Molecular Genetics & Genomic Medicine最新文献

Background: The aim of our study was to investigate the clinical characteristics, discrepancies in postnatal diagnosis, and outcomes of prenatally diagnosed arachnoid cysts without extra-CNS anomalies.

Methods: This study was a multi-center retrospective cohort study from 16 participating university hospitals in South Korea, with patient data pooled from January 2010 to December 2019. This study focused on cases with prenatally diagnosed arachnoid cysts and analyzed postnatal diagnoses related to CNS anomalies, the need for surgery, and clinical outcomes.

Results: Thirty-seven fetuses with fetal arachnoid cysts were ultimately included in our analysis. These included 27 supratentorial cysts and 10 posterior fossa cysts, with 11 cases (29.7%) presenting associated CNS anomalies. The most common associated anomalies were ventriculomegaly (18.9%) and callosal abnormalities (10.8%). No chromosomal abnormalities were detected during antenatal care. Postnatal regression was observed in 14.8% of supratentorial cysts and 10.0% of posterior fossa cysts. Neurologic complications, present in 21.6% of all cases, were more prevalent in cases with associated CNS anomalies compared to isolated arachnoid cysts.

Conclusion: In cases diagnosed with prenatal arachnoid cysts, ventriculomegaly and callosal anomalies are the most commonly associated CNS anomalies. The presence of additional CNS anomalies is the most critical factor affecting neurologic outcomes.

Background: PARN encodes poly(A)-specific ribonuclease, a 3 exoribonuclease important in regulating RNA stability and maturation. Rare germline PARN variants have been reported in telomere biology disorders (TBDs) leading to its inclusion on gene panels for bone marrow failure syndromes and pulmonary diseases.

Methods: To understand the extent of germline PARN variation in human disease, we conducted a comprehensive literature review, curated the TBD-associated PARN variants using AutoGVP and in silico prediction tools (MetaSVM, REVEL, and/or CADD) and assessed their frequency in the gnomAD database.

Results: Ninety-three unique PARN variants were identified in the literature as present in individuals or families affected by TBDs, but clinical features were not consistently reported. Forty-one variants (44.1%) were classified as pathogenic or likely pathogenic. These variants were spread across the entire gene with no obvious clustering. gnomAD data were notable for a paucity of common variants and metrics suggesting PARN variation would be tolerated.

Conclusion: The extent to which specific PARN variants can be associated with TBD etiology is limited due to incomplete literature, clinical data, lack of robust functional assays, and high frequency of rare variants.

Background: Imiglucerase (Cerezyme; Sanofi, Paris, France), an analogue of β-glucocerebrosidase produced by recombinant DNA technology, has been a safe and effective treatment for Gaucher disease (GD) for over 25 years. A new imiglucerase, Abcertin (Seongnam-si, Gyeonggi-do, Republic of Korea) has shown a similar safety and efficacy profile in previous clinical studies. This study compared the pharmacokinetics, immunogenicity, safety, and tolerability to EU-sourced Cerezyme following a single 60 IU/kg dose.

Methods: This phase 1, single-center, randomized, double-blind, two-way crossover study enrolled 36 healthy volunteers aged 18-45 years. Participants were randomly assigned to receive either Abcertin or Cerezyme in a predetermined sequence.

Results: Abcertin reached peak plasma concentrations at a median t_max of 61 min (range: 40-121 min). The mean C_max, AUC_0-last, and AUC_0-inf were 115.4 mU/mL, 12,190 min·mU/mL, and 12,210 min mU/mL, respectively, indicating bioequivalence to Cerezyme. The mean t_½, CL, and V_z were 6.88 min, 376.7 mL/min, and 3.62 L, respectively, and were comparable between the two treatments. One participant in the Cerezyme group developed anti-drug antibodies, which were non-neutralizing A total of 24 subjects experienced treatment-emergent adverse event (TEAE). The most common TEAE was headache (3 in the Abcertin group and 5 in the Cerezyme group), followed by general disorders and administration site condition (3 in Abcertin group and 5 in Cerezyme group). Two participants in the Cerezyme sequence experienced severe TEAEs: one had a urinary tract infection, and the other developed urticaria, which leading to study withdrawal.

Conclusion: Abcertin demonstrated pharmacokinetic equivalence to Cerezyme, with a comparable safety, immunogenicity, and tolerability profile. These findings support its potential as an affordable biosimilar for GD treatment.

Background: Although there a well-known correlation in genotype and phenotype, patients with 21-OHD caused by severe pathogenic variants have better correlation, whereas inconsistencies are more common in the presence of milder variants. This study aimed to evaluate CYP21A2 genotyping and reveal the genotype-phenotype correlation in children diagnosed with 21-OHD in the South-eastern Anatolia region, where ethnic diversity and consanguineous marriage rates are high.

Methods: The patients were divided into three groups: salt wasting (SW), simple virilizing (SV) and non-classical (NC). Pathogenic variants of the CYP21A2 gene were classified into six groups based on predicted 21-hydroxylase activity: null-A-B-C-D-E. CYP21A2 genotyping was performed by sequence-specific primer and sequenced with next generation sequencing (NGS), and the expected phenotypes were compared to the observed phenotypes.

Results: The overall genotype-phenotype concordance was found to be 73.1% (68/93). The expected concordance with the SW form of the null (n = 12) and A (n = 51) groups is 91.6% and 88.2%, respectively. While the percentage of the expected clinical form of SV in patients in group B (n = 5) was 80%, the concordance for the expected clinical form of NC for group C (n = 25) was not strong enough (32%).

Conclusion: This study demonstrates that children with 21-hydroxylase deficiency show a good correlation between severe pathogenic variants and predicted clinical phenotypes; however, the correlation is not strong enough between milder variants. The discrepancies could have resulted from the complex characteristics of 21-OHD genotyping and the limitations of using NGS alone without integrating with other comprehensive methods.

Objectives: Some previous studies examined the knowledge, attitudes, and practices (KAP) toward prenatal genetic testing of the fetus but not toward blood chromosomal testing in the preconception and premarital period. This study investigated the KAP of the general population regarding peripheral blood chromosomal testing in the premarital or preconception period.

Design: A cross-sectional study.

Setting: From October 2023 to December 2023 at the authors' hospital.

Participants: Enrolled individuals who participated in free premarital medical examinations and free prepregnancy health examinations.

Primary and secondary outcome measures: A self-designed questionnaire (Cronbach's α = 0.917) was used to collect the demographic information and KAP scores. KAP scores across variable categories were analyzed using the Mann-Whitney U test or Kruskal-Wallis H test. Correlations between KAP scores were evaluated by Pearson correlation analysis. Factors associated with KAP were identified by multivariable logistic regression.

Results: This study included 630 valid questionnaires. The mean knowledge, attitude, and practice scores were 18.90 ± 4.48 (/30, 63.00%), 40.99 ± 5.32 (/50, 81.98%), and 37.66 ± 4.43 (/45, 83.69%), respectively. The knowledge scores were similar between genders (p = 0.840). Compared with males, females had higher attitude scores (42.01 ± 5.40 vs. 40.01 ± 5.07, p < 0.001) and higher practice scores (38.17 ± 4.44 vs. 37.18 ± 4.37, p = 0.013). There were no significant differences between genders regarding the frequencies of having undergone chromosomal testing and recommending it to the partner. The knowledge scores (OR = 1.060, 95% CI: 1.018-1.103, p = 0.004) and attitude scores (OR = 1.198, 95% CI: 1.154-1.244, p < 0.001) were positively independently associated with the practice scores.

Conclusions: The general population in Hangzhou displays poor knowledge but favorable attitudes and proactive practices regarding peripheral blood chromosomal testing in the premarital or preconception period. Cultivating proper knowledge and attitude should improve practice.

Background: Tooth agenesis (TA) ranks among the most common dental abnormalities. This study aimed to explore the etiology and pathogenesis in Chinese families with non-syndromic TA.

Methods: Chinese families exhibiting non-syndromic TA were recruited. Exome sequencing was conducted to identify mutations in the candidate genes, followed by Sanger sequencing for validation. Functional studies, including bioinformatics analyses, western blots, and dual-luciferase assays, were performed to analyze the impact of the two mutations on the Wnt/β-catenin pathway.

Results: We identified a novel heterozygous frameshift insertion in AXIN2 [NM_001363813.1: c.1799dupG (p.Asn601GlnfsTer41)] and a novel de novo heterozygous non-frameshift deletion in LRP6 [NM_002336.3: c.3074_3082del (p.1025_1028del)]. Further functional studies indicated that AXIN2 p.Asn601GlnfsTer41 caused hyperactivation of the Wnt/β-catenin pathway, and LRP6 p.1025_1028del led to pathway suppression.

Conclusions: This study expands the spectrum of AXIN2 and LRP6 mutations associated with non-syndromic TA. Our study provided further functional evidence supporting the pathogenicity of suppression and excessive activation of the Wnt signaling pathway in TA.

Background: The intrauterine ultrasound phenotype, genotype, pregnancy outcome, and neonatal prognosis of fetuses with 1p36 deletion syndrome were retrospectively analyzed, as previous reports are limited.

Methods: Pregnant women (25,000) who underwent interventional prenatal diagnosis between December 2016 and March 2024 were selected. Fetal villus tissue, amniotic fluid, or umbilical cord blood were extracted for single nucleotide polymorphism array (SNP-array) detection under ultrasound guidance.

Results: Thirteen fetuses had 1p36 deletions involving fragments that were 0.46-22.5 Mb. Six and seven fetuses had large and small copy number variation (CNV) fragment deletions in the 1p36 region, respectively. Two fetuses had normal ultrasound phenotypes, three underwent early spontaneous abortion, one had isolated ventricular septal defect, one had isolated mild ventriculomegaly, two had mild ventriculomegaly associated with increased renal echogenicity, one had mild ventriculomegaly associated with ventricular septal defect, one had severe ventriculomegaly associated with ventricular septal defect and fetal growth restriction, one had tricuspid valve dysplasia, and one had nasal bone dysplasia. Three 1p36 deletions were de novo, and one was paternally inherited. There were three cases of early spontaneous abortion, seven terminations, and three routine postnatal follow-ups.

Conclusions: High-resolution SNP-arrays are suitable for the prenatal diagnosis of 1p36 deletion syndrome.

GJB2 and GJB6 variants, encoding Cx26 and Cx30 respectively, are the most frequently involved genes commonly contributing to hereditary hearing loss either isolated or in combination with skin abnormalities. GJB6 variations are classically associated with two distinct conditions: non-syndromic hearing loss and hidrotic ectodermal dysplasia, type Clouston, the latter typically not involving deafness.

Method: Whole genome sequencing (WGS) was used to find genetic variants after clinical features of a 13-year-old female patient were recorded.

Results: In this report, we describe the association of congenital hearing loss and ectodermal anomalies (palmoplantar keratoderma, knuckle pads, and nail dystrophy) in a female with the ENST00000647029.1 (GJB6): c.175G>A (p.(Gly59Arg)) GJB6 variant. As a result, we report on the third case of individuals showing this same missense variant and syndromic hearing loss.

Conclusion: This study underscores the overlapping phenotypes observed in patients with the p.Gly59Arg variant in the GJB6 gene. The findings suggest a continuum of phenotypic presentations for this variant, with the key clinical features being the combination of congenital hearing loss and hyperkeratosis.

Background: Craniosynostosis (CS), a heterogeneous craniofacial disorder caused by premature fusion of cranial sutures, is sub-classified anatomically by suture involvement (sagittal, metopic, coronal, lambdoid) and phenotypically into isolated/non-syndromic forms or syndromic (CS with extracranial anomalies). Pathogenic variants in multiple genetic loci have been implicated in CS, with particular significance attributed to allelic variants in IL11RA (interleukin-11 receptor alpha subunit; OMIM#600939). Clinical observations of individuals with IL11RA mutations indicate syndromic CS, characterized by dental anomalies and Crouzon-like facial features.

Methods: Genetic analyses were carried out utilizing whole-exome sequencing, with subsequent validation through direct Sanger sequencing. IL11RA biallelic pathogenic variants were detected and further analyzed by multiple in silico prediction tools, including 3D protein modeling.

Results: Our cohort comprises six pediatric patients presenting with CS linked to biallelic pathogenic mutations in IL11RA, including two previously unreported variants (p.Pro218Argfs*140, p.Trp132Ter). Three-dimensional protein structure modeling and molecular docking simulations demonstrated that four missense variants (p.Pro116Leu, p.Glu126Gly, p.Gly231Val, p.Leu236Pro) disrupt hydrogen bond networks critical for maintaining the IL-11 receptor alpha subunit's tertiary structure, significantly reducing ligand-binding affinity to both interleukin-11 (IL-11) and gp130.

Conclusion: This study describes the clinical phenotype of six children with craniosynostosis and reveals novel variants in the IL11RA gene, thereby broadening the genotypic spectrum associated with this gene. Given the scarcity of patients reported in the literature, a detailed examination of the specific clinical and molecular characteristics will benefit our understanding of craniosynostosis caused by IL11RA variants.