Prognosis of pediatric hepatic Wilson disease with ATP7B loss of function variants

[Clinical manifestation and analysis of FBN1 gene variants in eight patients with Marfan syndrome].

Clinical phenotype spectrum and prognostic analysis of DNM1L-related disorders: a single-center cohort study of 18 patients

To summarize the clinical and genetic characteristics of DNM1L -related disorders and explore genotype-phenotype correlations and prognosis. We retrospectively analyzed clinical data from 18 children with DNM1L variants diagnosed between 2015 and October 2025. Combined with systematic literature review (2007-October 2025) to analyze reported DNM1L variant types and clinical phenotypes. The cohort included 18 children (10 male, 8 female) with a median onset age of 3.5 years. Epilepsy occurred in 88.9% of patients, with 72.2% developing super-refractory status epilepticus; 66.7% had dystonia. Most patients exhibited brain MRI and EEG abnormalities. Eight novel pathogenic variants were identified (four missense, three frameshift, one compound heterozygous). Notably, eight patients with middle domain variants (primarily p.Arg403Cys) presented a novel “hemiconvulsion-hemiplegia-epilepsy syndrome” phenotype. At last follow-up, 83.3% had a modified Rankin Scale score ≥4, indicating severe disability and poor prognosis. Literatures review confirmed DNM1L variants are predominantly missense, with the middle domain as a hotspot. The p.Arg403Cys variant is recurrent and highly prevalent in the Chinese. Middle domain variants are more common in Asians, while GTPase domain variants are more frequent in Europeans. Missense variants in the middle domain correlated with higher rates of neurological dysfunction and mortality. This study represents an extension of our earlier work by incorporating an additional 18 cases, which expands the genetic and phenotypic spectrum of DNM1L -related disorders. It identifies “hemiconvulsion-hemiplegia-epilepsy syndrome” as a distinct feature and potential prognostic indicator for middle domain variants. The established genotype-phenotype patterns, based on protein domains and ethnic differences, provide critical insights for precise diagnosis and management.

Clinical significance of SQSTM1 variants in ALS: report of p.Arg119Cys and literature review

We analyzed the clinical features of a patient with amyotrophic lateral sclerosis (ALS) carrying a novel variant in the sequestosome 1 (SQSTM1) gene and explored the genotype-phenotype association of SQSTM1 gene variants in combination with previous literature. Clinical data and genetic testing results of an ALS patient treated at our hospital were collected. Whole-exome sequencing was used to screen for ALS-related genes, and candidate variants were validated by Sanger sequencing and family analysis. A systematic search was conducted in the PubMed database using the keywords (“amyotrophic lateral sclerosis”) OR (“motor neuron disease”) AND (“SQSTM1”) to summarize the clinical and genetic characteristics of previously reported ALS patients with SQSTM1 variants. The patient was a 49-year-old male with progressive weakness in both lower limbs for one year and weakness in the left upper limb for the past three months. Electromyography showed extensive neurogenic damage. Genetic testing identified a novel heterozygous missense variant, c.355 C > T (p.Arg119Cys), in the SQSTM1 gene. Family verification revealed that his phenotypically normal mother carried the same variant. The literature search identified 58 cases of ALS associated with SQSTM1 variants. Missense variants were the most common type. We identified a novel SQSTM1 variant, c.355 C > T (p.Arg119Cys), in a ALS patient. Although this finding expands the variant spectrum, its pathogenicity remains uncertain and requires further functional validation and pedigree confirmation. Our literature review further shows that SQSTM1-associated ALS predominantly presents with limb onset, with a subset of patients exhibiting frontotemporal dementia or Paget’s disease.

Phenotype and outcome of patients with hypertrophic cardiomyopathy MYH7 variants: A longitudinal cohort study.

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.

Clinical and genetic analysis of patients with Sjögren-Larsson syndrome in China.

OBJECTIVE To characterize the clinical features and genetic spectrum of Chinese patients with Sjögren-Larsson syndrome (SLS). METHODS We retrospectively reviewed genetically confirmed SLS cases managed in the Functional Neurosurgery Department of Beijing Children's Hospital. We also searched Chinese- and English-language databases to identify additional SLS cases for comparative analysis. Structural effects of detected variants on fatty aldehyde dehydrogenase (FALDH) were explored using PDB-derived models and PyMOL. RESULTS Three SLS patients were identified, including one carrying a novel variant not previously reported. Literature review yielded 19 additional Chinese cases. Globally, SLS has a broad distribution, with the highest case counts reported in the United States, Sweden, and China. Compared with cohorts from other countries, Chinese patients showed a higher proportion of females, and compound heterozygous variants were more frequent than homozygous variants. The c.1157A > G substitution emerged as the most common variant in Chinese SLS. Three-dimensional modeling suggested that several variants likely perturb FALDH conformation. CONCLUSION Chinese SLS patients exhibit distinctive clinical and genetic patterns relative to other populations, with c.1157A > G being the most frequent variant. Structural modeling supports a potential conformational impact of these variants on FALDH.

A novel PKHD1 missense variant disrupting splicing in a fetus with Caroli disease.

BACKGROUND Caroli disease (CD) is a rare inherited disorder characterized by dilatation of intrahepatic bile ducts, and prenatal diagnosis of this disease is extremely rare. PKHD1 is the only known causative gene, yet the pathogenicity of most missense variants remains unclear. METHODS Exome sequencing (ES) was performed on a fetus with clinical features of CD. Candidate variants were validated by Sanger sequencing in the family. The impact of the novel missense variant on pre-mRNA splicing was assessed using minigene assays, and structural modeling of the PKHD1 protein was conducted with AlphaFold 3. RESULTS At 23 weeks of gestation, the fetus showed hepatic cysts on ultrasound and a "central dot" sign on MRI, suggesting a diagnosis of CD. The fetus also exhibited features of autosomal recessive polycystic kidney disease and oligohydramnios. ES identified and Sanger sequencing confirmed three PKHD1 variants: a paternal nonsense variant c.5323C>T; p.(Arg1775*), and two maternal missense variants c.6682G>C; p.(Glu2228Gln) and c.8012G>T; p.(Arg2671Leu). The variant c.6682G>C is novel and minigene assays demonstrated that it caused exon 40 skipping, leading to an in‑frame deletion (c.6491_6682del; p.(Gly2164_Arg2227del)). Structural modeling predicts that this deletion lies within a large β‑barrel domain and may compromise its structural stability. Conclusion We characterize a novel missense variant that causes aberrant splicing of PKHD1 in CD. This finding underscores the necessity of functional analysis for evaluating the pathogenicity of missense variants, especially those at the last nucleotide of an exon. Our study expands the mutation spectrum of PKHD1 and provides insights into genotype‑phenotype correlations.