ジュベール症候群関連疾患

Joubert syndrome (JS) is a rare ciliopathy characterised by the molar tooth sign on brain MRI, cerebellar vermis hypoplasia, hypotonia and developmental delay. We report an elementary school-aged boy initially diagnosed with autism spectrum disorder without intellectual impairment because of early language delay, social communication difficulties and stereotyped behaviours. Developmental screening at 4 years of age using the Denver Developmental Screening Test II demonstrated delays in language and social communication domains. At presentation to our clinic at 8 years of age, cognitive evaluation with Wechsler Intelligence Scale for Children-Revised (WISC-R) demonstrated normal intellectual functioning (Full Scale IQ=98). The patient had mild axial hypotonia in infancy, a normal head circumference (50th-75th percentile) and later developed gait ataxia with oculomotor apraxia at 8 years of age. The first brain MRI performed at 4 years of age at an outside institution was reported as normal, whereas repeat MRI at 8 years of age demonstrated the molar tooth sign and cerebellar vermis hypoplasia.5 6 Genetic testing identified variants in ciliopathy-related genes. This case highlights that JS may present with preserved cognition and subtle early neuroimaging findings, emphasising the importance of repeating neuroimaging and comprehensive genetic evaluation when new cerebellar signs emerge.

Mutations in the ciliary gene INPP5E, encoding inositol polyphosphate-5-phosphatase E (INPP5E), can cause retinal degeneration as part of the ciliopathy Joubert syndrome or non-syndromic retinitis pigmentosa (RP). INPP5E regulates the membrane makeup of the primary cilium; however, its function in the specialized sensory photoreceptor cells of the human retina remain unclear. Here, we utilize control and CRISPR/Cas9-generated INPP5E knockout (INPP5ED477N/D477N) human induced pluripotent stem cells (iPSCs) to generate retinal organoids (ROs). Through proteomic and immunofluorescence analysis, we show that INPP5E plays an important role in early retinal development and photoreceptor progenitor cell differentiation. In mature ROs, INPP5E localizes to the connecting cilium of photoreceptors, and the loss of INPP5E leads to altered localization of ARL13B and rhodopsin in mature photoreceptors. Furthermore, photoreceptor outer segment structure is affected, leading to elongated outer segment membranes in both cone and rod photoreceptors, suggesting an important role for INPP5E in photoreceptor outer segment membrane biogenesis. Together, these data underline the importance of INPP5E in retina development and photoreceptor structure and highlight the usability of ROs to study protein function in a human context.

IFT172 is a core component of intraflagellar transport complex B (IFT-B), and pathogenic IFT172 variants disrupt ciliary transport, receptor localization, and tissue-specific signaling. This review summarizes evidence linking IFT172 dysfunction to neurological, retinal, skeletal, renal, and syndromic ciliopathy phenotypes, with emphasis on Bardet-Biedl syndrome, Joubert-spectrum disease, orofaciodigital syndrome, Mainzer-Saldino syndrome, and retinal degeneration. Current data support a primary role for IFT172 in IFT-train assembly, tip remodeling, anterograde-to-retrograde transition, and cilia-dependent signaling; downstream metabolic, oxidative, and inflammatory changes are interpreted as context-dependent secondary modules rather than uniform linear cascades. We further discuss diagnostic interpretation and the practical boundaries of gene, splice-correction, and pathway-modulation strategies. By aligning molecular mechanisms with organ vulnerability, this review provides a concise framework for interpreting IFT172-associated ciliopathies and for prioritizing future translational studies.

BACKGROUND: Joubert syndrome (JS) is a rare, predominantly autosomal recessive neurodevelopmental disorder characterized by hypotonia, motor delay, intellectual disability, oculomotor apraxia, and the hallmark "molar tooth sign" on axial view of MRI. JS is genetically heterogeneous, with pathogenic variants identified in more than 40 genes involved in primary cilia function. Among these, CEP290 is one of the most frequently mutated genes. RESULTS: In this study, we investigated two children-an 11-year-old boy (the proband) and his 5-year-old sister-both presenting with a similar phenotype consistent with JS. The parents, who self-identified as Chechen, reported distant consanguinity. The family also included a healthy 13-year-old daughter. The proband had previously been evaluated by a neurologist and underwent whole-genome sequencing (WGS); however, no causative variants were identified initially. After phenotype reassessment by a clinical geneticist, we performed a reanalysis of the raw WGS data and identified a novel homozygous intronic variant of uncertain significance (VUS), c.1910-15_1910-11delinsTTACA in CEP290 (NM_025114.4). Sanger sequencing confirmed that both the proband and his affected sister were homozygous for this variant, which they inherited from their heterozygous parents. Their healthy sister did not carry the variant. mRNA-sequencing and targeted cDNA sequencing (read depth ~ 100,000x) demonstrated that this intronic variant causes completely aberrant splicing of CEP290 pre-mRNA. Predominantly this variant causes the skipping of exon 20 in the main CEP290 transcript. Alternatively, the variant results in partial inclusion of intron 19 into the mRNA, elongation of exon 20 by 58 nucleotides, and a homozygous substitution chr12:88114573 (ACTGTGTA> TTACAGTA). No canonical mRNA isoform was detected when the variant was homozygous. Both the predicted severe truncation and the likely degradation of aberrant transcripts through nonsense-mediated decay (NMD) would correspond to complete loss of CEP290 function. Following the reclassification of this VUS to likely pathogenic, the family was able to pursue in vitro fertilization (IVF) with preimplantation genetic testing for monogenic disorders (PGT-M). CONCLUSION: Our study highlights the critical importance of proper phenotyping prior to referral for WES/WGS as well as of combining NGS with functional mRNA studies to achieve a molecular diagnosis for patients with predicted splice-site mutations in JS-associated genes. It also emphasizes the need for functional reassessment of VUS when genomic data are expected to guide reproductive decision-making within affected families.