Aug 2026· Molecular Genetics and Metabolism Reports· Vol 48· 0 citations· 35 references
Medicine
TL;DR
This study expands the mutational landscape of JS in the Iranian population and underscores the utility of WES as a first-tier diagnostic tool for JS and related ciliopathies.
Abstract
Background Joubert syndrome (JS) is a rare neurodevelopmental ciliopathy characterized by a distinctive midbrain-hindbrain malformation, manifested by hypotonia, ataxia, developmental delay, and variable multisystem involvement. The condition exhibits marked clinical and genetic heterogeneity, with over 40 genes implicated to date. However, the mutational spectrum and phenotypic presentation of JS in Middle Eastern populations, where consanguinity is prevalent, remain poorly characterized. Methods We retrospectively reviewed whole-exome sequencing (WES) data from patients referred to the Comprehensive Medical Genetics Center, Shiraz, Iran, between 2019 and 2024. Patients harboring variants in JS-related genes were identified, and their clinical records were analyzed to establish genotype–phenotype correlations. Results A total of 21 cases with variants in JS-associated genes were identified. Neurological manifestations, including developmental delay/intellectual disability, speech defects, seizures, and motor impairment, were the most prevalent findings. Vision problems, renal involvement and polydactyly were also present. Molecular analysis revealed variants in 14 distinct genes, with AHI1 being the most frequently mutated (3 cases), followed by KIAA0586, CSPP1, KIAA0556, CC2D2A, and TMEM67. Eight cases carried pathogenic or likely pathogenic variants, while 12 cases had variants of uncertain significance (VUS), highlighting the diagnostic challenges in this genetically heterogeneous condition. Conclusion This study expands the mutational landscape of JS in the Iranian population and underscores the utility of WES as a first-tier diagnostic tool for JS and related ciliopathies. The high rate of consanguinity in this cohort likely contributes to the enrichment of autosomal recessive forms. Further functional studies are warranted to clarify the pathogenicity of the numerous VUS identified, which will improve genetic counseling and prenatal decision-making for affected families.
Background KBG syndrome (KBGS) is a rare autosomal dominant neurodevelopmental disorder caused by heterozygous pathogenic variants in ANKRD11. It is characterized by developmental delay, intellectual disability, behavioral difficulties, macrodontia, craniofacial dysmorphism, short stature, and skeletal anomalies. Objectives To describe the clinical, radiological, and molecular findings of Saudi patients with molecularly confirmed KBGS and compare their presentation with reported features in the literature. Methods We conducted a retrospective case series at King Faisal Specialist Hospital and Research Centre, Riyadh, between January 2002 and December 2024. Clinical, dysmorphological, developmental, behavioral, family history, neuroimaging, and molecular data were reviewed for three pediatric patients with confirmed ANKRD11-related KBGS. Results All patients demonstrated core features of KBGS, including intellectual disability, speech and motor delay, learning difficulties, and behavioral manifestations such as autism spectrum features or aggression. Common dysmorphic findings included long philtrum and prominent ears in all patients, with a triangular face, macrodontia, and synophrys observed in two patients. Short stature and skeletal anomalies were also present. Molecular testing identified heterozygous pathogenic or likely pathogenic ANKRD11 variants: NM_013275.6:c.4087C > T (p.Arg1363Ter), NM_013275.6:c.3382_3383del (p.Asp1128GlufsTer41), and NM_013275.6:c.1977C > G (p.Tyr659Ter). All variants were predicted to result in premature termination. Renal fusion and complex vertebral anomalies were observed, suggesting possible underrecognized systemic involvement, although cautious interpretation is required given the small sample size. Conclusion This Saudi case series adds to the growing evidence of clinical heterogeneity in KBGS. Early recognition, molecular confirmation, multidisciplinary care, and longitudinal follow-up are essential to improve diagnosis, surveillance, and management.
Mai S. Labani, Z. Rahbeeni· Frontiers in Pediatrics· 0 citations
A novel homozygous missense variant in RNF216 gene c.1055T>G (p.(Phe352Cys)) in three siblings with Gordon Holmes syndrome is reported, contributing to the limited knowledge of GHS and highlighting the importance of hypogonadotropic hypogonadism treatment and close observation of neurological symptoms that may develop over time.
We present a family of five siblings who came to our attention with a clinical and radiological diagnosis of familial hypomyelinating leukodystrophy. Despite brain white matter abnormalities being present in all siblings, the clinical phenotype was variable: the three brothers presented with a clear-cut late-onset spastic paraplegia, whereas the two sisters displayed only mild pyramidal signs. Molecular analysis revealed a single relevant variant shared by all affected siblings, namely the likely pathogenic variant c.659C>T (p.Ser220Phe) in the GJA1 gene. Variants in this gene are generally associated with oculodentodigital dysplasia (ODDD), an autosomal dominant condition characterized by distinctive facial features and anomalies of the eyes, teeth, and digits. Neurological features are reported in about 30% of cases. In this family, ODDD manifested as a predominantly neurological phenotype. Although a clear explanation for this uncommon presentation is lacking, shared genetic modifiers, the effect of the specific variant, and a possible patient-population bias may have contributed. This case highlights the wide phenotypic spectrum of CX43-related disorders and suggests the importance of testing the GJA1 gene in individuals with atypical presentations, including predominant or isolated neurological phenotypes such as late-onset spastic paraplegia. MRI findings may also provide a useful diagnostic clue when ODDD is suspected.
Irene Ambrosetti, Flavia Palombo, Diego D'Angeli et al.· International Journal of Mol...· 0 citations
CASK-related disorders may present with severe neurodevelopmental impairment and cerebral palsy–like phenotypes, even in the absence of characteristic neuroimaging findings, which should raise suspicion for CASK-related disorders.
I. Pacheva, Elena Timova, T. Todorov et al.· Frontiers in Psychiatry· 0 citations
This case expands the molecular spectrum of KBG syndrome and highlights the importance of genomic testing in children presenting with developmental delay, learning difficulties, and subtle dysmorphic features, particularly when the diagnosis remains uncertain during early childhood.
