Background: SATB2-associated syndrome (SAS), also known as Glass syndrome, is a neurodevelopmental disorder (NDD) characterized by intellectual disability, developmental delay, absent or limited speech, and distinctive craniofacial and dental anomalies. It is caused by autosomal dominant pathogenic variants in the SATB2 gene, which plays a crucial role in brain, dental, and jaw development. Due to its variable phenotype, clinical diagnosis can be challenging, necessitating genetic confirmation. Methods: We present six new cases of SAS with SATB2 germline variants identified through next generation sequencing (NGS) technologies, expanding the known genetic and clinical spectrum of the syndrome. Detailed clinical phenotyping was performed for all patients. Results: Our cohort exhibits a broad range of clinical manifestations consistent with SAS, encompassing severe intellectual disability, profound speech delay, various palatal and dental abnormalities. We report the oldest adult patient (56 years old) carrying an in-frame duplication, and a pediatric patient with a missense variant who presented a significant reduction in visual acuity, likely of neurological or cortical origin, in the absence of ophthalmological abnormalities. SATB2 variants include three missenses, two in-frame deletion/duplication and one frameshift variant, several of which are novel and classified as likely pathogenic or pathogenic according to ACMG guidelines. Conclusions: This report provides new clinical and genetic insights into the landscape of SAS. Our findings confirm the phenotypic heterogeneity of SAS and highlight the critical role of comprehensive genetic testing for accurate diagnosis in NDD patients.

Ritscher-Schinzel syndrome (RTSC; 3C syndrome) is a rare syndromic neurodevelopmental disorder resulting from defects in endosomal recycling. Biallelic variants in VPS35L, encoding a core component of the Retriever complex, have only recently been implicated in RTSC. Trio-based-whole exome sequencing was performed in a male infant with classical RTSC features. Variant pathogenicity was assessed using population databases, multiple in-silico predictors, structural modeling, and splicing analyses. Segregation analysis was performed in the parents. A novel homozygous VPS35L variant (NM_020314.7: c.881T>C; p.(Phe294Ser)) affecting a highly conserved residue was identified. The variant is absent from population databases and is predicted to be deleterious. Structural modeling and stability calculations indicate a marked destabilizing effect, whereas splicing predictions do not support a major effect of nucleotide change on canonical splice site usage. Clinically, the patient exhibited cerebellar, craniofacial, skeletal, and cardiac anomalies with severe postnatal growth retardation. This patient provides additional evidence supporting the pathogenic role of VPS35L in RTSC and expands the emerging molecular and clinical spectrum of VPS35L-related disorder, highlighting the value of detailed genotype-phenotype correlation in ultra-rare syndromes.

Kidney transplantation is lifesaving treatment for end-stage renal disease, yet immune-mediated complications limit long-term graft survival. Non-HLA antibodies (NHLA), particularly anti-Angiotensin type 1 receptor antibodies (AT1R-abs), are emerging mediators of graft injury. This study investigated whether selective HLA alleles influence AT1R-ab development in kidney transplant recipients. We analyzed a cohort of 59 kidney recipients carrying the HLA-A*33:01-B*14:02-DRB1*01:02 haplotype and 52 controls. Pre- and post-transplant sera were tested for donor-specific anti-HLA antibodies via Luminex-based single antigen bead assay and AT1R-ab via enzyme-linked immunosorbent assay and categorized as positive (≥17 U/mL), intermediate (10.1-16.9 U/mL) and negative (≤10 U/mL). In silico analysis were performed to assess peptide binding to HLA haplotypes. AT1R-abs were markedly enriched in the DR1 patients, both pre- (p = 0.0009) and post-transplant (p < 0.0001), at variance with controls, who were rarely positive. In silico prediction revealed that HLA-DRB1*01:02, typically the involved DRB1*01 subtype of the above-mentioned haplotype, can present AT1R peptides with greater binding affinity. These results suggest a possible genetic link between HLA haplotypes and AT1R-ab development in kidney transplant recipients, probably due to a higher binding affinity of some AT1R-derived peptides to HLA-DRB1*01:02. Understanding this association may enable personalized immunosuppressive therapies.

Background: Autosomal recessive intellectual developmental disorder-13 (MRT13; OMIM #613192) is a rare neurodevelopmental disorder caused by pathogenic variants in TRAPPC9. Most reported variants are single-nucleotide variants (SNVs), small insertions/deletions, or copy number variants (CNVs), whereas complex structural variants (SVs) remain poorly characterized. Objectives: This study sought to review the clinical and molecular spectrum of TRAPPC9-related disorder, harmonize reported variants, explore genotype–phenotype correlations, and expand the mutational spectrum by reporting a novel patient with a cryptic SV. Methods: We report a novel patient whose diagnostic workup included array-CGH, whole-exome sequencing, karyotyping, and optical genome mapping. Additionally, a systematic literature search was primarily conducted in PubMed/MEDLINE from 2009 to January 2026, with Embase, Web of Science, Google Scholar, Orphanet, OMIM, and ClinVar used as supplementary sources. Patients carrying pathogenic/likely pathogenic TRAPPC9 variants were included. Clinical and molecular data were extracted and descriptively summarized. Genotype–phenotype correlations were explored. Reported variants were re-annotated using MANE Select reference transcripts. Results: The reported patient showed biallelic TRAPPC9 disruption due to two independently inherited structural variants: a maternal ~35 kb intragenic deletion involving exons 10–12, identified by 400K array-CGH, and a paternal balanced translocation t(4;8) disrupting TRAPPC9 within intron 8, characterized by trio-OGM and paired-end whole-genome sequencing (PE-WGS). Thirty-one studies reporting 75 previously published patients were included in the literature review; together with the novel patient described here, the final cohort comprised 76 patients. Intellectual disability was present in 100% of cases, followed by brain MRI abnormalities (95.9%), microcephaly (82.3%), motor delay (71.4%), dysmorphic features (69.8%), obesity (52.8%), behavioral abnormalities/autism spectrum disorder (49.2%/43.8%), and epilepsy (15.9%). Most patients (84.2%) harbored homozygous variants. Thirty-two distinct sequence variants were identified, predominantly loss-of-function. CNVs were identified in 13.2% of patients. No genotype–phenotype correlations were identified. Conclusions: The systematic review provides an updated and harmonized overview of the clinical and molecular spectrum of TRAPPC9-related disorder, supporting the presence of a recognizable phenotype and confirming the predominance of loss-of-function variants. Our case further highlights the contribution of cryptic structural variants to the mutational spectrum of TRAPPC9 and the diagnostic value of advanced genomic approaches.