Jul 2026· Annals of Medicine and Surgery· Vol 88, pp. 5468 - 5472· 0 citations· 16 references
Medicine
Abstract
Introduction and importance: SpADMiSS syndrome (SPOUT1-Associated Developmental delay, Microcephaly, Seizures, and Short stature) is a recently described autosomal recessive neurodevelopmental disorder caused by biallelic variants in SPOUT1/CENP-32. The phenotypic spectrum of this condition is still evolving. Reporting novel clinical features and complex genetic architectures is essential to refine genotype–phenotype correlations, particularly in consanguineous populations. Case presentation: We describe a 5.5-year-old girl born to consanguineous parents who presented with refractory early-onset seizures, severe global developmental delay, growth failure, and microcephaly. Neuroimaging revealed marked cerebral atrophy and previously unreported bilateral basal ganglia calcification. The patient also developed bilateral cataracts requiring surgical intervention. Whole-exome sequencing identified a recurrent homozygous missense variant in SPOUT1/CENP-32 (c.292 G > A; p.Gly98Ser), confirming the diagnosis of SpADMiSS. In addition, homozygous pathogenic variants were detected in XYLT2 and EYS, indicating multilocus genetic disease. Clinical discussion: This case expands the phenotypic spectrum of SpADMiSS by documenting basal ganglia calcification, a feature not previously reported in affected individuals. The presence of early-onset cataracts and ocular involvement is best explained by concurrent pathogenic variants in XYLT2 and EYS, illustrating a blended phenotype due to multilocus inheritance. These findings highlight the importance of comprehensive genomic analysis in consanguineous families to avoid misattribution of clinical features to a single genetic disorder. Conclusion: We report a novel presentation of SpADMiSS syndrome associated with basal ganglia calcification and multilocus pathogenic variation. This case underscores the expanding neuroimaging phenotype of SPOUT1/CENP-32-related disease and emphasizes the critical role of whole-exome sequencing in accurately delineating complex phenotypes in consanguineous populations.
Findings support a dose-dependent SLC20A2 disease spectrum and expand the phenotype associated with biallelic loss of function from primary brain calcification toward severe early-onset neurodevelopmental disorder with prominent vascular and leptomeningeal calcification.
Mehmet Burak Mutlu, Abdullah Sezer, Elif Özdemir et al.· Journal of Human Genetics· 0 citations
BACKGROUND
SPG46 is an autosomal recessive hereditary spastic paraplegia (HSP) caused by biallelic GBA2 mutations. As a rare and still poorly understood condition, information about its clinical and genetic spectrum is scarce.
OBJECTIVE
This study aimed to delineate the clinical, neuroimaging, and genetic characteristics of a Brazilian SPG46 cohort.
METHODS
We conducted a retrospective cross-sectional study at two referral centers, identifying nine patients from six unrelated families harboring pathogenic GBA2 variants through whole-exome sequencing. Demographic, clinical, neuroimaging, and genetic data were systematically analyzed.
RESULTS
The cohort (4 males, 5 females) presented disease onset between 6 and 24 years (mean, 10.7). All exhibited progressive spastic paraplegia associated with cerebellar ataxia, dysarthria, and cognitive impairment. Psychiatric manifestations, sleep disturbances, skeletal deformities, and dystonia were frequent. Cerebellar atrophy was observed in four cases, whereas corpus callosum thinning, cataracts, and hearing impairment were absent.
CONCLUSION
The recurrent GBA2 c.1365G>C;p.(Trp455Cys) variant suggests a potential founder effect and expands the phenotypic spectrum of SPG46 in Brazil.
Raphael Pinheiro Camurugy da Hora, Victor Rebelo Procaci, Julian Letícia de Freitas et al.· Movement Disorders Clinical...· 0 citations
BackgroundTANGO2-related disorder (TDD) is a rare autosomal recessive condition characterized by episodic metabolic crises, rhabdomyolysis, encephalopathy, and life-threatening cardiac arrhythmias, with marked phenotypic variability that often contributes to delayed diagnosis.Case presentationWe report 2 sisters homozygous for the recurrent TANGO2 variant c.460G>A (p.Gly154Arg), identified in a family of Hispanic/Latino ancestry, who exhibited divergent clinical presentations. The older sibling presented with developmental delay and recurrent fasting-induced hypoglycemia associated with hyperCKemia and episodic weakness, whereas the younger sibling showed early hypotonia, ataxia, behavioral dysregulation, and subclinical hypothyroidism without initial metabolic crises. Brain magnetic resonance imaging studies were normal in both patients. In both cases, routine metabolic testing was largely unremarkable between episodes, and early manifestations were interpreted within isolated subspecialty frameworks, delaying diagnostic integration.ConclusionThese cases highlight intrafamilial variability within the recognized TDD spectrum and underscore the importance of early recognition of neurologic and endocrine features as potential red flags. Prompt molecular diagnosis is essential to guide anticipatory management and reduce morbidity and mortality.
Diego Armando Nájera-Eguía, Estefanía Villarreal-Garza, L. Martínez-de-Villarreal et al.· Journal of Child Neurology· 0 citations
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.
Sheyda Khalilian, Mohadeseh Fathi, Zahra Farbood et al.· Molecular Genetics and Metab...· 0 citations
Background: Gordon Holmes syndrome (GHS) is a rare genetic disorder, usually manifesting as a broad spectrum of neurological symptoms and hypogonadotropic hypogonadism. Only a limited number of cases presenting this congenital disorder have been reported in the literature. Since the genetic and phenotypic heterogeneity of GHS, it is crucial to report novel cases.
Case presentation: Here we report a novel homozygous missense variant in RNF216 gene c.1055T>G (p.(Phe352Cys)) in three siblings. Primary concerns were absence of secondary sexual characteristics, and amenorrhea occurred among female patients. Based on laboratory test results and clinical features, hypogonadotropic hypogonadism was diagnosed. Neurological examination revealed no signs of ataxia in siblings. However, brain magnetic resonance imaging revealed pronounced changes in the cerebral white matter for female patients. Due to primary amenorrhea and the absence of secondary sexual characteristics, treatment was initiated. Treatment might be adjusted in the presence of fertility considerations.
Conclusions: This case contributes to the limited knowledge of GHS and highlights the importance of hypogonadotropic hypogonadism treatment and close observation of neurological symptoms that may develop over time.
The novel NR2F1 variant was classified as likely pathogenic according to ACMG guidelines, confirming the diagnosis of BBSOAS and the ARF3 variant, identified as a secondary finding of uncertain clinical significance, is unlikely to account for the patient's phenotype.
Sina Babaei, Haneieh Honarmand, Mortaza Bonyadi et al.· Molecular Biology Reports· 0 citations