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Irreversible blindness from glaucoma and optic neuropathies is attributed to retinal ganglion cells (RGCs) losing the ability to regenerate axons. While several transcription factors and proteins have demonstrated enhancement of axon regeneration after optic nerve injury, mechanisms contributing to the age-related decline in axon regenerative capacity remain elusive. In this study, we show that microRNAs are differentially expressed during RGC development and identify microRNA-19a (miR-19a) as a heterochronic marker; developmental decline of miR-19a relieves suppression of phosphatase and tensin homolog (PTEN), a key regulator of axon regeneration, and serves as a temporal indicator of decreasing axon regenerative capacity. Intravitreal injection of miR-19a promotes axon regeneration after optic nerve crush in adult mice, and it increases axon extension in RGCs isolated from aged human donors. This study uncovers a previously unrecognized involvement of the miR-19a-PTEN axis in RGC axon regeneration, and it demonstrates therapeutic potential of microRNA-mediated restoration of axon regenerative capacity in optic neuropathies.

Introduction: This study aimed to report the screening performance of cell‐free DNA (cfDNA) testing for chromosomal abnormalities in twins, triplets, and vanishing twin pregnancies. Material and Methods: Data were obtained from pregnant women with a multiple pregnancy or a vanishing twin pregnancy at ≥10 weeks' gestation who requested self‐financed cfDNA testing between May 2015 and December 2021. Those that had positive screening results had diagnostic confirmatory procedures after counseling and consent. The performance of screening of the cfDNA test was determined by calculating confirmation rate and combined false‐positive rate (cFPR). Results: Data from 292 women were included after exclusion of those lost to follow‐up, with no‐result on cfDNA testing, or had reductions. Of the 292 pregnancies, 10 (3.4%) were triplets, including no cases of trisomy 21 and trisomy 18; 249 (85.3%) were twins, including 3 cases of trisomy 21 and no cases of trisomy 18 and 13; and 33 (11.3%) were vanishing twins, including 3 cases of trisomy 21 and 1 case of trisomy 18. The median (IQR) maternal age was 34 years (31–37). For triplet pregnancies, the initial no‐result rate was 10.3% (95% confidence interval [CI] 3.6–26.4), all with results after redraw. For twin pregnancies, the initial no‐result rate was 12.9% (95% CI 9.6–17.0), and the no‐result rate after redraw was 1.6% (95% CI 0.7–3.6). For vanishing twins, there were no cases with no‐result. All triplets had low‐risk cfDNA results. The confirmation rate for trisomy 21 was 100% with a FPR at 0% due to the small number of positive cases for twins. For vanishing twins, one high‐risk case for trisomy 21 and the only high‐risk case for trisomy 18 were confirmed with a cFPR of 8.3% (n = 2/24; 95% CI 2.3–25.9). Conclusions: cfDNA testing in twin pregnancies has sufficient screening performance for trisomy 21 but the number of affected cases for other conditions is limited to draw any meaningful conclusion. The use of cfDNA testing in triplet pregnancies and vanishing twins remains an area for further research. [ABSTRACT FROM AUTHOR]

Objectives: To determine whether the new classification system published by Jordans et al for cesarean scar pregnancy (CSP) can guide management and treatment outcomes. Methods: A retrospective study of women diagnosed with CSP from October 2010 to December 2022 in a single tertiary center was performed. Sonographic records of these women were classified into three types according to the classification published by Jordans et al. Treatment outcomes were compared across each type of CSP. Results: The study included a total of 84 women, where 60 (71.4%), 17 (20.2%), and 7 (8.3%) of them were categorized into Type 1, 2, and 3 CSP, respectively. A total of 47 (55.9%) women were managed with methotrexate, 22 (26.2%) underwent surgical management of the CSP without removal of the Cesarean section (CS) niche, and 11 (13.1%) underwent surgery to remove the CSP and the CS niche. Overall treatment success rates for medical management and surgical management were 70 and 97%, respectively. Four women were managed expectantly and continued their pregnancies, among which three carried beyond 34 weeks and had good neonatal outcomes. Conclusions: The classification as published by Jordans et al is easily replicable and readily implemented clinically. Our findings show that a higher proportion of Type 1 and Type 2 CSP were treated successfully by a less invasive medical approach with a high success rate, whereas most Type 3 CSP required surgical resection to successfully remove the CSP and the CS niche. Prospective studies are required to confirm these findings and further validate the clinical utility of this nomenclature system. [ABSTRACT FROM AUTHOR]

Background: Conventional thalassemia screening takes a stepwise approach and has limitations in comprehensively identifying all spectrums of mutations. This study aimed to investigate the performance of third-generation sequencing (TGS) compared to conventional molecular testing. Methods: TGS was applied to validate all known variants detected by conventional testing and to detect missing variants in undiagnosed cases. The study was conducted at Maharaj Nakorn Chiang Mai Hospital between December 2021 and April 2022. Results: In total, 19 cases were included in this study, among which 52.6% (10/19) had known thalassemia variants, while 47.7% (9/19) cases were undiagnosed by conventional methods. All 16 variants previously detected were validated by TGS, and TGS additionally detected 43.8% (7/16) thalassemia variants for 36.8% (7/19) cases. Conclusion: TGS could provide additional genetic diagnoses compared with conventional methods. Further cost-effectiveness studies with a larger sample size are needed to explore the role of TGS in clinical practices. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the local incidence of orofacial cleft (OFC) encountered in fetal morphology scan and prenatal diagnosis, genetic etiology of fetuses with or without other structural abnormalities, and their pregnancy outcomes. Design: Retrospective cohort study. Setting: Two maternal fetal medicine units, tertiary hospitals, Hong Kong. Participants: All pregnant women with antenatal diagnosis of fetal OFC between January 2016 and December 2020 (N = 66). Results: OFC has an incidence of 0.13% among pregnancies in Hong Kong and 28.8% (19/66) were syndromic cleft that exhibited other fetal structural anomalies. There were 55 cases (84.6%) who opted for invasive prenatal diagnostic testing. Genetic defects were identified in 25.8% (17/66) of this cohort, including 14 pathogenic variants. The detection rate in the syndromic cases is 68.4% (13/19) which was significantly higher than 8.5% (4/47) among non-syndromic cases. Aneuploidies would be the most common cause, accounting for 9.1% (6/66). Chromosomal microarray analysis (CMA) provided an incremental diagnostic yield of 6.1% compared to conventional karyotyping. A total of 29 live births including 3 cases of a variant of uncertain significance and 26 cases without genetic abnormalities detected have continued pregnancy to birth. There were 87.5% (21/24) without detectable pathogenic genetic abnormality reported good long-term outcomes. The chance of OFC fetuses having a good long-term outcome was significantly higher if no genomic variant was detected (P <.001). Conclusions: Invasive prenatal tests with CMA should be offered to pregnancies with OFC regardless of the type. It has provided incremental diagnostic yield over conventional karyotyping and helped in prenatal and genetic counseling. A negative result in non-syndromic OFC favors couples to keep the pregnancy. [ABSTRACT FROM AUTHOR]

We report a fetus with prenatal ultrasound at 21 gestational weeks showing left cystic renal dysplasia with subcapsular cysts and echogenic parenchyma, right echogenic kidney with absent corticomedullary differentiation, and left congenital diaphragmatic hernia (CDH) with bowel herniation, with intestinal atresia (IA) found on postmortem examination. Whole genome sequencing of fetal blood DNA revealed a heterozygous pathogenic variant c.344 + 2 T>G in the HNF1B gene (NM_000458). Sanger sequencing of the parental samples suggested that it arose de novo in the fetus. HNF1B‐associated disorders affect multiple organs with significant phenotypic heterogeneity. In pediatric and adult patients, renal cystic disease and cystic dysplasia are the dominant phenotypes. In prenatal settings, renal anomaly is also the most common presentation, typically with bilateral hyperechogenic kidneys. Our case presented with two uncommon extra‐renal phenotypes of CDH and IA besides the typical bilateral cystic renal dysplasia. This association has been reported in fetuses with 17q12 microdeletion but not with HNF1B point mutation. Our case is the first prenatal report of such an association and highlights the possible causal relationship of HNF1B defects with CDH and IA in addition to the typical renal anomalies. Key points: What's already known about this topic? Renal anomaly is the dominant phenotype in HNF1B‐associated disorders.Congenital diaphragmatic hernia (CDH) and intestinal atresia (IA) have been reported in fetuses with 17q12 microdeletion but not with HNF1B point mutation. What does this study add? This is the first prenatal report of CDH and IA with HNF1B point mutation, which highlights the possible causal relationship of HNF1B defects with these two extra‐renal phenotypes. [ABSTRACT FROM AUTHOR]

Heterozygous loss‐of‐function variants in the PKD1 gene are commonly associated with adult‐onset autosomal dominant polycystic kidney disease (ADPKD), where the formation of renal cysts depends on the dosage of the PKD1 gene. Biallelic null PKD1 variants are not viable, but biallelic hypomorphic variants could lead to early‐onset PKD. We report a non‐consanguineous Chinese family with recurrent fetal polycystic kidney and negative findings in the coding region of the PKHD1 gene or chromosomal microarray analysis. Trio exome analysis revealed compound heterozygous variants of uncertain significance in the PKD1 gene in the index pregnancy: a novel paternally inherited c.7863 + 5G > C and a maternally inherited c.9739C > T, p.(Arg3247Cys). Segregation analysis through long‐range PCR followed by nested PCR and Sanger sequencing confirmed another affected fetus had both variants, while the other two normal siblings and the parents carried either variant. Thus, these two variants, both of which were hypomorphic as opposed to null variants, co‐segregated with prenatal onset polycystic kidney disease in this family. Functional studies are needed to further determine the impact of these two variants. Our findings highlight the biallelic inheritance of hypomorphic PKD1 variants causing prenatal onset polycystic kidney disease, which provides a better understanding of phenotype‐genotype correlation and valuable information for reproductive counseling. Key points: What is already known about this topic? Heterozygous loss of function variant in the PKD1 gene is the most common cause of autosomal dominant polycystic kidney disease.Renal cyst formation depends on the reduced functional polycystin level.Biallelic null variants in PKD1 are incompatible with life. However, biallelic hypomorphic variants could lead to very early onset PKD. What does this study add? This report expands the spectrum of biallelic hypomorphic PKD1 variants in prenatal‐ onset PKD.Studying the family members can significantly assist in the interpretation and counseling of variants of uncertain significance. [ABSTRACT FROM AUTHOR]