A pooled analysis delineates the phenotypic spectrum of ALG13-related epilepsy and emphasizes the prominence of the N107S hotspot variant, which is associated with more severe neurodevelopmental outcomes.
Abstract
Background
Pathogenic variants in Asparagine-linked glycosylation 13 (ALG13) gene are associated with developmental and epileptic encephalopathy 36 (DEE36). The recurrent missense variant c.320A>G (p.Asn107Ser, N107S) represents the most frequently reported disease associated hotspot variant. However, genotype-phenotype correlations and factors associated with seizure and neurodevelopmental outcomes remain incompletely defined.
Methods
We performed a systematic literature review and pooled analysis of published cases pathogenic or likely pathogenic ALG13 variants, as classified according to ACMG/AMP criteria. Extracting clinical, electroencephalographic (EEG), and magnetic resonance imaging (MRI) features and inheritance pattern. Phenotypes were compared between N107S and non-N107S variants and within the N107S subgroup.
Results
Twenty eight publications (111 individuals) were identified, 100 patients were included after exclusions. The N107S variant accounted for 70% (70/100) of cases, with female predominance (79/97, 81.4%). Epilepsy was present in 87% (87/100) of the overall cohort, and in 98.6% (69/70) of individuals with N107S variant. Seizures typically began in infancy, with a median onset age of 6.0 months (IQR, 4.0-8.0) overall and 5.0 months (IQR, 4.0-6.0) in individuals with the N107S variant. Infantile epileptic spasms syndrome (IESS) was the most frequent epilepsy syndrome, occurring in 84.2% of the overall cohort and 88.5% of individuals with N107S. Hypsarrhythmia was observed in 84.9% of cases with available EEG data. Brain MRI was normal in approximately two-thirds of cases, whereas cerebral atrophy and benign enlargement of subarachnoid spaces (BESS) were the most common abnormalities. Among cases with available outcome data, 42.9% achieved seizure freedom, whereas 57.1% had drug resistant epilepsy (DRE). Compared with non-N107S variants, those with N107S more frequently presented with epilepsy, IESS, and de novo inheritance pattern. Earlier seizure onset was associated with more severe neurodevelopmental disorder (NDD) in both the overall cohort and the N107S subgroup.
Conclusions
This pooled analysis delineates the phenotypic spectrum of ALG13-related epilepsy and emphasizes the prominence of the N107S hotspot variant. Earlier seizure onset is associated with more severe neurodevelopmental outcomes. These findings refine the genotype-phenotype spectrum of ALG13-related disease and support early genetic testing and standardized long-term follow-up.
The findings support a possible domain‐related genotype–phenotype association for the role of ALG13 in neurodevelopmental disorders and provide additional developmental context for the role of ALG13 in neurodevelopmental disorders.
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The findings expand the genotypic and phenotypic spectrum of DEE96, demonstrating that DEE96 manifests as a multisystem disorder with prenatal onset, and supports considering NSF variants in the differential diagnosis of complex fetal syndromes with neurological and hematological abnormalities.
Qi Yang, Zailong Qin, Jiao Li et al.· Frontiers in Genetics· 0 citations
Abstract The KCNT1 gene encodes for a sodium-activated potassium channel involved in neuronal excitability. Since its initial description in 2012 in patients with Epilepsy of Infancy with Migrating Focal Seizures (EIMFS) and in Sleep-related Hypermotor Epilepsy (SHE), the associated phenotypic spectrum has broadened—encompassing other focal epilepsies and Developmental and Epileptic Encephalopathies (DEEs)—and has included extra-neurological features. We aimed to characterize the neurological outcomes, extra-neurological features, mortality and genotype-phenotype correlations expanding the follow-up of the reported cases with KCNT1 variants. A comprehensive literature review was performed to identify all reported cases of KCNT1 pathogenic or likely pathogenic variants. Corresponding authors were contacted to obtain updated clinical data, including current vital status, epilepsy progression, extra-neurological features, cognitive and psychiatric status. The entire dataset, including updated data from the literature, was combined for subsequent analyses. A total of 316 patients from 88 publications were included. Follow-up data were obtained for 60 patients (from 28 papers and 11 countries), increasing the median age at last assessment from 4.4 to 6.0 years. 181 patients had an EIMFS phenotype, 62 had SHE, and 59 had various DEEs. Five individuals were asymptomatic parents, six had other focal epilepsies, and three had other phenotypes. Extra-neurological features were predominantly observed in patients with EIMFS and DEE, notably systemic-to-pulmonary collateral arteries, other vascular or cardiac malformations and various respiratory, orthopaedic or gastrointestinal disorders. The main cause of death was pulmonary complications (haemorrhage or infection). Genotype–phenotype correlations revealed a trend for variants in the first regulator of conductance of potassium (RCK1) domain to associate with EIMFS/non-EIMFS DEE, while SHE-associated variants were predominantly located in the second regulator of conductance of potassium (RCK2) domain. Additionally, variants p.Arg474Cys may confer increased risk for vascular malformations, but the issue appears to be broader, and systematic screening of patients carrying pathogenic KCNT1 variants would allow us to better define this risk. This study offers a comprehensive understanding of the clinical spectrum and genotype-phenotype correlation in KCNT1-related disorders. This study has inherent biases related to the retrospective collection of already published data and underscores the need to develop multisource data methodologies and registries to reduce follow-up loss in real-world data collections based on health records.
Mathilde Gras, Gaëlle Quentin-Romand, N. Chemaly et al.· Brain Communications· 0 citations
This case expands the clinical spectrum associated with RFX3 variants, supporting a potential role in IESS and early neurodevelopmental disruption, and highlights the relevance of including RFX3 in the genetic evaluation of patients with IESS and co-occurring neurodevelopmental disorders.
Graziana Ceraolo, Giulia Spoto, M. Trivisano et al.· International Journal of Mol...· 0 citations
CACNA1C is potentially a candidate causative gene of focal epilepsy and the genotype-phenotype correlation of CACNA1C helps explain phenotypic heterogeneity.
Yanfang Li, Pei Mo, Lan-Zhen Zhang et al.· Journal of Medical Genetics· 0 citations
Background Genotype-phenotype correlations in Wilson disease (WD) have so far been inconclusive. Purpose ATP7B variants with loss of function (LOF) may have a different trajectory. Since genotypes in Asia differ from the West, we aimed to correlate LOF variants of ATP7B with the severity and outcome of hepatic WD. Methods Patients with a confirmed diagnosis of WD (Leipzig criteria ≥4) were prospectively enrolled. Genetic sequencing of ATP7Bmutations was assessed by Whole-exome sequencing. For patients with variants of uncertain significance, Sanger sequencing was additionally performed on their parents to identify the inherited variants. In silico analyses were used to predict the pathogenicity of variants. Mutations that resulted in at least one truncation (nonsense, frameshift, splice site, deletions) and nontruncation (missense, synonymous) protein were defined as LOF and no LOF (NLF) respectively. Phenotypes, biochemical parameters, and outcomes were analyzed. Results One hundred sixteen hepatic WD children (84 boys, median age at diagnosis 8.9±3.3 years) with biallelic ATP7B mutations (62 different variants) were enrolled. The most common LOF (n=79) and NLF (n=37) variants were c.813C>A and c.3809A>G. Advanced liver disease (76% vs. 4%, P=0.004), portal hypertension (44% vs. 24%, P=0.03), neurological (39% vs. 16%, P=0.01) and renal involvement (44% vs. 13%, P=0.01) were significantly higher in LOF than in NLF. c.813C>A had higher serum exchangeable copper (6.8±4.4 μmol/L vs. 1.4±3.5 μmol/L, P=0.04) and lower disappearance of the Kayser-Fleischer ring (4% vs. 49%, P= 0.01) than c.3809A>G variants. Over a follow-up of 6.1±4.7 years, a single LOF variant did not show a poorer liver or overall outcomes in comparison to ≥2 LOF variants. Conclusion A single ATP7B LOF variant, especially c.813C>A was associated with advanced liver disease, portal hypertension, and extrahepatic involvement. LOF variants did not affect liver or overall outcomes.
A. K. Mishra, M. Sarma, Anchal Dubey et al.· Clinical and experimental pe...· 0 citations