. In vivo, acute expression via in utero electroporation promoted premature cell cycle exit of neural stem cells, impaired cortical neuron migration, and disrupted dendritic arborization, whereas axonal projections to the contralateral hemisphere remained unaffected. Additionally, cortical neurons expressing WDR83-L218P exhibited reduced spine head diameter. In vitro, WDR83-L218P expression inhibited axon elongation in primary cultured hippocampal neurons. Collectively, these findings suggest that WDR83 is a novel gene associated with neurodevelopmental disorders. Based on expression profiles and functional analyses, we conclude that WDR83 plays a crucial role in regulating neuronal morphology during brain development, and that the p.L218P variant disrupts this function, contributing to the patient’s phenotype.

Congenital disorders of glycosylation (CDG) represent an emerging and significant category within the spectrum of inborn errors of metabolism. CDG comprise a heterogeneous group of diseases caused by defects at various stages of the glycosylation pathway. Each year, new types of CDG are identified, and to date, pathogenic variants in 189 genes have been associated with over 200 distinct human glycosylation-related disorders. Each type of CDG exhibits characteristic clinical features. Many of CDG result in multisystem involvement, with the central nervous system being particularly affected. Clinical manifestations are highly variable and may include developmental delays, growth impairment, neurological abnormalities such as ataxia, hepatic dysfunction, cardiac defects, coagulation disorders, and abnormal fat distribution. In patients with unexplained neurological symptoms, it is now standard practice to include CDG in the differential diagnosis. Detection of altered glycosylation patterns in serum proteins is essential in the diagnostic evaluation of CDG. Analytical techniques allow the identification of defects in N-glycosylation, O-glycosylation, and combined glycosylation pathways. Once abnormalities in glycosylation are detected, subsequent genetic analysis is necessary to identify causative variants. Our research institute has contributed to the CDG diagnostic support center in Japan by developing novel analytical methods utilizing mass spectrometry. Through these efforts, we have facilitated the molecular diagnosis of 66 patients with CDG across Japan. In this report, we provide an overview of the current landscape of CDG in Japan, along with a summary of the screening and diagnostic processes.

ReNU syndrome, also known as neurodevelopmental disorder with hypotonia, brain anomalies, distinctive facies, and absent language (NEDHAFA), is characterized by hypotonia, global developmental delay, intellectual disability with poor or absent speech, delayed motor development, feeding difficulties, short stature, seizures, and dysmorphic features. Neuroradiological abnormalities, including ventriculomegaly, hypoplasia of the corpus callosum, and a decreased white matter volume, are observed in many individuals. Most individuals have the same highly recurrent single base insertion (n.64_65insT) in RNU4‐2 . RNU4‐2 encodes U4 small nuclear RNA, which is a critical component of the U4/U6.U5 tri‐snRNP complex of the major spliceosome. We reviewed exome sequencing and genome sequencing data from previous patients with neurodevelopmental disorders that matched the clinical features of ReNU syndrome and performed a hotspot analysis using the Sanger method. A recurrent variant in RNU4‐2 was identified in eight patients, while the rare variant, n.66A>G, was detected in one patient. Nine patients aged between 3 and 29 years all showed severe developmental delay and/or intellectual disability. Independent walking was achieved by five patients. In six patients, meaningful words had not been acquired, even after the age of 5 years. All patients showed a distinctive pattern of dysmorphic features, including hooded upper eyelids, full cheeks, a tented philtrum, and a mouth constantly slightly open with an everted lower lip vermilion. All patients had neuroradiological abnormalities. The identification of nine patients at a single institution reaffirmed that ReNU syndrome is an important cause of ID. ReNU syndrome is considered a clinically recognizable syndrome. If clinically suspected, it is reasonable to examine the 18‐base pair region using the Sanger method.

Trio-based genome sequencing (GS) is useful for genetic analysis of cases in which exome sequencing failed to resolve the disease-causing variants. In this paper, we report two unrelated families with pathogenic deletions (one outside exome-covering genomic regions and the other involving a single exon) successfully identified by GS. Notably, mosaic deletions were found in both families, which were carefully evaluated in detail by analyzing GS data using Integrative Genomics Viewer, breakpoint PCR, quantitative PCR, and digital PCR. This study emphasizes the benefit of trio-based GS, enabling straightforward interpretation, further aided by other confirmatory experimental methods.

Congenital disorders of glycosylation (CDG) are a heterogeneous group of diseases caused by defects in various steps of the glycosylation pathway. There are over 200 known human glycosylation‐related disorders. Many of these defects lead to multisystemic manifestations, commonly involving the central nervous system, with symptoms ranging from mild to severe. The phenotypic presentation of CDG can vary significantly. Identifying altered protein glycosylation is crucial for accurate diagnosis. Our research institute has contributed to the CDG diagnostic support center in Japan, developing new analytical techniques utilizing mass spectrometry. These techniques allow for the identification of defects in N‐glycosylation, O‐glycosylation, and combined glycosylation pathways. Advances in genetic analysis, including whole exome sequencing, have revealed that certain types of CDG are more prevalent than previously recognized. We have contributed to the molecular diagnosis of 66 CDG patients in Japan. Although PMM2‐CDG is the most common form of CDG, it was only detected in 17% of the patients in the present study, suggesting that its incidence is much lower in Japan compared to European countries. We also conducted a comprehensive review of case reports of CDG in Japan, further describing the clinical and molecular spectrum of the disease in this population.