BACKGROUND: Low serum ceruloplasmin concentration is considered robust marker for Wilson disease (WD) screening, measuring serum ceruloplasmin oxidase activity might be an even more valuable diagnostic tool, but it has not been sufficiently studied.
METHODS: All patients who were assessed for serum ceruloplasmin oxidase activity between January 1, 2016, and September 2, 2019, were enrolled in this study. The diagnostic performance of serum ceruloplasmin oxidase activity was analyzed using receiver operating characteristic curve analysis (ROC), Spearman\'s rank correlation, and Mann-Whitney U test.
RESULTS: Serum ceruloplasmin oxidase activity was significantly decreased in WD patients (0.87 U/L, IQR 0.61-1.54). The optimal cut-off of serum ceruloplasmin oxidase activity to identified WD is 7 U/L, with sensitivity and specificity of 97.03 % and 98.19 %, respectively. Furthermore, this study revealed a positive correlation between enzymatic and immunoreactive serum ceruloplasmin tests. As primary diagnostic methods, serum ceruloplasmin levels below the diagnostic cut-offs for either the enzymatic or immunoreactive tests were observed in 818 out of 842 WD patients (97.15 %). Compared with the presence of K-F rings in asymptomatic patients, the accuracy of serum ceruloplasmin tests was significantly higher (56.12 % VS 95.08 %). Moreover, the positive rate of cranial MRI in neurological patients was similar to the tests of serum ceruloplasmin (92.91 % VS 97.40 %). Moreover, 71 patients had ambiguous genetic results, complicating the diagnosis. However, serum ceruloplasmin tests successfully identified 65 out of these 71 patients (91.55 %).
CONCLUSIONS: Serum ceruloplasmin oxidase activity has excellent performance in diagnosing WD, which should be widely used as preferred test in WD patients.

UNASSIGNED: Preimplantation genetic testing (PGT) can reduce the risk of familial genetic diseases, chromosome abnormalities, and recurrent abortions. It is unclear whether genetic counselees with PGT indications understand and accept the implications of PGT. A well-developed and validated tool is needed to evaluate the knowledge, attitude, and practice (KAP) levels of genetic counselees with PGT indications. The purpose of this study was to develop and validate a PGT KAP questionnaire (PGT-KAP-Q) for genetic counselees with PGT indications.
UNASSIGNED: First, we established an item pool based on a literature review and qualitative interviews. Second, we developed the PGT-KAP-Q using the Delphi method. Third, we evaluated the quality of the questionnaire using item analysis and psychometric evaluation. The item analysis included extreme value comparison, application of the correlation and Cronbach\'s alpha (α) coefficient methods, and factor analysis. We also evaluated the content and structural validity of the questionnaire, as well as the internal consistency, test-retest reliability, and split-half reliability.
UNASSIGNED: After the literature review and interviews, and based on three rounds of expert consultations, we formed a 43-item questionnaire. In the validity analysis, the item\'s content validity index (I-CVI) and the average scale level CVI (S-CVI/Ave) values (>0.78 and >0.95, respectively) confirmed the questionnaire\'s content validity. Exploratory factor analysis showed that all 43 items had strong factor loadings (>0.4), and the three factors of the PGT-KAP-Q explained 51.97 % of the total variance. The Cronbach\'s α coefficient for the questionnaire was 0.95 (p < 0.05), the split-half reliability was 0.76 (p < 0.05) and the test-retest reliability coefficient was 0.78 (p < 0.05).
UNASSIGNED: The 43-item PGT-KAP-Q for genetic counselees with PGT indications is reliable and valid. It contains a moderate number of items, is easy for patients to understand and accept, and can be used for clinical research and applications.

The global prevalence rate for congenital hydrocephalus (CH) is approximately one out of every five hundred births with multifaceted predisposing factors at play. Genetic influences stand as a major contributor to CH pathogenesis, and epidemiological evidence suggests their involvement in up to 40% of all cases observed globally. Knowledge about an individual\'s genetic susceptibility can significantly improve prognostic precision while aiding clinical decision-making processes. However, the precise genetic etiology has only been pinpointed in fewer than 5% of human instances. More occurrences of CH cases are required for comprehensive gene sequencing aimed at uncovering additional potential genetic loci. A deeper comprehension of its underlying genetics may offer invaluable insights into the molecular and cellular basis of this brain disorder. This review provides a summary of pertinent genes identified through gene sequencing technologies in humans, in addition to the 4 genes currently associated with CH (two X-linked genes L1CAM and AP1S2, two autosomal recessive MPDZ and CCDC88C). Others predominantly participate in aqueduct abnormalities, ciliary movement, and nervous system development. The prospective CH-related genes revealed through animal model gene-editing techniques are further outlined, focusing mainly on 4 pathways, namely cilia synthesis and movement, ion channels and transportation, Reissner\'s fiber (RF) synthesis, cell apoptosis, and neurogenesis. Notably, the proper functioning of motile cilia provides significant impulsion for cerebrospinal fluid (CSF) circulation within the brain ventricles while mutations in cilia-related genes constitute a primary cause underlying this condition. So far, only a limited number of CH-associated genes have been identified in humans. The integration of genotype and phenotype for disease diagnosis represents a new trend in the medical field. Animal models provide insights into the pathogenesis of CH and contribute to our understanding of its association with related complications, such as renal cysts, scoliosis, and cardiomyopathy, as these genes may also play a role in the development of these diseases. Genes discovered in animals present potential targets for new treatments but require further validation through future human studies.

BACKGROUND: Clinicians traditionally aim to identify a singular explanation for the clinical presentation of a patient; however, in some cases, the diagnosis may remain elusive or fail to comprehensively explain the clinical findings. In recent years, advancements in next-generation sequencing, including whole-exome sequencing, have led to the incidental identification of dual diagnoses in patients. Herein we present the cases of five pediatric patients diagnosed with dual rare genetic diseases. Their natural history and diagnostic process were explored, and lessons learned from utilizing next-generation diagnostic technologies have been reported.
RESULTS: Five pediatric cases (3 boys, 2 girls) with dual diagnoses were reported. The age at diagnosis was from 3 months to 10 years. The main clinical presentations were psychomotor retardation and increased muscular tension, some accompanied with liver dysfunction, abnormal appearance, precocious puberty, dorsiflexion restriction and varus of both feet, etc. After whole-exome sequencing, nine diseases were confirmed in these patients: Angelman syndrome and Krabbe disease in case 1, Citrin deficiency and Kabuki syndrome in case 2, Homocysteinemia type 2 and Copy number variant in case 3, Isolated methylmalonic acidemia and Niemann-Pick disease type B in case 4, Isolated methylmalonic acidemia and 21-hydroxylase deficiency in case 5. Fifteen gene mutations and 2 CNVs were identified. Four novel mutations were observed, including c.15292de1A in KMT2D, c.159_164inv and c.1427G > A in SLC25A13, and c.591 C > G in MTHFR.
CONCLUSIONS: Our findings underscore the importance of clinicians being vigilant about the significance of historical and physical examination. Comprehensive clinical experience is crucial for identifying atypical clinical features, particularly in cases involving dual rare genetic diseases.

Previous studies on genetic diseases predominantly focused on protein-coding variations, overlooking the vast noncoding regions in the human genome. The development of high-throughput sequencing technologies and functional genomics tools has enabled the systematic identification of functional noncoding variants. These variants can impact gene expression, regulation, and chromatin conformation, thereby contributing to disease pathogenesis. Understanding the mechanisms that underlie the impact of noncoding variants on genetic diseases is indispensable for the development of precisely targeted therapies and the implementation of personalized medicine strategies. The intricacies of noncoding regions introduce a multitude of challenges and research opportunities. In this review, we introduce a spectrum of noncoding variants involved in genetic diseases, along with research strategies and advanced technologies for their precise identification and in-depth understanding of the complexity of the noncoding genome. We will delve into the research challenges and propose potential solutions for unraveling the genetic basis of rare and complex diseases.

Third-generation sequencing (TGS) has led to a brave new revolution in detecting genetic diseases over the last few years. TGS has been rapidly developed for genetic disease applications owing to its significant advantages such as long read length, rapid detection, and precise detection of complex and rare structural variants. This approach greatly improves the efficiency of disease diagnosis and complements the shortcomings of short-read sequencing. In this paper, we first briefly introduce the working mechanism of one of the most important representatives of TGS, single-molecule real-time (SMRT) sequencing by Pacific Bioscience (PacBio), followed by a review and comparison of the advantages and disadvantages of different sequencing technologies. Finally, we focused on the progress of SMRT sequencing applications in genetic disease detection. Future perspectives on the applications of TGS in other fields were also presented. With the continuous innovation of the SMRT technologies and the expansion of their fields of application, SMRT sequencing has broad clinical application prospects in genetic diseases detection, and is expected to become an important tool for the molecular diagnosis of other diseases.

The solute carrier family 4 (SLC4) is an important protein responsible for the transport of various ions across the cell membrane and mediating diverse physiological functions, such as the ion transporting function, protein-to-protein interactions, and molecular transduction. The deficiencies in SLC4 molecules may cause multisystem disease involving, particularly, the respiratory system, digestive, urinary, endocrine, hematopoietic, and central nervous systems. Currently, there are no effective strategies to treat these diseases. SLC4 proteins are also found to contribute to tumorigenesis and development, and some of them are regarded as therapeutic targets in quite a few clinical trials. This indicates that SLC4 proteins have potential clinical prospects. In view of their functional characteristics, there is a critical need to review the specific functions of bicarbonate transporters, their related diseases, and the involved pathological mechanisms. We summarize the diseases caused by the mutations in SLC4 family genes and briefly introduce the clinical manifestations of these diseases as well as the current treatment strategies. Additionally, we illustrate their roles in terms of the physiology and pathogenesis that has been currently researched, which might be the future therapeutic and diagnostic targets of diseases and a new direction for drug research and development.

Incontinentia pigmenti (IP) is a rare X-linked dominant genodermatosis that affects skin, hair, teeth, eyes and central nervous system. We present the case of a female patient with mild IP caused by a hypomorphic pathogenic variant of the inhibitor of the kappa light polypeptide gene enhancer in B cells, kinase gamma (IKBKG) gene. This is the first report of a female IP patient with the hypomorphic variant, NM_001099856.6: c.1423dup, which is causative of anhidrotic ectodermal dysplasia with immune deficiency in males.

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RNA therapeutics inhibit the expression of specific proteins/RNAs by targeting complementary sequences of corresponding genes or encode proteins for the synthesis desired genes to treat genetic diseases. RNA-based therapeutics are categorized as oligonucleotide drugs (antisense oligonucleotides, small interfering RNA, RNA aptamers), and mRNA drugs. The antisense oligonucleotides and small interfering RNA for treatment of genetic diseases have been approved by the FDA in the United States, while RNA aptamers and mRNA drugs are still in clinical trials. Chemical modifications can be applied to RNA drugs, such as pseudouridine modification of mRNA, to reduce immunogenicity and improve the efficacy. The secure and effective delivery systems such as lipid-based nanoparticles, extracellular vesicles, and virus-like particles are under development to address stability, specificity, and safety issues of RNA drugs. This article provides an overview of the specific molecular mechanisms of eleven RNA drugs currently used for treating genetic diseases, and discusses the research progress of chemical modifications and delivery systems of RNA drugs.
RNA药物能够通过识别互补序列靶向对应基因以抑制特定蛋白或RNA的表达，或通过翻译合成目的基因编码的蛋白来发挥遗传性疾病治疗作用。RNA药物主要分为寡核苷酸药物（包括反义寡核苷酸、小干扰RNA和RNA适配体）和信使RNA药物等。其中，反义寡核苷酸和小干扰RNA已用于临床治疗遗传病，而RNA适配体和信使RNA药物目前还处于临床试验阶段。当前主要通过对RNA药物进行化学修饰（如对信使RNA进行假尿嘧啶修饰）来降低免疫原性和提升药物疗效，以及开发纳米粒载体、细胞外囊泡和类病毒载体等递送载体来解决RNA药物的稳定性、特异靶向性和安全性等问题。本文概述了目前用于治疗遗传病的11种RNA药物的具体作用分子机制，并简单讨论了RNA药物的化学修饰及递送载体的研究现状。.