[Analysis of KCNA2 gene variant in a Chinese pedigree affected with developmental and epileptic encephalopathy].

[Clinical characterization and genetic analysis of a patient with Fahr disease due to a homozygous variant of JAM2 gene].

Genetic analysis of childhood-onset dystonia-28 caused by a variant (c.5076G>A) in the KMT2B gene

Objective To investigate the clinical manifestations and genetic basis of childhood-onset dystonia-28 (DYT28) associated with a variant in the KMT2B gene. Methods A female patient, her mother, and her husband, who presented at Zhejiang Provincial People’s Hospital in November 2024, were enrolled in this study. Clinical data were collected, and trio-based whole-exome sequencing (WES) was performed using peripheral blood samples obtained from all three individuals. To further evaluate the effect of the identified variant on RNA splicing, mRNA sequencing (mRNA-seq) and Sanger sequencing were subsequently performed. This study was approved by the Medical Ethics Committee of Zhejiang Provincial People’s Hospital (Approval No. QT2026084). Results The patient presented with gait abnormalities beginning after 10 years of age, accompanied by impaired mathematical ability and language communication difficulties. Her mother exhibited similar clinical manifestations, including gait disturbance, language impairment, and a history of scoliosis. WES identified a heterozygous synonymous variant in exon 23 of the KMT2B gene, c.5076 G>A (p.Lys1692 =), in both the patient and her mother. mRNA-seq analysis demonstrated that the variant produced two aberrantly spliced transcripts: complete skipping of exon 23 and retention of an 18-bp sequence derived from the 5′ end of intron 23. According to the guidelines of the American College of Medical Genetics and Genomics (ACMG), the variant was classified as likely pathogenic based on the following evidence: PVS1_Strong, PP4 and PM2_Supporting. Conclusion The KMT2B c.5076 G>A (p.Lys1692 =) variant is likely the genetic cause of childhood-onset dystonia-28 in this patient. This study expands the mutational spectrum of KMT2B and provides additional evidence to support the genetic diagnosis and counseling of patients with KMT2B-related dystonia.

[Clinical and genetic analysis of a child with Relapsing encephalopathy with cerebellar ataxia due to variant of ATP1A3 gene].

Identification and prenatal diagnosis of a novel likely pathogenic ANOS1 variant in a large Chinese Kallmann syndrome family

Background This study aimed to systematically analyze a Chinese family with Kallmann syndrome (KS), evaluate the pathogenicity of a candidate variant through co-segregation analysis and bioinformatic predictions, and provide clinical intervention for the family. Methods This study included a Chinese family with KS comprising 40 members in total (37 living, 3 deceased). Whole-genome sequencing (WGS) was performed on the proband, followed by Sanger sequencing for co-segregation analysis with 22 family members. Multiple bioinformatics tools were used to assess evolutionary conservation, and AlphaFold3 modeling was employed to predict the potential impact on protein structure. Based on the genetic findings, prenatal diagnosis was subsequently offered to and performed for a female carrier in the family. Results A hemizygous ANOS1:c.1879T>C (p.Ser627Pro) variant was identified. Among the eight males with clinical features of KS in this family, five of whom underwent genetic testing, and all carried the variant. The variant fully co-segregated with KS among the genotyped individuals: all five tested males carried the variant (with their mothers confirmed as carriers), while five unaffected male relatives were wild-type. Bioinformatics analysis predicted that the variant site is evolutionarily conserved across species. AlphaFold3 modeling further suggested that the p. Ser627Pro substitution disrupts the original hydrogen bonding network, potentially leading to protein instability and function impairment. Based on these genetic findings, prenatal diagnosis was performed for a female carrier in the family, and the results showed that the fetus did not carry the variant. Conclusion Combining family co-segregation (PP1) and population frequency data (PM2), the ANOS1 c.1879T>C variant was classified as likely pathogenic, providing important information for genetic counseling. This study demonstrated that even in the absence of functional experiments, comprehensive family analysis can provide crucial clues for variant of uncertain significance (VUS) interpretation. This study also guided prenatal diagnosis, offering a referable strategy for the management of similar rare diseases.

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

[Clinical and genetic analysis of a child with MRXS34 syndrome due to variant of NONO gene].