Molecular Genetics & Genomic Medicine最新文献

Background: Hereditary pulmonary alveolar proteinosis (PAP) is a rare interstitial lung disease caused by variations in genes such as CSF2RA and CSF2RB, which disrupt granulocyte-macrophage colony-stimulating factor signaling and impair surfactant clearance. These defects lead to progressive surfactant accumulation in alveoli, resulting in respiratory dysfunction.

Methods: We describe a 3-year-old girl with Turner syndrome who presented with recurrent cough and dyspnea and was diagnosed with hereditary PAP. Diagnostic evaluation included high-resolution computed tomography (HRCT), lung biopsy, and whole-exome sequencing of peripheral blood cells. The patient received anti-inflammatory antibiotics and underwent therapeutic whole lung lavage via endobronchial endoscopy. A systematic literature review of CSF2RA-associated hereditary PAP was performed.

Results: HRCT demonstrated characteristic "crazy paving" patterns, and bronchoalveolar lavage fluid showed positive Periodic acid-Schiff staining. Genetic analysis identified a novel hemizygous variation in CSF2RA (NM_000402.4:c.200_204del, p.Asn67SerfsTer8), confirmed as a de novo pathogenic variant. Whole lung lavage resulted in marked clinical improvement.

Conclusions: We report the first documented case of hereditary PAP caused by the CSF2RA variant NM_000402.4:c.200_204del (p.Asn67SerfsTer8), expanding the genetic spectrum of this disease. Our findings reinforce that CSF2RA-related PAP exhibits phenotypic heterogeneity and confirm whole lung lavage as the cornerstone therapy. This case highlights the importance of genetic testing in diagnosing rare PAP subtypes.

Background: Prenatal diagnosis of X-linked hydrocephalus caused by variants in the L1CAM gene is often complicated by the identification of Variants of Uncertain Significance (VUSs). This study showcases an accelerated diagnostic workflow using artificial intelligence (AI) to rapidly interpret a novel missense variant for a family with a history of the disorder.

Methods: We performed exome sequencing (ES) on a male fetus with significant sonographic brain anomalies from a 29-year-old pregnant woman. To efficiently analyze the resulting VUSs, we used the AI tool AlphaMissense to predict their pathogenicity and prioritize them for validation. The top candidate variant was then assessed via Sanger sequencing for co-segregation across eight maternal relatives. The structural impact of the mutation was visualized using the AlphaFold 3 model.

Results: Exome sequencing identified four VUSs. AlphaMissense predicted only one, L1CAM c.1228C>G (p.His410Asp), as 'likely pathogenic'. Subsequent Sanger sequencing confirmed that this variant co-segregated perfectly with the disease phenotype in the family. Based on this strong genetic evidence, the variant was reclassified from a VUS to 'Likely Pathogenic'. Structural modeling revealed that the p.His410Asp substitution disrupts a critical salt bridge, likely compromising protein stability.

Conclusion: Our two-step approach-using AI for rapid VUS prioritization followed by targeted Sanger validation-proved to be a highly efficient strategy. It provided a definitive and clinically actionable diagnosis that facilitated genetic counseling and enabled the family to pursue Preimplantation Genetic Testing (PGT). This workflow significantly enhances the power of genomic testing in the prenatal setting.

Introduction: Meckel-Gruber syndrome (MKS, OMIM 24,900), also known as Meckel syndrome, is a rare and severe autosomal recessive disorder. The syndrome is typically characterized by a triad of occipital encephalocele, bilateral renal cystic dysplasia, and postaxial polydactyly. MKS shows significant clinical heterogeneity, which poses challenges for accurate prenatal diagnosis. Prenatal ultrasound is an important tool for detecting potential cases, but the complexity of MKS often requires additional advanced techniques such as prenatal whole-exome sequencing (WES) to provide more accurate molecular genetic evidence.

Methods: In this study, we used whole-exome sequencing (WES) to analyze the genetic causes of suspected MKS in a Chinese fetus. Sanger sequencing was used to confirm the origin of the variants. The classification of variants was carried out in accordance with the guidelines of the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP).

Results: A 26-year-old pregnant woman was referred to our antenatal centre for genetic diagnosis at 13 + 5 weeks of gestation due to fetal occipital encephalocele and renal cysts detected by ultrasound. Two novel heterozygous variants, c.1047delA (p.Val351fs*1) and c.1336C>T (p.Arg446*), were identified in TCTN2. Sanger sequencing revealed that the c.1047delA (p.Val351fs*1) variant was inherited from the mother and the c.1336C>T (p.Arg446*) variant was inherited from the father. According to the ACMG/AMP guidelines, these two variants were evaluated as pathogenic.

Conclusions: This study further expands the genetic mutation spectrum of TCTN2 and is conducive to further clarifying the relationship between the genotype and phenotype of MKS8. Severe variants in the TCTN2 gene appear to be more likely to lead to MKS8. Clinically, the triad is an important basis for the diagnosis of MKS8, while other variable phenotypes of MKS8 can provide additional information for prenatal diagnosis. The combination of prenatal ultrasound and WES can provide a more comprehensive and accurate diagnosis of MKS8, which will greatly aid support for early intervention and treatment.

Background: To evaluate the utility of prenatal whole exome sequencing (WES) in cases of isolated increased nuchal translucency (NT).

Methods: Retrospective analysis of the prenatal WES results in fetuses with increased NT (≥ 3.0 mm) and normal fetal anatomy, normal karyotype, and chromosomal microarray analysis (CMA). Subgroup analysis was performed based on NT measurements.

Results: Diagnostic variants were identified in 3 of 118 fetuses (2.5%) with isolated increased NT (≥ 3.0 mm). The distribution of positive findings was as follows: NT 3.0-3.4 mm group (n = 13): 1 case (7.7%) with diagnostic genetic variants; NT ≥ 3.5 mm group (n = 105): 2 cases (1.9%) with diagnostic genetic variants (both in the NT 5.0-6.4 mm subgroup). Fisher's exact test (two-tailed) showed no statistically significant differences in diagnostic yield between: NT 3.0-3.4 mm versus NT ≥ 3.5 mm (p = 0.298); NT 3.0-3.4 mm versus NT 5.0-6.4 mm (p = 1.000); NT ≥ 3.0 mm versus NT ≥ 3.5 mm (p = 1.000).

Conclusion: Our analysis revealed a low diagnostic yield (2.5%) for prenatal WES in cases of isolated increased NT ≥ 3.0 mm. Our findings provide valuable evidence for clinical counseling, particularly when patients inquire about the likelihood of isolated findings. These data offer meaningful guidance for their decision-making process regarding further testing options.

Introduction: Rare diseases sometimes present with deceptively common symptoms, complicating diagnosis and decisions about genetic testing. While testing for rare disease offers important benefits, it also carries risks that warrant careful consideration.

Methods: We review illustrative cases of rare diseases, along with current screening and diagnostic practices, to reexamine guiding principles for genetic testing. The analysis focuses on balancing clinical utility, patient-centered care, and broader policy implications.

Results: We propose a number of recommendations to guide testing, including ruling out common causes before proceeding, ensuring the presentation is atypical for other common conditions, confirming consistency with a specific, treatable rare disease entity or group, assessing patient or family capacity for informed decision-making, and matching test invasiveness to expected diagnostic utility. Comparison with newborn screening and diagnostic testing highlights discrepancies between these principles and common practices, highlighting the difficulty of achieving consistency.

Conclusions: Establishing uniform guidelines for genetic testing remains challenging, particularly given the limited knowledge surrounding rare disorders. Coordinated efforts are needed to protect patient interests, assess the utility of diagnoses across varied contexts, and ensure that both clinical practice and policy development maximize benefits while minimizing harms.

Backgroud: To investigate the clinical features and genetic etiology of one child with Okur-Chung neurodevelopmental syndrome (OCNDS). The pathogenic variation spectrum of the CSNK2A1 gene and the phenotype spectrum of OCNDS were analyzed retrospectively.

Methods: A patient was selected from the endocrinology department of Dongying People's Hospital in July 2024. The genetic etiology of the phenotypic abnormality was identified by whole-exome sequencing (WES). All previously reported cases of OCNDS were retrieved from China National Knowledge Infrastructure (CNKI), Wanfang Data, PubMed, and the ClinVar database, and the phenotype and pathogenicity of the CSNK2A1 gene were retrospectively summarized. The differences in the mutation location and clinical phenotype of the CSNK2A1 gene were analyzed in combination with the literature on cell and molecular genetics.

Results: One variant (NM_001895.4: c.149A>G:p.Tyr50Cys) were de novo and previously reported within the CSNK2A1 gene and has been identified as a potential cause of OCNDS. The clinical data of 65 patients with OCNDS were retrospectively analyzed. The main clinical characteristics of OCNDS were developmental retardation of the nervous system, intellectual disability, facial deformity, language disorder, and other system abnormalities. This specific variant is located within the Glycine-Rich loop domain. There were significant differences in sleep disorders, autism spectrum disorders, short stature, and developmental delays.

Conclusion: This study diagnosed an OCNDS patient caused by a heterozygous mutation NM_001895.4: c.149A>G:p.Tyr50Cys in the CSNK2A1 gene through exome sequencing technology, further expanding the pathogenic variant spectrum of this gene. A systematic literature review and analysis was conducted to provide a foundation for the subsequent demonstration, which was based on the findings of the review. The demonstration revealed that variants in critical residues within the kinase domain disrupt the protein's spatial conformation and impair its function. This provides molecular evidence for genotype-phenotype correlation. These findings contribute to the advancement of knowledge in the field of OCNDS pathogenesis and provide a foundation for the development of genetic counselling and targeted therapeutic interventions.

Background: Noonan syndrome is a congenital genetic disorder characterized by distinctive craniofacial features, short stature, and congenital heart disease. Dysregulation of the RAS/mitogen-activated protein kinase (MAPK) pathway is a common molecular mechanism underlying the pathogenesis of these disorders. Germline mutations in RIT1 have also been identified in patients with Noonan syndrome. Patients with RIT1 mutations frequently exhibit cardiovascular abnormalities such as hypertrophic cardiomyopathy and lymphatic disorders. However, it remains unclear when cardiovascular abnormalities and lymphatic disorders develop and whether these disorders influence prognosis during the fetal period.

Methods: We investigated the cardiovascular and lymphatic phenotypes of Rit1^A57G/+ embryos. To elucidate that the activation of MEK/ERK is the involvement of cardiac abnormalities in Rit1^A57G/+ embryos, we administered a MEK1/2 inhibitor to Rit1^A57G/+ embryos and investigated the cardiovascular phenotypes.

Results: At E16.5, Rit1^A57G/+ embryos exhibited cardiac hypertrophy without cardiomyocyte hypertrophy and demonstrated progressive cell proliferation. Furthermore, Rit1^A57G/+ embryos exhibited pulmonary valve stenosis and lymphatic vessel expansion. Maternal intraperitoneal injection of PD0325901, a MEK1/2 inhibitor, prevented cardiac hypertrophy in Rit1^A57G/+ embryos.

Conclusions: Rit1 mutation causes cardiovascular and lymphatic abnormalities in the fetal period, and that the activation of MEK/ERK is the potential pathogenesis of cardiac hypertrophy.

Background: Hypochondroplasia (HCH) is a rare genetic skeletal dysplasia characterized by short stature, disproportionate limbs, and complications such as learning differences. Currently, no treatments are approved to address HCH-related short stature, which can adversely affect quality of life. This study aimed to explore diagnostic processes, care pathways, daily life impacts, and unmet needs in HCH.

Methods: Ninety-minute interviews were conducted with nine children and young adults and 25 caregivers who had physician-confirmed HCH. Participants discussed diagnostic journeys, treatment considerations, and day-to-day challenges. Following interviews, two 90-min focus groups among caregivers (n = 10) were conducted to explore themes emerging during interviews.

Results: We found that diagnostic pathways vary significantly, with signs of HCH identified in utero or during infancy or early childhood. Families described complex psychosocial burdens that include impacts on daily activities and emotional challenges due to height differences and disproportionate limb length. Additionally, many people with HCH have complications that go beyond short stature and include developmental delays, learning differences, and seizures. Families desire more support and resources related to HCH.

Conclusion: Future efforts should focus on holistic, patient-centered strategies to better support individuals with HCH and their families.

Background: Congenital long QT syndrome (LQTS) is an inherited arrhythmia characterized by QT prolongation and increased risk of ventricular arrhythmias. Type 2 LQTS (LQT2) results from mutations in the KCNH2 gene encoding the hERG potassium channel. With the widespread use of next-generation sequencing, many KCNH2 variants have been identified but remain classified as variants of uncertain significance (VUS), including p.L693P, requiring functional validation.

Methods: A proband with recurrent syncope and prolonged QTc underwent whole-exome and family-based Sanger sequencing, which detected a heterozygous KCNH2-L693P mutation. HEK293 cells were transiently transfected with wild-type (WT) and/or mutant hERG plasmids. Western blotting, immunofluorescence, and whole-cell patch clamp were performed to assess protein maturation, trafficking, and channel kinetics.

Results: Western blot showed reduced levels of the 155 kDa mature hERG and accumulation of the 135 kDa immature form, consistent with trafficking defects. Immunofluorescence confirmed endoplasmic reticulum (ER) retention. Electrophysiology revealed complete current loss in homozygotes and ~39% residual WT current in heterozygotes, indicating dominant-negative-like suppression. The mutation shifted steady-state inactivation and delayed recovery.

Conclusions: The KCNH2-L693P mutation impairs hERG maturation and function, supporting its reclassification from variants of uncertain significance (VUS) to pathogenic and providing evidence for improved clinical management.

Purpose: To evaluate the disease biomarker response of venglustat in patients with Fabry disease (FD), utilizing data from a single-arm phase 2 study of venglustat and a placebo-controlled phase 3 study of agalsidase beta through historical control and case-matched analyses.

Methods: Eleven venglustat-treated male patients with classic FD in the phase 2 study were matched with placebo- or agalsidase beta-treated patients from the phase 3 study based on propensity scores at baseline. Changes from baseline in plasma globotriaosylceramide (GL-3 or Gb3) concentrations were analyzed at approximately 6-36 months.

Results: Venglustat treatment resulted in greater significant reductions in plasma GL-3 concentrations at 6 months from baseline vs. placebo (mean difference -2.56 μg/mL, p < 0.001), and at 24 and 36 months from baseline vs. agalsidase beta (mean difference -1.8 μg/mL, p < 0.05 and -2.35 μg/mL, p < 0.01, respectively). GL-3 concentrations continued to decline with venglustat for up to 3 years without plateauing.

Conclusions: Venglustat showed significantly greater reductions in plasma GL-3 concentrations than placebo after 6 months and agalsidase beta after 24 and 36 months. These findings support the potential of long-term venglustat treatment to reduce GL-3 accumulation in patients with classic FD. Further studies are needed to confirm clinical benefit.