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Lancet (London, England) Aug 2019One of the primary goals of genomic medicine is to improve diagnosis through identification of genomic conditions, which could improve clinical management, prevent... (Review)
Review
One of the primary goals of genomic medicine is to improve diagnosis through identification of genomic conditions, which could improve clinical management, prevent complications, and promote health. We explore how genomic medicine is being used to obtain molecular diagnoses for patients with previously undiagnosed diseases in prenatal, paediatric, and adult clinical settings. We focus on the role of clinical genomic sequencing (exome and genome) in aiding patients with conditions that are undiagnosed even after extensive clinical evaluation and testing. In particular, we explore the impact of combining genomic and phenotypic data and integrating multiple data types to improve diagnoses for patients with undiagnosed diseases, and we discuss how these genomic sequencing diagnoses could change clinical management.
Topics: Adult; Child; Early Diagnosis; Genomics; Humans; Phenotype; Prenatal Diagnosis; Rare Diseases; Sequence Analysis, DNA; Exome Sequencing; Whole Genome Sequencing
PubMed: 31395441
DOI: 10.1016/S0140-6736(19)31274-7 -
Genes Sep 2022Background: There are few studies on the burden of chromosomal abnormalities and single gene disorders in fetal hemivertebra (HV). We aim to investigate the cytogenetic...
Background: There are few studies on the burden of chromosomal abnormalities and single gene disorders in fetal hemivertebra (HV). We aim to investigate the cytogenetic and monogenic risk and evaluate prenatal outcomes of fetal HV. Method: This study included fetuses diagnosed with HV divided into two groups: isolated HV and non-isolated HV. Data on other sonographic structural anomalies, chromosomal and sub-chromosomal abnormalities, monogenic variations detected by WES, and prenatal outcomes are recorded and reviewed. Results: Among 109 fetal HV cases, forty-seven (43.1%) non-isolated HV cases were associated with structural anomalies. Chromosomal test results were available in 58 cases, identifying six (10.3%) chromosomal aberrations involved in four isolated and two non-isolated HV. WES identified four (likely) pathogenic variants in three cases among 16 fetuses with HV, involving three novel variants, 1250G > T and c.1277G> inherited from parents, respectively, in DLL3 and c.7213C > A ** in the FLNB. The live birth rate (LB) was higher in the isolated fetal HV group than in the non-isolated group (67.7% (42/62) vs. 12.5% (12/47), p < 0.001). Conclusion: This study emphasizes the risk of cytogenetic abnormalities in isolated HV. WES yields a diagnostic rate of 18.3% in HV with normal CMA, probably aiding the prenatal counseling and management of fetal HV.
Topics: Chromosome Aberrations; Female; Fetus; Humans; Intracellular Signaling Peptides and Proteins; Membrane Proteins; Pregnancy; Prenatal Diagnosis
PubMed: 36140791
DOI: 10.3390/genes13091623 -
Prenatal Diagnosis Feb 2023There is a paucity of knowledge regarding the prenatal presentation of Klinefelter syndrome, or 47, XXY. Accurate prenatal counseling is critical and in utero diagnosis... (Review)
Review
OBJECTIVE
There is a paucity of knowledge regarding the prenatal presentation of Klinefelter syndrome, or 47, XXY. Accurate prenatal counseling is critical and in utero diagnosis is currently limited by a poor understanding of the prenatal phenotype of this condition.
METHODS
This is a case series of fetuses with cytogenetically confirmed 47, XXY in the prenatal period or up to age 5 years, with prenatal records available for review from four academic institutions between 2006 and 2019. Ultrasound reports were reviewed in detail to assess for increased nuchal translucency and structural abnormalities. Additionally, we reviewed results of cell-free DNA and serum analyte testing when performed to inform our understanding of the detection of fetal 47, XXY through standard genetic screening tests.
RESULTS
Forty-one cases with confirmed cytogenetic diagnosis of 47, XXY and prenatal records available for review were identified: 37 had a prenatal diagnosis and 4 had a postnatal diagnosis. Nuchal translucency was increased ≥3.0 mm in 23.1% (6/26) of cases with a documented measurement. In 29.2% (7/24) of cases with a second trimester anatomical ultrasound available for review, a fetal abnormality was identified (3 brain anomalies, 1 cardiac abnormality, 1 echogenic bowel, and 2 limb abnormalities). Among those who had cell-free DNA and serum analytes performed, 92.6% (25/27) and 36.3% (4/11) had an abnormal result respectively.
CONCLUSION
This case series expands our knowledge of the prenatal presentation of 47, XXY by identifying first and second trimester fetal sonographic abnormalities. Prenatal identification of this condition enables accurate counseling, focused prenatal management, and early postnatal interventions to ameliorate some of the known complications.
Topics: Pregnancy; Female; Humans; Klinefelter Syndrome; Prenatal Diagnosis; Ultrasonography, Prenatal; Nuchal Translucency Measurement; Phenotype; Cell-Free Nucleic Acids
PubMed: 34874073
DOI: 10.1002/pd.6071 -
Journal of Oral Pathology & Medicine :... Nov 2022Vascular anomalies are rare lesions of diverse nature that may affect the head and neck region. Any mass in or around the upper airway has the potential to obstruct or... (Review)
Review
Vascular anomalies are rare lesions of diverse nature that may affect the head and neck region. Any mass in or around the upper airway has the potential to obstruct or compromise it. The absolute priority, before etiologic treatment, is the evaluation of the risk for the airway and its management. Prenatal diagnosis of an upper airway obstruction requires a planned delivery in a center having a specialized team experienced in managing a compromised feto-neonatal airway, and who could perform an ex-utero intrapartum treatment to secure the airway. Even after birth, the airway remains central in the patient's overall management. Signs and symptoms of airway compromise must be evaluated keeping in mind the specific requirements of infants and small children and being aware that rapid worsening may occur. The treatment is then tailored to the patient and his lesion with the goal of improving symptoms while avoiding treatment-related complications. Maintaining reasonable expectations by the patient and families are part of a successful management. Cure is achievable for small and localized lesions, but symptom relief and mitigation of functional, esthetic and psychological impairments is the goal for large and complex lesions. If a tracheotomy was required, decannulation is one of the primary management goals.
Topics: Child; Female; Humans; Infant; Infant, Newborn; Pregnancy; Airway Obstruction; Esthetics, Dental; Laryngostenosis; Prenatal Diagnosis; Tracheotomy; Vascular Malformations
PubMed: 35347777
DOI: 10.1111/jop.13297 -
The Journal of Maternal-fetal &... Dec 202315q11.2 microdeletion can lead to syndromes affecting the nervous system. However, 15q11.2 microdeletion has large phenotypic differences and incomplete penetrance,... (Review)
Review Meta-Analysis
OBJECTIVE
15q11.2 microdeletion can lead to syndromes affecting the nervous system. However, 15q11.2 microdeletion has large phenotypic differences and incomplete penetrance, which brings challenges to prenatal diagnosis. We reported 21 cases of 15q11.2 microdeletion fetuses in Eastern China and reviewed literature on the prenatal clinical characteristics related to the deletion variants to provide a basis for prenatal genetic counseling.
METHODS
The clinical data of 21 cases of 15q11.2 microdeletion fetuses collected from June 2018 to September 2021 were retrospectively analyzed, and chromosomal microarray analysis was performed. The reported prenatal clinical features of 15q11.2 microdeletion fetuses were reviewed and summarized. A meta-analysis of 20 studies was performed to test heterogeneity, data integration, and sensitivity on the correlation between 15q11.2 microdeletion and neuropsychiatric diseases.
RESULTS
The median age of the women was 29.5 years. The median gestational age at interventional examination was 24 weeks. All fetuses showed deletion variants of the 15q11.2 fragment, and the median deletion range was approximately 0.48 MB. Ultrasound of five cases showed no abnormalities; however, four of them showed a high risk of Down's syndrome (risk values were 1/184, 1/128, 1/47, and 1/54, respectively). The remaining 16 fetuses showed congenital heart disease (7/16), elevated nuchal translucency (5/16), abnormal brain structure (2/16) and renal disease (2/16). In a literature review of 82 prenatal cases, 44% (36/82) had abnormal ultrasound features, 31% (11/36) showed abnormal nuchal translucency, approximately 28% (10/36) showed abnormal cardiac structure, and 14% (5/36) had brain structural abnormalities. The meta-analysis revealed that the frequency of the 15q11.2 microdeletion mutation in patients with schizophrenia and epilepsy was significantly higher (odds ratio 2.04, 95% confidence interval: 1.78-2.33, < 0.00001; odds ratio 5.23, 95% confidence interval: 2.83-9.67, < 0.00001) than that in normal individuals.
CONCLUSION
More than half of the 15q11.2 microdeletion cases presented no abnormalities in prenatal ultrasound examination. The cases with ultrasound features mainly showed isolated malformations such as elevated nuchal translucency, congenital heart disease, and brain structural abnormalities. Postpartum 15q11.2 microdeletion patients are at an increased risk of suffering from schizophrenia, epilepsy, and other neurological and mental diseases from 15q11.2 microdeletion. Therefore, prenatal diagnosis of 15q11.2 microdeletion not only depends on molecular diagnostic techniques but also requires cautious genetic counseling.
Topics: Adult; Female; Humans; Pregnancy; Fetus; Heart Defects, Congenital; Nuchal Translucency Measurement; Prenatal Diagnosis; Retrospective Studies; Ultrasonography, Prenatal
PubMed: 37770195
DOI: 10.1080/14767058.2023.2262700 -
Journal of Cellular and Molecular... Sep 2021Pallister-Killian syndrome (PKS) is a rare sporadic genetic disorder usually caused by mosaicism of an extra isochromosome of 12p (i(12p)). This retrospective study...
Pallister-Killian syndrome (PKS) is a rare sporadic genetic disorder usually caused by mosaicism of an extra isochromosome of 12p (i(12p)). This retrospective study analysed the prenatal ultrasound manifestations and molecular and cytogenetic results of five PKS foetuses. Samples of amniotic fluid and/or cord blood, skin biopsy and placenta were collected. Conventional karyotyping and single nucleotide polymorphism array (SNP array) were performed on all the amniotic fluid or cord blood samples. Copy number variants sequencing (CNV-seq) and fluorescence in situ hybridization (FISH) were also used for the validation for one foetus. All the five foetuses were from pregnancies with advanced parental age. Two foetuses involved structural abnormalities and one foetus had only soft markers, all of which included increased nuchal translucency. The rest two foetuses had normal ultrasounds in the second trimester, which has rarely been reported before. The karyotype revealed typical i(12p) in four cases and a small supernumerary marker chromosome consisting of 12p and 20p in the remaining one case. The proportion of cells with i(12p) ranged from 0 to 100% in cultural cells, while SNP array results suggested 2-4 copies of 12p. For one foetus, metaphase FISH showed normal results, but the interphase FISH suggested cell lines with two, three and four copies of 12p in the amniotic fluid. Advanced parental age may be an important risk factor for PKS, and there were no typical ultrasound manifestations related to PKS. A combination of karyotype analysis and molecular diagnosis is an effective method for the diagnosis of PKS.
Topics: Adult; Chromosome Disorders; Chromosomes, Human, Pair 12; Female; Fetus; Humans; Karyotyping; Pregnancy; Prenatal Diagnosis; Retrospective Studies
PubMed: 34405543
DOI: 10.1111/jcmm.16853 -
Ultrasound in Obstetrics & Gynecology :... Aug 2022Outcome of common arterial trunk (CAT) depends mainly on truncal valve function, presence of coronary artery abnormalities and presence of interrupted aortic arch. The...
OBJECTIVES
Outcome of common arterial trunk (CAT) depends mainly on truncal valve function, presence of coronary artery abnormalities and presence of interrupted aortic arch. The main objective of this study was to evaluate the accuracy of prenatal diagnosis of CAT by analyzing prenatal vs postnatal assessment of: (1) anatomic subtypes and (2) truncal valve function. The secondary objective was to assess the potential impact of prenatal diagnosis of CAT on postnatal mortality and morbidity by comparing prenatally vs postnatally diagnosed patients.
METHODS
This was a retrospective analysis of all CAT patients diagnosed either prenatally, with postnatal or fetopsy confirmation, or postnatally, from 2011 to 2019 in a single tertiary center. Cohen's kappa statistic was used to evaluate agreement between pre- and postnatal assessment of anatomic subtypes according to Van Praagh and of truncal valve function. Mortality and morbidity variables were compared between prenatally vs postnatally diagnosed CAT patients.
RESULTS
A total of 84 patients (62 liveborn with prenatal diagnosis, 16 liveborn with postnatal diagnosis and six terminations of pregnancy with fetopsy) met the inclusion criteria. The accuracy of prenatal diagnosis of CAT anatomic subtype was 80.3%, and prenatal and postnatal concordance for subtype diagnosis was only moderate (κ = 0.43), with no patient with CAT Type A3 (0/4) and only half of patients with CAT Type A4 (8/17) being diagnosed prenatally. Fetal evaluation of truncal valve function underestimated the presence (no agreement; κ = 0.09) and severity (slight agreement; κ = 0.19) of insufficiency. However, four of five cases of postnatally confirmed significant truncal valve stenosis were diagnosed prenatally, with fair agreement for both presence and severity of stenosis (κ = 0.38 and 0.24, respectively). Mortality was comparable in patients with and those without prenatal diagnosis (log-rank P = 0.87). CAT patients with fetal diagnosis underwent earlier intervention (P < 0.001), had shorter intubation time (P = 0.047) and shorter global hospital stay (P = 0.01).
CONCLUSIONS
The accuracy of prenatal diagnosis of CAT is insufficient to tailor neonatal management and to predict outcome. Fetal assessment of truncal valve dysfunction appears unreliable due to perinatal transition. Improvement is necessary in the fetal diagnosis of anatomic subtypes of CAT requiring postnatal prostaglandin infusion. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.
Topics: Constriction, Pathologic; Female; Heart Defects, Congenital; Humans; Pregnancy; Prenatal Diagnosis; Retrospective Studies; Truncus Arteriosus, Persistent; Ultrasonography, Prenatal
PubMed: 35118719
DOI: 10.1002/uog.24873 -
Molecular Genetics & Genomic Medicine Jul 2023The short arm of chromosome 16 consists of several copy number variants (CNVs) that are crucial in neurodevelopmental disorders; however, incomplete penetrance and...
BACKGROUND
The short arm of chromosome 16 consists of several copy number variants (CNVs) that are crucial in neurodevelopmental disorders; however, incomplete penetrance and diverse phenotypes after birth aggravate the difficulty of prenatal genetic counseling.
METHODS
We screened 15,051 pregnant women who underwent prenatal chromosomal microarray analysis between July 2012 and December 2017. Patients with positive array results were divided into four subgroups based on the type of mutation identified on screening (16p13.3, 16p13.11, 16p12.2, and 16p11.2), and the maternal characteristics, prenatal examinations, and postnatal outcomes of different cases were reviewed.
RESULTS
Chromosome 16 CNVs were identified in 34 fetuses, including four with 16p13.3 CNVs, 22 with 16p13.11 CNVs, two with 16p12.2 microdeletions, and six with 16p11.2 CNVs. Of the 34 fetuses, 17 delivered without early childhood neurodevelopmental disorders, three developed neurodevelopmental disorders during childhood, and 10 were terminated.
CONCLUSION
Incomplete penetrance and variable expressivity make prenatal counseling challenging. Most cases with inherited 16p13.11 microduplication were reported to have normal development in early childhood, and we also report a few cases of de novo 16p CNVs without further neurodevelopmental disorders.
Topics: Pregnancy; Child, Preschool; Humans; Female; Prenatal Diagnosis; DNA Copy Number Variations; Chromosomes, Human, Pair 16; Chromosome Disorders; Fetus
PubMed: 37013606
DOI: 10.1002/mgg3.2174 -
Disease Markers 2022Copy number variations (CNVs) at the chromosomal 1q21.1 region represent a group of hot-spot recurrent rearrangements in human genome, which have been detected in...
Copy number variations (CNVs) at the chromosomal 1q21.1 region represent a group of hot-spot recurrent rearrangements in human genome, which have been detected in hundreds of patients with variable clinical manifestations. Yet, report of such CNVs in prenatal scenario was relatively scattered. In this study, 17 prenatal cases involving the 1q21.1 microdeletion or duplication were recruited. The clinical survey and imaging examination were performed; and genetic detection with karyotyping and CNV analysis using chromosomal microarray (CMA) or CNVseq were subsequently carried out. These cases were all positive with 1q21.1 CNV, yet presented with exceedingly various clinical and utrasonographic indications. Among them, 12 pregnancies carried 1q21.1 deletions, while the other 5 carried 1q21.1 duplications, all of which were within the previously defined breaking point (BP) regions. According to the verification results, 9 CNVs were , 7 were familial, and the other 1 was not certain. We summarized the clinical information of these cases, and the size and distribution of CNVs, and attempted to analyze the association between these two aspects. The findings in our study may provide important basis for the prenatal diagnosis and genetic counseling on such conditions in the future.
Topics: Pregnancy; Female; Humans; DNA Copy Number Variations; Chromosome Deletion; Prenatal Diagnosis; Abnormalities, Multiple
PubMed: 37284664
DOI: 10.1155/2022/5487452 -
The Journal of Maternal-fetal &... Dec 2023This study aimed to analyze the ultrasound characteristics of fetal congenital vertical talus (CVT) to provide a detailed basis for the prenatal diagnosis of CVT.
OBJECTIVE
This study aimed to analyze the ultrasound characteristics of fetal congenital vertical talus (CVT) to provide a detailed basis for the prenatal diagnosis of CVT.
METHODS
We retrospectively analyzed the ultrasonographic findings of fetuses with CVT confirmed by X-ray, surgery, or autopsy from 2010 to 2020. Clinical characteristics and ultrasonographic findings of CVT, including foot morphology, ossification center of the calcaneus and talus, associated deformities, and chromosomal test results, were recorded.
RESULTS
Thirteen patients diagnosed with CVT by prenatal ultrasound were confirmed postpartum. Nine cases were bilateral, and four were unilateral. Under two-dimensional ultrasound, 13/13 cases had abnormal foot morphology, and 10 of 13 cases (76.9%) showed that the ossification center of the talus moved downward, and the calcaneus moved laterally. Under three-dimensional ultrasound, 11 cases (84.6%) presented a "rocking chair" appearance, and two cases did not obtain satisfactory three-dimensional image due to oligohydramnios and fetal position. In this group of cases, two cases (15.4%) were isolated CVT, and the other 11 cases (84.6%) were complicated with other abnormalities. Eleven cases of non-isolated CVT and 1 case of isolated CVT were induced, and another patient with isolated CVT had undergone postnatal surgery, which had been followed up for 8 years and recovered well.
CONCLUSIONS
The combination of fetal foot morphology, ossification center position of the calcaneus and talus, and three-dimensional ultrasound can provide a reliable diagnosis of CVT. Furthermore, we should pay more attention to the evaluation of other systemic and chromosomal abnormalities in CVT cases.
Topics: Female; Humans; Pregnancy; Flatfoot; Retrospective Studies; Prenatal Diagnosis; Talus; Ultrasonography, Prenatal
PubMed: 36948222
DOI: 10.1080/14767058.2023.2192323