Severe Congenital Disease Research Articles

Гипохолестеринемия – важный симптом редких болезней

Hypocholesterolemia is an important symptom that may indicate the presence of severe hereditary metabolic disease or acquired secondary pathology. This lecture discusses the criteria for hypocholesterolemia in children, issues of cholesterol metabolism and its disorders, and the most common causes of hypocholesteremia. Issues of pathogenesis, clinical picture, diagnosis, and treatment of cholesterol synthesis disorders (Smith–Lemli–Opitz syndrome) and abetalipoproteinemia are considered in detail, and clinical cases of patients with these diseases are presented. Key words: hereditary metabolic diseases, hypocholesterolemia, Smith–Lemli–Opitz syndrome, abetalipoproteinemia

Neuroprotective effect of silymarin against 3-Nitropropionic acid-induced neurotoxicity in rats

(HD) Huntington's disease is a severe hereditary catastrophic neurological disease with an autosomal dominant heritable changes manifested by cognitive, behavioural, and motor progression deficits, resulting in death. Several mechanisms are involved in the pathogenesis of this complex and rare disease, including excitotoxicity, mitochondrial dysfunction, neurotransmitters imbalance, and oxidative stress. Silymarin was selected as an investigational drug, due to its numerous activities in current research, it possesses substantial antioxidant and neuroprotective functionalities. The present research attempts, i.p. injections of 3-NPA (10 ​mg/kg) were given for 21 days to trigger Huntington-like symptoms in rats. The percentage fluctuations in body weight, the footfall counts, and the time required to transverse the beam and motor functions were analyzed at multiple time points. Oxidative stress markers like MDA/LPO, GSH, protein, nitrite, catalase, and superoxide dismutase levels were examined in the striatum region. The current study results conclusively demonstrate that chronic 3-NPA administration significantly decreased the body weight and showed marked abnormalities in motor coordination, locomotion, and increased striatal generation of free radicals. Furthermore, treatment with silymarin (100 & 200 ​mg/kg/p.o.), mitigated 3-NPA triggered behavioural and biochemical alterations. Our study results could conclude that Silymarin may be advantageous and might develop an adjuvant treatment for the management of Huntington's disease.

A Clinical Dataset and Various Baselines for Chromosome Instance Segmentation.

In medicine, chromosome karyotyping analysis plays a crucial role in prenatal diagnosis for diagnosing whether a fetus has severe defects or genetic diseases. However, chromosome instance segmentation is the most critical obstacle to automatic chromosome karyotyping analysis due to the complicated morphological characteristics of chromosome clusters, restricting chromosome karyotyping analysis to highly depend on skilled clinical analysts. In this paper, we build a clinical dataset and propose multiple segmentation baselines to tackle the chromosome instance segmentation problem of various overlapping and touching chromosome clusters. First, we construct a clinical dataset for deep learning-based chromosome instance segmentation models by collecting and annotating 1,655 privacy-removal chromosome clusters. After that, we design a chromosome instance labeled dataset augmentation (CILA) algorithm for the clinical dataset to improve the generalization performance of deep learning-based models. Last, we propose a chromosome instance segmentation framework and implement multiple baselines for the proposed framework based on various instance segmentation models. Experiments evaluated on the clinical dataset show that the best baseline of the proposed framework based on the Mask-RCNN model yields an outstanding result with 77% mAP, 97.5% AP50, and 95.5% AP75 segmentation precision, and 95.38% accuracy, which exceeds results reported in current chromosome instance segmentation methods. The quantitative evaluation results demonstrate the effectiveness and advancement of the proposed method for the chromosome instance segmentation problem. The experimental code and privacy-removal clinical dataset can be found at Github.

A suite of in vitro and in vivo assays for monitoring the activity of the pseudokinase Bud32.

Bud32 is a member of the protein kinase superfamily that is invariably conserved in all eukaryotic and archaeal organisms. In both of these kingdoms, Bud32 forms part of the KEOPS (Kinase, Endopeptidase and Other Proteins of Small size) complex together with the three other core subunits Kae1, Cgi121 and Pcc1. KEOPS functions to generate the universal and essential tRNA post-transcriptional modification N6-theronylcarbamoyl adenosine (t6A), which is present at position A37 in all tRNAs that bind to codons with an A in the first position (ANN decoding tRNAs) and is essential for the fidelity of translation. Mutations in KEOPS genes in humans underlie the severe genetic disease Galloway-Mowat syndrome, which results in childhood death. KEOPS activity depends on two major functions of Bud32. Firstly, Bud32 facilitates efficient tRNA substrate recruitment to KEOPS and helps in positioning the A37 site of the tRNA in the active site of Kae1, which carries out the t6A modification reaction. Secondly, the enzymatic activity of Bud32 is required for the ability of KEOPS to modify tRNA. Unlike conventional protein kinases, which employ their enzymatic activity for phosphorylation of protein substrates, Bud32 employs its enzymatic activity to function as an ATPase. Herein, we present a comprehensive suite of assays to monitor the activity of Bud32 in KEOPS in vitro and in vivo. We present protocols for the purification of the archaeal KEOPS proteins and of a tRNA substrate, as well as protocols for monitoring the ATPase activity of Bud32 and for analyzing its role in tRNA binding. We further present a complementary protocol for monitoring the role Bud32 has in cell growth in yeast.

Orphan diseases (mucopolysaccharidosis) and damage of the cardiovascular system. Literature review

The paper presents literature data, outlining topical issues of the cardiovascular pathology at mucopolysaccharidosis. It is damage to the heart and blood vessels, one of the cardinal signs of this pathology, that is often fatal. Cardiac pathology is recorded in all types of mucopolysaccharidosis, but it is most significant for patients with three clinical variants of Hurler syndrome, Hunter, and Maroteaux–Lamy syndromes. Typical signs of damage to the cardiovascular system in mucopolysaccharidosis are thickening of the valves with the development of their dysfunction (while the severity of damage to the left‑sided valves is more pronounced), myocardial hypertrophy, conduction disturbance, coronary artery disease, arterial hypertension. Many researchers emphasize the difficulties of clinical and functional examination of the cardiovascular system in patients with mucopolysaccharidosis, which is due to the presence of physical and intellectual limitations in patients, and a gradual symptoms aggravation. For the treatment of cardiovascular pathology at mucopolysaccharidosis, medical and surgical methods are used, including enzyme replacement therapy and stem cell transplantation.
 Gene therapy is considered one of the priority areas in the treatment of mucopolysaccharidosis. Significant progress in this aspect has been achieved with the use of viral vectors under experimental conditions in mice with mucopolysaccharidosis type VII. The basis of mucopolysaccharidosis prevention is medical and genetic counseling of families with subsequent prenatal diagnosis using molecular genetic methods (eg, DNA diagnosis). Thus, early diagnosis and timely pathogenetic treatment of mucopolysaccharidosis will help to prevent disability and adequate integration into society, and effective medical and genetic counseling of families will significantly reduce the incidence of new cases of these severe inherited diseases.

Transgenic Epidermal Cultures for Junctional Epidermolysis Bullosa — 5-Year Outcomes

SummaryInherited junctional epidermolysis bullosa is a severe genetic skin disease that leads to epidermal loss caused by structural and mechanical fragility of the integuments. There is no established cure for junctional epidermolysis bullosa. We previously reported that genetically corrected autologous epidermal cultures regenerated almost an entire, fully functional epidermis on a child who had a devastating form of junctional epidermolysis bullosa. We now report long-term clinical outcomes in this patient. (Funded by POR FESR 2014–2020 — Regione Emilia-Romagna and others.)

Mechanism of Rad26-assisted rescue of stalled RNA polymerase II in transcription-coupled repair

Transcription-coupled repair is essential for the removal of DNA lesions from the transcribed genome. The pathway is initiated by CSB protein binding to stalled RNA polymerase II. Mutations impairing CSB function cause severe genetic disease. Yet, the ATP-dependent mechanism by which CSB powers RNA polymerase to bypass certain lesions while triggering excision of others is incompletely understood. Here we build structural models of RNA polymerase II bound to the yeast CSB ortholog Rad26 in nucleotide-free and bound states. This enables simulations and graph-theoretical analyses to define partitioning of this complex into dynamic communities and delineate how its structural elements function together to remodel DNA. We identify an allosteric pathway coupling motions of the Rad26 ATPase modules to changes in RNA polymerase and DNA to unveil a structural mechanism for CSB-assisted progression past less bulky lesions. Our models allow functional interpretation of the effects of Cockayne syndrome disease mutations.

Restoring Iron Homeostasis in Pts Who Achieved Transfusion Independence after Treatment with Betibeglogene Autotemcel Gene Therapy: Results from up to 7 Years of Follow-up

Restoring Iron Homeostasis in Pts Who Achieved Transfusion Independence after Treatment with Betibeglogene Autotemcel Gene Therapy: Results from up to 7 Years of Follow-up

Osteogenesis imperfecta: a literature review and a clinical case of a perinatal-lethal type of disease

The article presents the modern views of clinicians and geneticists on one of the most severe genetic disorders of skeletal and connective tissues - osteogenesis imperfecta. The review provided the literature data that showed the incidence rates, genetic heterogeneity of osteogenesis imperfecta, as well as the role of some proteins involved in the construction of bone tissue, as well as a clinical classification of the main types of the disorder. The authors described a clinical case: a girl with typical clinical and radiological manifestations of the rarest of all types of osteogenesis imperfecta - type II (perinatal-lethal, congenital osteogenesis imperfecta, Vrolik’s syndrome). The child’s diagnosis was verified by a parallel DNA sequence analysis which showed a heterozygous mutation in exon 29 (c.1966G> A) of COL1A1 gene not previously described in the literature. It caused the substitution of glycine for serine at position 656. The role of antenatal diagnostics and the importance of medical genetic counselling of the family before planning the next pregnancy due to the existing risk of re-birth of a sick child is outlined. Due to the fact that majority of the patients with the most prognostically unfavourable type II osteogenesis imperfecta, as a rule, die in utero, the described case of observation of the girl with typical clinical and X-ray signs of the disorder for almost 3 months of postpartum period is extremely rare and highly indicative. The detection of the heterozygous mutation in exon 29 (c.1966G > A) of COL1A1 gene by a parallel DNA sequence analysis which was not previously described in the literature gives an additional significance to the described observation.

Predicting Emergence of Primary and Secondary Syphilis Among Women of Reproductive Age in US Counties.

Syphilis, a sexually transmitted infection that can cause severe congenital disease when not treated during pregnancy, is on the rise in the United States. Our objective was to identify US counties with elevated risk for emergence of primary and secondary (P&S) syphilis among women of reproductive age. Using syphilis case reports, we identified counties with no cases of P&S syphilis among women of reproductive age in 2017 and 1 case or more in 2018. Using county-level syphilis and sociodemographic data, we developed a model to predict counties with emergence of P&S syphilis among women and a risk score to identify counties at elevated risk. Of 2451 counties with no cases of P&S syphilis among women of reproductive age in 2017, 345 counties (14.1%) had documented emergence of syphilis in 2018. Emergence was predicted by the county's P&S syphilis rate among men; violent crime rate; proportions of Black, White, Asian, and Hawaiian/Pacific Islander persons; urbanicity; presence of a metropolitan area; population size; and having a neighboring county with P&S syphilis among women. A risk score of 20 or more identified 75% of counties with emergence. Jurisdictions can identify counties at elevated risk for emergence of syphilis in women and tailor prevention efforts. Prevention of syphilis requires multidisciplinary collaboration to address underlying social factors.

Cardiolipin function in the yeast S. cerevisiae and the lessons learned for Barth syndrome.

Cardiolipin (CL) is the signature phospholipid (PL) of mitochondria and plays a pivotal role in mitochondrial and cellular function. Disruption of the CL remodeling gene tafazzin (TAZ) causes the severe genetic disorder Barth syndrome (BTHS). Our current understanding of the function of CL and the mechanism underlying the disease has greatly benefited from studies utilizing the powerful yeast model Saccharomyces cerevisiae. In this review, we discuss important findings on the function of CL and its remodeling from yeast studies and the implications of these findings for BTHS, highlighting the potential physiological modifiers that may contribute to the disparities in clinical presentation among BTHS patients.

In Silico Analysis of a De Novo OTC Variant as a Cause of Ornithine Transcarbamylase Deficiency.

Ornithine transcarbamylase deficiency (OTCD) is the most common X-linked hereditary disorder of urea cycle disorders that is caused by neonatal hyperammonemia. OTC gene sequence variations are common causes of OTCD. The current study presents a 28-month-old baby girl proband with phenotypical characteristics of OTCD such as irritability, somnolence, intermittent vomiting, and high levels of serum ammonium. Whole-exome sequencing revealed a de novo c.275G>A p.(Arg92Gln) variant within the OTC gene. In silico analysis revealed a possible differential affinity between wild-type and mutant OTCase, while Arg92Gln decreases the binding ability of OTCase to the substrate, which can disrupt the urea cycle and explains the molecular pathogenicity of clinical hyperammonemia. In light of the fact that the genotype and phenotype correlation of OTCD is still uncertain, the present in silico analysis outcome can enhance our knowledge on this complicated, rare, and severe genetic disorder.

Ganciclovir Treatment in Symptomatic Congenital CMV Infection at Siriraj Hospital: 11 Year-Review (2008 to 2019)

Background: Congenital cytomegalovirus (CMV) infection is the most common non-genetic cause of permanent sensorineural hearing loss in infants and children. A 6-month course of intravenous ganciclovir or valganciclovir is recommended for treatment of patients with moderate to severe symptomatic congenital CMV disease. Hearing status improvement has been reported in those that received treatment within the first month of life. In Thailand, there has been no data of antiviral treatment in symptomatic congenital CMV patients. Objective: To determine the incidence of symptomatic congenital CMV infection in the past 11 years and to evaluate the hearing, neurological, and developmental outcomes of the antiviral treatment and factors associated with hearing outcomes. Materials and Methods: A retrospective observational study was performed at Siriraj Hospital, between January 2008 and December 2019. The medical records of the patients diagnosed of symptomatic congenital CMV infection (ICD10-P351) were reviewed. Results: The incidence of symptomatic congenital CMV infection was 0 to 1.01 case per 1,000 livebirths. Of the 52 patients, 18 received 6-week course of ganciclovir and five continued with oral valganciclovir for three to six months. Developmental delayed was found in 69.2% (36). No difference in hearing outcomes at 6 and 12 months of age between the patients who did or did not receive treatment. Among 24 (46.1%) children who underwent hearing test at two to three years of age, the birth characteristics, as well as antiviral treatment (attributable risk 0.007, 95% CI –0.4 to 0.4, p=0.973), had no difference in hearing outcome. Long-term disability was diagnosed in the lower proportion among the patients receiving antiviral treatment (attributable risk –0.3, 95% CI –0.5 to –0.1, p=0.030). Conclusion: Symptomatic congenital CMV infection resulted in poor hearing and developmental outcomes. Antiviral treatment reduced risk of disability but did not improve hearing outcomes. The results underscore the need for early diagnosis and initiation of antiviral treatment in infants with symptomatic congenital CMV. Keywords: Congenital infection; CMV; Hearing loss; Ganciclovir; Valganciclovir; Disability

Lysosomal storage diseases: mucopolysaccharidosis type I and II

Mucopolysaccharidosis (MPS) are a genetically heterogeneous group of rare monogenic metabolic diseases associated with hereditary insufficiency of lysosomal enzymes involved in the catabolism of glycosaminoglycans, or mucopolysaccharides. The pathogenesis of MPS is due to the accumulation of non-cleaved glycosaminoglycans in lysosomes, which can destroy cells. All MPS are characterized by a polysystemic manifestation, the simultaneous involvement of many organs and tissues in the pathological process, first of all, connective tissues, bones and cartilaginous. This review presents the epidemiology, clinical, biochemical, and molecular genetic characteristics of MPS types I and II, caused by the recessive mutations in the alpha-L-iduronidase and iduronate-2-sulfatase genes, respectively, and by the accumulation of dermatan and heparan sulfate. Each of these diseases is characterized by clinical polymorphism, especially observed in MPS I, which often manifests in a severe form of Hurler syndrome, but can also occur in a milder form of Scheie syndrome. Currently, there is an increased interest in MPS in the world due to the identification of the spectrum and frequencies of mutations in theIDUAandIDSgenes in various populations, including in Russia, and the practical availability of methods for individual molecular diagnostics. The description of the existing experimental models, their role in the study of the biochemical basis of the pathogenesis of these severe hereditary diseases and the development of various therapeutic approaches are given. Discusses the possibility of early diagnosis of MPS I and II types based on neonatal screening in order to increase the effectiveness of their prevention and treatment, as well as the advantages and disadvantages of the main approaches to the treatment of these serious diseases, such as hematopoietic stem cell transplantation, enzyme replacement and substrate-reducing therapy. A clinical example of a combination therapy for a severe form of mucopolysaccharidosis type I Hurler syndrome is presented

Is There a Functional Role of Mitochondrial Dysfunction in the Pathogenesis of ARPKD?

Polycystic kidney diseases (PKD) form a group of severe genetic kidney diseases that are characterized by fibrocystic changes of the kidneys and the liver. The main forms of PKD are autosomal dominant and autosomal recessive polycystic kidney disease (ADPKD, ARPKD). In general, cystic kidney diseases are the most common genetic cause of chronic kidney failure in both children and adults (1). ARPKD is a disorder that typically is diagnosed very early in life or even prenatally. Typically, the kidneys show bilateral massive enlargement although they keep their reniform shape. Kidney disease results in a need for kidney replacement therapy (KRT) in around 50% of patients in the first two decades of life (2, 3). Liver involvement is obligatory in ARPKD, typically presenting with congenital hepatic fibrosis and portal hypertension or with dilated bile ducts. Both are considered to be a consequence of a defect during development of the bile ducts (“ductal plate malformation”) (4). Adult patients with ARPKD have been described with variable disease manifestations. Hepatic disease may be the leading clinical issue in adults with ARPKD (5). In ADPKD renal cystogenesis starts early in life or even before birth but does not present with obvious clinical symptoms until adulthood in most patients (1, 6, 7). Liver involvement is typically characterized by liver cysts. Additional extrarenal symptoms in ADPKD include for example intracranial aneurysms, cardiac valve anomalies like mitral prolapse or abdominal wall diverticula in a subset of patients (1, 7). Extrarenal manifestations may be very helpful for clinical differential diagnosis and to distinguish ADPKD from ARPKD. ADPKD is mainly caused by variants in the genes PKD1 and PKD2 with the large majority of patients carrying PKD1 variants (1). Variants in other genes e.g., with atypical forms of ADPKD have been identified (7). Variants in PKHD1 are the main cause of ARPKD with phenotypical overlay e.g., of kidney disease in patients with other underlying genetic changes (1, 8), including biallelic hypomorphic PKD1 variants. Genotype-phenotype correlations in ADPKD show more rapid progression of kidney disease in patients with PKD1 variants and especially in those patients carrying variants resulting in protein truncation (7, 9). For ARPKD it was shown by various groups that biallelic truncating variants are associated with severe phenotypes. A recent study extended the findings and revealed that for missense variants the affected region in PKHD1 also seems to be important (10). In a study on 304 children with the clinical diagnosis of ARPKD and detected PKHD1 variants it was found that patients with either two missense variants affecting the amino acids 709–1837 or a null variant and a missense variant in this region less frequently showed progression to chronic kidney failure when being compared during their follow-up when compared to patients with variants affecting other regions of PKHD1. On the other hand patients with variants affecting the amino acids 2625–4074 showed less favorable hepatic outcome (10). The underlying molecular mechanisms of these associations remain to be explored.

156 Targeted ex-vivo correction of COL7A1 through RNP-based CRISPR/Cas9 and Homology- Directed Repair to treat recessive dystrophic epidermolysis bullosa

RDEB is a rare and severe genetic skin disease responsible for blistering of the skin and mucosa after minor trauma. RDEB is caused by a wide variety of mutations in COL7A1 encoding type VII collagen, the major component of anchoring fibrils critical attachment structures that adhere the epidermis to the dermis. Here, we achieved highly efficient COL7A1 editing in primary RDEB keratinocytes, fibroblasts, and 3D-skin grafts through CRISPR/Cas9-mediated Homology Directed Repair. First, we designed three guide RNAs (gRNAs) targeting the specific mutation or sequences in close distance to the c.6508C>T (p.Gln2170*) mutation to be corrected in exon 80.

ATF6 is essential for human cone photoreceptor development

Endoplasmic reticulum (ER) stress and Unfolded Protein Response (UPR) signaling promote the pathology of many human diseases. Loss-of-function variants of the UPR regulator Activating Transcription Factor 6 (ATF6) cause severe congenital vision loss diseases such as achromatopsia by unclear pathomechanisms. To investigate this, we generated retinal organoids from achromatopsia patient induced pluripotent stem cells carrying ATF6 disease variants and from gene-edited ATF6 null hESCs. We found that achromatopsia patient and ATF6 null retinal organoids failed to form cone structures concomitant with loss of cone phototransduction gene expression, while rod photoreceptors developed normally. Adaptive optics retinal imaging of achromatopsia patients carrying ATF6 variants also showed absence of cone inner/outer segment structures but preserved rod structures, mirroring the defect in cone formation observed in our retinal organoids. These results establish that ATF6 is essential for human cone development. Interestingly, we find that a selective small molecule ATF6 signaling agonist restores the transcriptional activity of some ATF6 disease-causing variants and stimulates cone growth and gene expression in patient retinal organoids carrying these variants. These findings support that pharmacologic targeting of the ATF6 pathway can promote human cone development and should be further explored for blinding retinal diseases.

Cystic Fibrosis in two Ghanaian Children

Cystic fibrosis (CF) is a severe life-limiting genetic disorder resulting from mutations in the cystic fibrosis transmembrane regulator gene and is reported to be more prevalent among Caucasians than people of African descent. The past three decades have seen a gradual increase in the reporting of CF in non-European populations with CF in all regions including Africa. We report on the first two known Ghanaian children diagnosed with CF presenting early in infancy. The first patient presented with severe acute malnutrition and persistent diarrhea resulting from severe exocrine pancreatic insufficiency. In the second patient, there were recurrent wheeze and recurrent pneumonia, severe dehydration with metabolic alkalosis. Diagnosis of CF in Ghana is challenging due to the absence of diagnostic tools such as sweat testing equipment. In the first patient, sweat testing and genetic testing were done in South Africa. In the second patient, sweat testing was not done but diagnosis was confirmed by genetic testing. Both patients presented with classical CF symptoms including Pseudomonas aeruginosa airway infection before age 6 months. Both children are currently alive and healthy on appropriate treatment. These case reports highlight the growing evidence of CF occurring in people of African descent and the diagnostic challenges faced in Africa.

Insights Into the Molecular Mechanisms of Polycystic Kidney Diseases.

Autosomal dominant (AD) and autosomal recessive (AR) polycystic kidney diseases (PKD) are severe multisystem genetic disorders characterized with formation and uncontrolled growth of fluid-filled cysts in the kidney, the spread of which eventually leads to the loss of renal function. Currently, there are no treatments for ARPKD, and tolvaptan is the only FDA-approved drug that alleviates the symptoms of ADPKD. However, tolvaptan has only a modest effect on disease progression, and its long-term use is associated with many side effects. Therefore, there is still a pressing need to better understand the fundamental mechanisms behind PKD development. This review highlights current knowledge about the fundamental aspects of PKD development (with a focus on ADPKD) including the PC1/PC2 pathways and cilia-associated mechanisms, major molecular cascades related to metabolism, mitochondrial bioenergetics, and systemic responses (hormonal status, levels of growth factors, immune system, and microbiome) that affect its progression. In addition, we discuss new information regarding non-pharmacological therapies, such as dietary restrictions, which can potentially alleviate PKD.

Obstetric and neonatal outcomes of pregnancies resulting from preimplantation genetic testing: a systematic review and meta-analysis.

Preimplantation genetic testing (PGT) includes methods that allow embryos to be tested for severe inherited diseases or chromosomal abnormalities. In addition to IVF/ICSI and repeated freezing and thawing of the embryos, PGT requires a biopsy to obtain embryonic genetic material for analysis. However, the potential effects of PGT on obstetric and neonatal outcomes are currently uncertain. This study aimed to investigate whether pregnancies conceived after PGT were associated with a higher risk of adverse obstetric and neonatal outcomes compared with spontaneously conceived (SC) pregnancies or pregnancies conceived after IVF/ICSI. PubMed, EMBASE, MEDLINE, Web of Science and The Cochrane Library entries from January 1990 to January 2021 were searched. The primary outcomes in this study were low birth weight (LBW) and congenital malformations (CMs), and the secondary outcomes included gestational age, preterm delivery (PTD), very preterm delivery (VPTD), birth weight (BW), very low birth weight (VLBW), neonatal intensive care unit (NICU) admission, hypertensive disorders of pregnancy (HDP), gestational diabetes, placenta previa and preterm premature rupture of membranes (PROM). We further pooled the results of PGT singleton pregnancies. Subgroup analyses included preimplantation genetic diagnosis (PGD), preimplantation genetic screening (PGS), cleavage-stage biopsy combined with fresh embryo transfer (CB-ET) and blastocyst biopsy combined with frozen-thawed embryo transfer (BB-FET). This meta-analysis included 15 studies involving 3682 babies born from PGT pregnancies, 127 719 babies born from IVF/ICSI pregnancies and 915 222 babies born from SC pregnancies. The relative risk (RR) of LBW was higher in PGT pregnancies compared with SC pregnancies (RR = 3.95, 95% confidence interval [CI]: 2.32-6.72), but the risk of CMs was not different between the two groups. The pooled results for the risks of LBW and CMs were similar in PGT and IVF/ICSI pregnancies. The risks of PTD (RR = 3.12, 95% CI: 2.67-3.64) and HDP (RR = 3.12, 95% CI: 2.18-4.47) were significantly higher in PGT pregnancies compared with SC pregnancies. Lower gestational age (mean difference [MD] = -0.76 weeks, 95% CI -1.17 to -0.34) and BW (MD = -163.80 g, 95% CI: -299.35 to -28.24) were also noted for PGT pregnancies compared with SC pregnancies. Nevertheless, compared with IVF/ICSI pregnancies, the risks of VPTD and VLBW in PGT pregnancies were significantly decreased by 41% and 30%, respectively, although the risk of HDP was still significantly increased by 50% in PGT pregnancies compared with IVF/ICSI pregnancies. The combined results of obstetric and neonatal outcomes of PGT and IVF/ICSI singleton pregnancies were consistent with the overall results. Further subgroup analyses indicated that both PGD and PGS pregnancies were associated with a higher risk of PTD and a lower gestational age compared with SC pregnancies. This meta-analysis showed that PGT pregnancies may be associated with increased risks of LBW, PTD and HDP compared with SC pregnancies. The overall obstetric and neonatal outcomes of PGT pregnancies are favourable compared with those of IVF/ICSI pregnancies, although PGT pregnancies were associated with a higher risk of HDP. However, because the number of studies that could be included was limited, more randomised controlled trials and prospective cohort studies are needed to confirm these conclusions.