Jul 2026· Clinical and experimental pediatrics· Vol 69, pp. 646 - 654· 0 citations· 32 references
Medicine
TL;DR
A single ATP7B LOF variant, especially c.813C>A was associated with advanced liver disease, portal hypertension, and extrahepatic involvement and over a follow-up of 6.7 years, a single LOF variant did not show a poorer liver or overall outcomes in comparison to ≥2 LOF variants.
Abstract
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.
Findings have enriched the mutational spectrum of the FBN1 gene among Chinese MFS patients and provided a basis for the genetic counseling and clinical management.
Renhua Wu, Lei Sun, Bao-Zhu Liu et al.· Zhonghua yi xue yi chuan xue...· 0 citations
“hemiconvulsion-hemiplegia-epilepsy syndrome” is identified as a distinct feature and potential prognostic indicator for middle domain variants in DNM1L variants, which are predominantly missense, with the middle domain as a hotspot.
Han Xu, Chaolong Xu, Ying Zou et al.· Frontiers in Neurology· 0 citations
It is shown that SQSTM1-associated ALS predominantly presents with limb onset, with a subset of patients exhibiting frontotemporal dementia or Paget’s disease, and its pathogenicity remains uncertain and requires further functional validation and pedigree confirmation.
Boyan Su, Ling Li, Xiaoxiao Zheng et al.· Neurogenetics· 0 citations
INTRODUCTION AND OBJECTIVES
Hypertrophic cardiomyopathy (HCM) is primarily caused by mutations in the MYH7 and MYBPC3 genes which exhibit diverse clinical expression and prognosis. This study aims to outline the clinical features and long-term cardiovascular outcome of patients with MYH7-related HCM, and to look for clinical and prognostic implications of specific variants.
METHODS
A retrospective longitudinal analysis was conducted on 30 unrelated HCM families with pathogenic/likely pathogenic (P/LP) MYH7 mutations. A composite endpoint encompassing hospitalisation for heart failure, cardiovascular admissions, or all-cause mortality was evaluated. Kaplan-Meier survival analysis was used to compare outcomes across prevalent variants and genetic profiles.
RESULTS
Among 118 individuals (30 probands, 88 relatives), 77 were carriers of P/LP MYH7 variants - 69% with HCM (G+/Ph+) at diagnosis and 31% P/LP MYH7 variant carriers only (G+/Ph-). Thirteen different P/LP variants were identified in the 30 families, with four (p.Ile263Thr, p.Ala797Thr, p.Glu1356Lys, p.Arg663His) accounting for two-thirds of cases. HCM patients had a mean age at diagnosis of 40.4±18.1 years and 49% were male. Baseline maximal wall thickness (MWT) was 18.6±0.8 mm, left atrial diameter (LAD) was 41.3±9.4 mm, and 23% exhibited resting left ventricular outflow tract obstruction (LVOTO); 68% had abnormal ECGs, but only one patient had atrial fibrillation (AF). Probands showed significantly larger LAD than relatives (p=0.004). A history of premature familial sudden cardiac death (SCD) was reported in 43% families. During a median follow-up of 9.5 years (IQR 3.4-24.7, range 0.2-46.8 years), 35% of patients reached the composite endpoint, including 16 deaths (1 SCD) and 6 heart failure (HF) -related hospitalisations; 30% of patients developed AF, 17% received an ICD for primary prevention of SCD and 17% had a pacemaker implantation. Older age at diagnosis (p<0.01) and increased LAD (p=0.048) predicted poorer outcomes. The composite endpoint was similar between probands and relatives with HCM (p=0.08) and across the main variants (p=0.06). Overall penetrance was 70%, with only one carrier progressing to mild HCM. ESC HCM Risk SCD scores were similar across variants, both at baseline (p=0.601) and at last follow-up (p=0.286).
CONCLUSIONS
Most patients with MYH7-related HCM presented with a benign phenotype over the long term. Nonetheless, the risks of AF, SCD, and worsening HF throughout life justify regular monitoring, and the need to look for particular genetic profiles that may potentially help tailored management strategies.
C. Gregório, M. Vilela, Ana Beatriz Garcia et al.· Revista Portuguesa de Cardio...· 0 citations
Chinese SLS patients exhibit distinctive clinical and genetic patterns relative to other populations, with c.1157A > G being the most frequent variant andStructural modeling supports a potential conformational impact of these variants on FALDH.
Feng Chen, Bowen Yu, Yangshuo Wang et al.· Orphanet Journal of Rare Dis...· 0 citations
A novel missense variant is characterized that causes aberrant splicing of PKHD1 in CD and underscores the necessity of functional analysis for evaluating the pathogenicity of missense variants, especially those at the last nucleotide of an exon.