The translation of genetic findings from genome-wide association studies into actionable therapeutics persists as a critical challenge in Alzheimer's disease (AD) research. Here, we present PI4AD, a computational medicine framework that integrates multi-omics data, systems biology, and artificial neural networks for therapeutic discovery. This framework leverages multi-omic and network evidence to deliver three core functionalities: clinical target prioritisation; self-organising prioritisation map construction, distinguishing AD-specific targets from those linked to neuropsychiatric disorders; and pathway crosstalk-informed therapeutic discovery. PI4AD successfully recovers clinically validated targets like APP and ESR1, confirming its prioritisation efficacy. Its artificial neural network component identifies disease-specific molecular signatures, while pathway crosstalk analysis reveals critical nodal genes (e.g., HRAS and MAPK1), drug repurposing candidates, and clinically relevant network modules. By validating targets, elucidating disease-specific therapeutic potentials, and exploring crosstalk mechanisms, PI4AD bridges genetic insights with pathway-level biology, establishing a systems genetics foundation for rational therapeutic development. Importantly, its emphasis on Ras-centred pathways-implicated in synaptic dysfunction and neuroinflammation-provides a strategy to disrupt AD progression, complementing conventional amyloid/tau-focused paradigms, with the future potential to redefine treatment strategies in conjunction with mRNA therapeutics and thereby advance translational medicine in neurodegeneration.

OBJECTIVE: To analyze the correlation between variants in the start codon of the α-globin gene and phenotypes of thalassemia, so as to provide a basis for the diagnosis and prevention of α-thalassemia. METHODS: A retrospective study was conducted on 7 patients diagnosed by Yangjiang People's Hospital and Guangzhou Hybribio Co. Ltd., from June 2019 to October 2022. Routine blood tests and hemoglobin electrophoresis were carried out. Potential variants were identified through polymerase chain reaction (PCR) combined with Reverse dot blotting (RDB), Gap-PCR, and Sanger sequencing. This study has been approved by the Medical Ethics Committee of People's Hospital of Yangjiang (Ethics No: 20240001). RESULTS: For the 7 patients, results of blood routine test of one case was unknown, and that of another was normal. The remaining 5 cases had presented with microcytic hypochromic anemia. The results of hemoglobin electrophoresis showed that one case had normal Hb A and slightly lower Hb A2, whilst another had significantly decreased Hb A and Hb A2, in addition with the appearance of a Hb H band. The content of Hb Bart's in four neonates was ≥ 0.4%. The remaining one case had no result. Genetic testing has identified 4 rare start codon mutations, namely HBA2: c.2delT, HBA2: c.1A>G, HBA2: c.1A>T, and HBA1: c.2T>C. Among these, Patient 1 had harbored compound heterozygous variants of HBA2: c.427T>C (Hb CS) and HBA2: c.2delT. Patient 4 had harbored compound heterozygous variants of HBA2: c.1A>G and Southeast Asian type deletion. CONCLUSION Heterozygotes with HBA start codon variants usually present as silent or mild thalassemia, and the symptoms of anemia may deteriorate when combined with other α-thalassemia variant. The HBA2: c.1A>T start codon variant was unreported previously in China. The detection of start codon variants has helped to clarify the causes of anemia, genetic counseling, and guidance for reproduction.
Humans ; Phenotype ; Codon, Initiator/genetics* ; Female ; Male ; Retrospective Studies ; alpha-Globins/genetics* ; alpha-Thalassemia/genetics* ; Hemoglobin A/genetics* ; Adult ; Mutation

OBJECTIVE: To explore the clinical features of a child with Lamb-Shaffer syndrome (LAMSHF) due to a variant of SOX5 gene. METHODS: A child who was admitted to Children's Hospital Affiliated to Zhengzhou University in July 2022 was selected as the study subject. Clinical data of the child was collected. Whole exome sequencing (WES) was carried out on peripheral blood samples from the child and his parents, and candidate variant was verified by Sanger sequencing and bioinformatic analysis. The study has been approved by the Medical Ethics Committee of the Children's Hospital Affiliated to Zhengzhou University (Ethics No. 2024-K-100). RESULTS: The child, an one-year-and-seven-month-old male, has manifested delayed development in speech and language, intelligence and movement, in addition with mild facial deformities and eye signs. Whole exome sequencing revealed that he has harbored a heterozygous c.1828_1829insGACT (p.Y610fs*1) frameshifting variant of the SOX5 gene. Sanger sequencing confirmed the variant to be de novo in origin. The variant was also unreported previously. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was rated as pathogenic (PVS1+PS2+PM2_supporting). CONCLUSION The c.1828_1829insGACT (p.Y610fs*1) variant of the SOX5 gene probably underlay the pathogenesis of LAMSHF in this child. For children with delayed mental, language, intellectual, and motor development, genetic testing should be conducted to facilitate early diagnosis. Above finding has enriched the mutational spectrum of the SOX5 gene.
Humans ; SOXD Transcription Factors/genetics* ; Male ; Infant ; Exome Sequencing ; Genetic Testing ; Mutation

Objective:To analyze the correlation between variants in the start codon of the α-globin gene and phenotypes of thalassemia, so as to provide a basis for the diagnosis and prevention of α-thalassemia.Methods:A retrospective study was conducted on 7 patients diagnosed by Yangjiang People′s Hospital and Guangzhou Hybribio Co. Ltd., from June 2019 to October 2022. Routine blood tests and hemoglobin electrophoresis were carried out. Potential variants were identified through polymerase chain reaction (PCR) combined with Reverse dot blotting (RDB), Gap-PCR, and Sanger sequencing. This study has been approved by the Medical Ethics Committee of People′s Hospital of Yangjiang (Ethics No: 20240001).Results:For the 7 patients, results of blood routine test of one case was unknown, and that of another was normal. The remaining 5 cases had presented with microcytic hypochromic anemia. The results of hemoglobin electrophoresis showed that one case had normal Hb A and slightly lower Hb A 2, whilst another had significantly decreased Hb A and Hb A 2, in addition with the appearance of a Hb H band. The content of Hb Bart′s in four neonates was ≥0.4%. The remaining one case had no result. Genetic testing has identified 4 rare start codon mutations, namely HBA2: c. 2delT, HBA2: c. 1A>G, HBA2: c. 1A>T, and HBA1: c. 2T>C. Among these, Patient 1 had harbored compound heterozygous variants of HBA2: c. 427T>C (Hb CS) and HBA2: c. 2delT. Patient 4 had harbored compound heterozygous variants of HBA2: c. 1A>G and Southeast Asian type deletion. Conclusion:Heterozygotes with HBA start codon variants usually present as silent or mild thalassemia, and the symptoms of anemia may deteriorate when combined with other α-thalassemia variant. The HBA2: c. 1A>T start codon variant was unreported previously in China. The detection of start codon variants has helped to clarify the causes of anemia, genetic counseling, and guidance for reproduction.

Objective:To explore the clinical features of a child with Lamb-Shaffer syndrome (LAMSHF) due to a variant of SOX5 gene. Methods:A child who was admitted to Children′s Hospital Affiliated to Zhengzhou University in July 2022 was selected as the study subject. Clinical data of the child was collected. Whole exome sequencing (WES) was carried out on peripheral blood samples from the child and his parents, and candidate variant was verified by Sanger sequencing and bioinformatic analysis. The study has been approved by the Medical Ethics Committee of the Children′s Hospital Affiliated to Zhengzhou University (Ethics No. 2024-K-100).Results:The child, an one-year-and-seven-month-old male, has manifested delayed development in speech and language, intelligence and movement, in addition with mild facial deformities and eye signs. Whole exome sequencing revealed that he has harbored a heterozygous c. 1828_1829insGACT (p.Y610fs*1) frameshifting variant of the SOX5 gene. Sanger sequencing confirmed the variant to be de novo in origin. The variant was also unreported previously. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was rated as pathogenic (PVS1+ PS2+ PM2_supporting). Conclusion:The c. 1828_1829insGACT (p.Y610fs*1) variant of the SOX5 gene probably underlay the pathogenesis of LAMSHF in this child. For children with delayed mental, language, intellectual, and motor development, genetic testing should be conducted to facilitate early diagnosis. Above finding has enriched the mutational spectrum of the SOX5 gene.

Objective:To analyze the correlation between variants in the start codon of the α-globin gene and phenotypes of thalassemia, so as to provide a basis for the diagnosis and prevention of α-thalassemia.Methods:A retrospective study was conducted on 7 patients diagnosed by Yangjiang People′s Hospital and Guangzhou Hybribio Co. Ltd., from June 2019 to October 2022. Routine blood tests and hemoglobin electrophoresis were carried out. Potential variants were identified through polymerase chain reaction (PCR) combined with Reverse dot blotting (RDB), Gap-PCR, and Sanger sequencing. This study has been approved by the Medical Ethics Committee of People′s Hospital of Yangjiang (Ethics No: 20240001).Results:For the 7 patients, results of blood routine test of one case was unknown, and that of another was normal. The remaining 5 cases had presented with microcytic hypochromic anemia. The results of hemoglobin electrophoresis showed that one case had normal Hb A and slightly lower Hb A 2, whilst another had significantly decreased Hb A and Hb A 2, in addition with the appearance of a Hb H band. The content of Hb Bart′s in four neonates was ≥0.4%. The remaining one case had no result. Genetic testing has identified 4 rare start codon mutations, namely HBA2: c. 2delT, HBA2: c. 1A>G, HBA2: c. 1A>T, and HBA1: c. 2T>C. Among these, Patient 1 had harbored compound heterozygous variants of HBA2: c. 427T>C (Hb CS) and HBA2: c. 2delT. Patient 4 had harbored compound heterozygous variants of HBA2: c. 1A>G and Southeast Asian type deletion. Conclusion:Heterozygotes with HBA start codon variants usually present as silent or mild thalassemia, and the symptoms of anemia may deteriorate when combined with other α-thalassemia variant. The HBA2: c. 1A>T start codon variant was unreported previously in China. The detection of start codon variants has helped to clarify the causes of anemia, genetic counseling, and guidance for reproduction.

Objective:To explore the clinical features of a child with Lamb-Shaffer syndrome (LAMSHF) due to a variant of SOX5 gene. Methods:A child who was admitted to Children′s Hospital Affiliated to Zhengzhou University in July 2022 was selected as the study subject. Clinical data of the child was collected. Whole exome sequencing (WES) was carried out on peripheral blood samples from the child and his parents, and candidate variant was verified by Sanger sequencing and bioinformatic analysis. The study has been approved by the Medical Ethics Committee of the Children′s Hospital Affiliated to Zhengzhou University (Ethics No. 2024-K-100).Results:The child, an one-year-and-seven-month-old male, has manifested delayed development in speech and language, intelligence and movement, in addition with mild facial deformities and eye signs. Whole exome sequencing revealed that he has harbored a heterozygous c. 1828_1829insGACT (p.Y610fs*1) frameshifting variant of the SOX5 gene. Sanger sequencing confirmed the variant to be de novo in origin. The variant was also unreported previously. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was rated as pathogenic (PVS1+ PS2+ PM2_supporting). Conclusion:The c. 1828_1829insGACT (p.Y610fs*1) variant of the SOX5 gene probably underlay the pathogenesis of LAMSHF in this child. For children with delayed mental, language, intellectual, and motor development, genetic testing should be conducted to facilitate early diagnosis. Above finding has enriched the mutational spectrum of the SOX5 gene.

Objective:To analyze clinical characteristics of acromegaly patients who have discordant growth hormone(GH) or insulin-like growth factor-1(IGF-1) levels and evaluate impact of different GH cut-offs on discordance rate.Methods:A retrospective analysis was conducted on data from 66 acromegaly patients treated at Nanjing Drum Tower Hospital from November 2017 to March 2023. Patients were categorized based on the nadir GH(GHn) and IGF-1 levels at the last follow-up into four groups: controlled, high GH, high IGF-1, and active. Clinical and metabolic parameters were compared across these groups, and impact of different GHn and fasting growth hormone(GHf) cut-offs on discordance rate was evaluated.Results:No statistically significant differences were observed among groups in age, duration of follow-up, imaging characteristics(all P>0.05). High IGF-1 group had higher fasting insulin and homeostasis model assessment for β cell function compared to controlled and high GH group(all P<0.05), while these parameters did not differ between high GH and controlled group. High IGF-1 group had higher carboxy-terminal cross-linked telopeptide of type 1 collagen, osteocalcin and procollagen type 1 N-terminal propeptide compared to controlled and high GH group, but differences were not statistically significant(all P>0.05). These parameters also did not differ between high GH and controlled group. Discordance rate was not significantly different when GHn cut-offs was 1.0 μg/L or 0.4 μg/L(30.3% vs 21.3%, P=0.146). Compared to 2.5 μg/L, discordance rate was lower when GHf cut-off was 1.0 μg/L(39.4% vs 24.3%, P=0.041). Conclusion:The discordance rate in treated acromegaly patients during follow-up is approximately 30%. Different GH measurement timings and cut-offs significantly impact discordance rate. Patients with normal GH and elevated IGF-1 levels are at potential risk of active disease, and require closer follow-up. This study provides a valuable reference for treatment of patients with discordant GH and IGF-1 levels.

Objective:To explore the hematological phenotype and genotypic characteristics of five Chinese individuals with a rare thalassemia mutation HBB: c. 93-21G>A. Methods:A retrospective study was carried out on five individuals identified by the People′s Hospital of Yangjiang and Guangzhou Hybribio Co., Ltd. from May 2018 to September 2022. Routine blood test and hemoglobin electrophoresis were performed, and the genotypes of five subjects were determined by using PCR combined with reverse dot blotting (RDB), nested PCR, Gap-PCR and Sanger sequencing. This study was approved by Medical Ethics Cornmittee of the People′s Hospital of Yangjiang (Ethics No. 20240001).Results:Among the five individuals, hematological data of one was unavailable, and the remaining four had presented with microcytosis and hypochromia. The results of hemoglobin electrophoresis indicated that all of them had a HbA 2 level of ≥4.7%. Genetic analysis showed that one case had harbored compound heterozygous mutations of ααα anti3.7 triplet and HBB: c. 93-21G>A, one had compound heterozygous mutations of -α 3.7 and HBB: c. 93-21G>A, whilst the remaining three were heterozygous for the HBB: c. 93-21G>A mutation. Conclusion:The hematological phenotype of β-thalassemia carriers ( HBB: c. 93-21G>A) is similar to that of other β + thalassemia heterozygotes with mild β-thalassemia characteristics.

Objective To analyze the relationship between serum microRNA(miR)-204 and miR-200b lev-els and clinical efficacy in patients with oral submucosal fibrosis(OSF).Methods A total of 110 patients with OSF who visited Affiliated Hospital of Hebei Engineering University from December 2021 to December 2022 were collected as the study group,another 50 healthy people who underwent physical examination during the same period were collected as the control group.The quantitative real-time PCR(qRT-PCR)method was ap-plied to detect and compare the serum levels of miR-204 and miR-200b in the study group and the control group.The study group was divided into miR-204 high expression group and low expression group,and miR-200b high expression group and low expression group.The clinical efficacy,transforming growth factor β1(TGF-β1),interleukin-6(IL-6),clinical pathological features,and visual analogue scale(VAS)of patients with different levels of serum miR-204 and miR-200b were compared,and Spearman and Pearson methods were applied to analyze the correlation between serum miR-204 and miR-200b levels and various indicators in the study group.Results The serum level of miR-204 and miR-200b in the study group was obviously lower than those in the control group,and the difference was statistically significant(P＜0.05).The total effective rates of patients in the high expression group of miR-204 and the high expression group of miR-200b were both 100.00％,which were higher than the total effective rates of the low expression group of miR-204 and the low expression group of miR-200b(86.79％and 88.89％)respectively,and the differences were statisti-cally significant(P＜0.05).The results of univariate analysis showed that the serum levels of miR-204 and miR-200b in OSF patients with chewing betel nut,mouth opening degree≤28 mm,oral mucosal lesion area＞4 cm2,and VAS score＞3 points were obviously lower than those with non chewing betel nut,mouth opening degree＞28 mm,oral mucosal lesion area≤4 cm2,and VAS score≤3 points,and the differences were statis-tically significant(P＜0.05).The levels of TGF-β1 and IL-6 in patients with high expression of miR-204 and miR-200b were obviously lower than those in patients with low expression of miR-204 and miR-200b,and the differences were statistically significant(P＜0.05).The correlation analysis results showed that the serum levels of miR-204 and miR-200b in patients with OSF were negatively correlated with oral mucosal lesion are-a,VAS score,TGF-β1,IL-6(P＜0.05),and positively correlated with mouth opening degree(P＜0.05).Conclusion The serum levels of miR-204 and miR-200b in patients with OSF are closely related to clinical ef-ficacy,and when the serum levels of miR-204 and miR-200b increase,OSF patients have better clinical efficacy.