Australian Genomics: Outcomes of a 5-year national program to accelerate the integration of genomics in healthcare

The American Journal of Human Genetics, Journal Year: 2023, Volume and Issue: 110(3), P. 419 - 426

Published: March 1, 2023

Language: Английский

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Prevalence of chromosomal alterations in first-trimester spontaneous pregnancy loss

Nature Medicine, Journal Year: 2023, Volume and Issue: 29(12), P. 3233 - 3242

Published: Nov. 23, 2023

Pregnancy loss is often caused by chromosomal abnormalities of the conceptus. The prevalence these and allocation (ab)normal cells in embryonic placental lineages during intrauterine development remain elusive. In this study, we analyzed 1,745 spontaneous pregnancy losses found that roughly half (50.4%) products conception (POCs) were karyotypically abnormal, with maternal paternal age independently contributing to increased genomic aberration rate. We applied genome haplarithmisis a subset 94 normal parental POC karyotypes. Genotyping DNA as well extra-embryonic mesoderm chorionic villi DNA, representing trophoblastic tissues, enabled characterization landscape both lineages. Of losses, 35.1% had aberrations not previously detected karyotyping, increasing rate 67.8% extrapolation. contrast viable pregnancies where mosaic are restricted villi, such confined mosaicism, higher degree imbalances rather than villi. Our results stress importance scrutinizing full allelic architecture improve clinical management basic research devastating condition.

Language: Английский

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New insights into the physiology and pathophysiology of the atypical sodium leak channel NALCN

Physiological Reviews, Journal Year: 2023, Volume and Issue: 104(1), P. 399 - 472

Published: Aug. 24, 2023

Cell excitability and its modulation by hormones neurotransmitters involve the concerted action of a large repertoire membrane proteins, especially ion channels. Unique complements coexpressed channels are exquisitely balanced against each other in different excitable cell types, establishing distinct electrical properties that tailored for diverse physiological contributions, dysfunction any component may induce disease state. A crucial parameter controlling is resting potential (RMP) set extra- intracellular concentrations ions, mainly Na + , K Cl − their passive permeation across through leak Indeed, dysregulation RMP causes significant effects on cellular excitability. This review describes molecular channel NALCN, which associates with accessory subunits UNC-79, UNC-80, NLF-1/FAM155 to conduct depolarizing background currents various neurons. Studies animal models clearly demonstrate NALCN contributes fundamental processes nervous system including control respiratory rhythm, circadian sleep, locomotor behavior. Furthermore, associated severe pathological states humans. The critical involvement physiology now well established, but study has been hampered lack specific drugs can block or agonize vitro vivo. Molecular tools available accelerate our understanding how key functions development novel therapies channelopathies.

Language: Английский

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Extending the new era of genomic testing into pregnancy management: A proposed model for Australian prenatal services

Australian and New Zealand Journal of Obstetrics and Gynaecology, Journal Year: 2024, Volume and Issue: unknown

Published: April 5, 2024

Background Trio exome sequencing can be used to investigate congenital abnormalities identified on pregnancy ultrasound, but its use in an Australian context has not been assessed. Aims Assess clinical outcomes and changes management after expedited genomic testing the prenatal period guide development of a model for widespread implementation. Materials methods Forty‐three prospective referrals whole sequencing, including 40 trios (parents pregnancy), two singletons one duo were assessed tertiary hospital setting with access state‐wide pathology laboratory. Diagnostic yield, turn‐around time (TAT), gestational age at reporting, outcome, change future status each family. Results A clinically significant diagnosis was made 15/43 pregnancies (35%), average TAT 12 days. Gestational report ranged from 16 + 5 31 6 weeks (median 21 3 weeks). Molecular diagnoses included neuromuscular skeletal disorders, RASopathies range other rare Mendelian disorders. The majority families actively results decision making as well pregnancies. Conclusions Rapid second trimester successfully delivered structural pregnancy, providing crucial guidance current management. time‐sensitive nature this requires close laboratory collaboration ensure appropriate referral result communication. We found establishment coordinator role dedicated reporting team important facilitators. propose services.

Language: Английский

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Improving prenatal diagnosis through standards and aggregation

Prenatal Diagnosis, Journal Year: 2024, Volume and Issue: 44(4), P. 454 - 464

Published: Jan. 19, 2024

Advances in sequencing and imaging technologies enable enhanced assessment the prenatal space, with a goal to diagnose predict natural history of disease, direct targeted therapies, implement clinical management, including transfer care, election supportive selection surgical interventions. The current lack standardization aggregation stymies variant interpretation gene discovery, which hinders provision precision medicine, leaving clinicians patients without an accurate diagnosis. With large amounts data generated, it is imperative establish standards for collection, processing, aggregation. Aggregated homogeneously processed genetic phenotypic permits dissection genomic architecture presentations disease provides dataset on analysis algorithms can be tuned space. Here we discuss importance generating aggregate sets how space driving development interoperable phenotype-driven tools.

Language: Английский

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The expanded spectrum of human disease associated with GREB1L likely includes complex congenital heart disease

Prenatal Diagnosis, Journal Year: 2024, Volume and Issue: 44(3), P. 343 - 351

Published: Jan. 29, 2024

Abstract Objective GREB1L has been linked prenatally to Potter's sequence, as well less severe anomalies of the kidney, uterus, inner ear, and heart. The full phenotypic spectrum is unknown. purpose this study was characterize known novel pre‐ postnatal phenotypes associated with . Methods We solicited cases from Fetal Sequencing Consortium, screened a population‐based genomic database, conducted comprehensive literature search identify disease present detailed molecular changes. Results One hundred twenty‐seven individuals 51 unique pathogenic or likely variants were identified. 24 (47%) isolated kidney anomalies, 19 (37%) multiple systems, including one case hypoplastic left heart syndrome, five (10%) sensorineural hearing loss, two (4%) uterine agenesis; (2%) tetralogy Fallot. Conclusion may cause complex congenital (CHD) in humans. Clinicians should consider testing setting CHD, cardiac screening variants.

Language: Английский

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Fetal genetic factors in pregnancy loss: Insights from a meta-analysis and effectiveness of whole exome sequencing

PLoS ONE, Journal Year: 2025, Volume and Issue: 20(2), P. e0319052 - e0319052

Published: Feb. 25, 2025

Spontaneous pregnancy loss commonly occurs during the first trimester and can be caused by various factors including chromosomal abnormalities submicroscopic aberrations. After trimester, etiology of most losses remains undetermined. This study aims to fill this gap an in-depth investigation fetal genome its effect on outcome. Data from 1016 spontaneously aborted fetuses previously referred for genetic testing (2017–2023) were used meta-analysis. Fetuses categorized based gestational age test result. Additionally, 35 second-third fetuses, that aborted, terminated or died neonatally, with abnormal ultrasounds unrevealing routine collected. Trio-based whole-exome sequencing was performed identification variants may have loss. The meta-analysis revealed 822 (80.91%) 569 (69.22%) successfully diagnosed using conventional testing. remaining 194 (19.09%) trimester. Of 163 (84.02%) lacked diagnosis (karyotype array-CGH). Aneuploidies leading cause spontaneous in both followed polyploidies. Thus, demonstrated undiagnosed are more likely benefit further investigation. Application whole exome losses, causative 6 33 families (18.18%), genes linked Mendelian disorders associated phenotypes interest. Pathogenic findings identified two additional heterozygosity following autosomal recessive inheritance. Accurate such creates new genotype-in utero phenotype associations, prospect additions preconception/prenatal diagnostic panels. highlights importance resolving losses.

Language: Английский

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Antiphospholipid syndrome in patients with fetal death: a prospective longitudinal cohort study

Clinical and Experimental Medicine, Journal Year: 2025, Volume and Issue: 25(1)

Published: March 10, 2025

Language: Английский

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Neonatally Lethal Fanconi Anemia due to an Amish Founder FANCE Gene Variant; Evidence for Genotype–Phenotype Correlation

American Journal of Medical Genetics Part A, Journal Year: 2025, Volume and Issue: unknown

Published: March 14, 2025

ABSTRACT Prenatal and neonatal presentations of multiple congenital anomalies are difficult to diagnose associated with an increased risk lethality. The differential diagnosis antenatal radial ray malformations includes Fanconi anemia (FA), inherited bone marrow failure disorder in around 75% affected individuals. Although no definitive genotype–phenotype correlations have been demonstrated, a more severe presentation has proposed association biallelic loss function variants as opposed hypomorphic missense variants. FA founder identified several ethnic groups. Here we report the first description FANCE variant ( NM_021922.3:c.1510‐1G>A), Amish death four individuals from extended pedigree comprising three nuclear families. Biparental whole exome sequencing was used identify candidate confirmed homozygous state All had malformations, at least one additional anomaly, died within day life. We recommend that testing for this be considered fetus or infant anomalies, especially malformations.

Language: Английский

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Whole Genome Sequencing in Prenatal Diagnostics: The Danish Approach to Guideline Formation and Implementation Within Public Healthcare

Prenatal Diagnosis, Journal Year: 2025, Volume and Issue: unknown

Published: March 23, 2025

ABSTRACT Objective To describe the implementation of whole genome sequencing (WGS) in prenatal diagnostics and outline national guideline system facilitating this. Methods Clinical guidelines for WGS were developed implemented by Danish Fetal Medicine Society. Results Guidelines expert consensus following a review 75 studies. Diagnostic yield served as key factor prioritizing various phenotypes, improving diagnostic accuracy informing clinical decisions. Phenotypes include nuchal translucency ≥ 6.0 mm, multiple anomalies, skeletal dysplasia, neuromuscular diseases, non‐immune hydrops fetalis, central nervous malformations, congenital diaphragmatic hernia severe fetal growth restriction (< 3 SDs not explained placental insufficiency). Small regional variations exist indications, bioinformatics, funding, but is now routinely used nationwide these indications. Conclusion The Society's development, emphasizing gradual implementation, has supported relatively uniform integration into diagnostics.

Language: Английский

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