scholarly journals A genomic autopsy identifies causes of perinatal death and provides options to prevent recurrence

2022 ◽  
Author(s):  
Hamish Scott ◽  
Alicia Byrne ◽  
Peer Arts ◽  
Thuong Ha ◽  
Karin Kassahn ◽  
...  
Keyword(s):  
Prenatal Diagnosis ◽  
Developmental Disorders ◽  
Perinatal Death ◽  
Genetic Diagnosis ◽  
Clinical Importance ◽  
Recurrence Risk ◽  
In Utero ◽  
Disease Genes ◽  
Genomic Disorders

Abstract Perinatal death, of a fetus or newborn, is a devastating event for families. Following nationwide multicentre recruitment, we assessed ‘genomic autopsy’ as an adjunct to standard autopsy for 200 families who experienced perinatal death, and provided a definite or candidate genetic diagnosis in 105 families. From this understudied cohort, half of the (candidate) diagnoses were phenotype expansions or novel disease genes, revealing previously unknown in-utero presentations of existing developmental disorders, and genomic disorders that are likely incompatible with life. Among the definite diagnoses, 43% were recessively or dominantly inherited, posing a 25% or 50% recurrence risk for future pregnancies. Ten families used their diagnosis for preimplantation or prenatal diagnosis of 12 pregnancies, facilitating the delivery of ten healthy newborns and management of two affected pregnancies. We emphasize the clinical importance of genomic investigations of perinatal death, with short turn-around times, enabling accurate counselling and options for families to prevent recurrence.

scholarly journals Information and genetic counselling for psychiatric risks in children with rare disorders

2019 ◽  
Author(s):  
Andrew Cuthbert ◽  
Aimee Challenger ◽  
Jeremy Hall ◽  
Marianne BM van den Bree
Keyword(s):  
Mental Health ◽  
Intellectual Disability ◽  
Support Groups ◽  
Genetic Counselling ◽  
Odds Ratio ◽  
Developmental Disorders ◽  
Best Practice ◽  
Genetic Diagnosis ◽  
General Medicine ◽  
Genomic Disorders

AbstractBackground:The diagnosis of developmental disorders is being transformed by advances in whole genome technologies. However, continuing uncertainties about the individual risks and potential severity of psychiatric impacts attributed to causal genomic variants limits the availability of comprehensive family-oriented information. In addition, there is insufficient evidence about how the parents of children with developmental disorders comprehend the facts and implications of their diagnosis through genetic counselling, nor how they gather developmental and mental health information to guide their understanding.Methods:Parents of children (aged 0–17 years) referred to paediatric genetics services completed an anonymous online 46-item survey about: (i) the experience of attending services to receive their child’s genetic diagnosis, and (ii) the availability, quality and helpfulness of information about psychiatric and neurodevelopmental conditions associated with genomic disorders.Findings:Two-hundred and eighty-six families (199 UK and 87 USA) completed the survey. One-in-three UK and one-in-five US respondents were dissatisfied with how their child’s genetic diagnosis was communicated. Satisfaction was predicted by face-to-face communication (odds ratio 2·91 [95% CI 1·43–5·94]; p=0·003); results being presented by genetics specialists (2·97 [1·41–6·26]; p=0·004); receiving clear explanations (5·14 [2·58– 10·26]; p<0·001); receiving support (2·99 [1·21–7·36], p=0·017); and male gender of the tested child (2·56 [1·28–5·14]; p=0·008). Compared to health-related information on developmental delay or intellectual disability, parents were more likely to obtain information about psychiatric manifestations from non-professional lay sources than from clinical specialists (p<0·001). This was particularly evident for families in the UK compared to the USA (p<0·001). Parents considered information from rare disorder support groups to be more helpful than from genetics specialists (odds ratio 11·0 [95% CI 5·08–86·75]; p<0·001), or paediatricians (11·0 [1·42–85·20]; p=0·006), or internet sites (15·5 [3·71–64·77]; p<0·001), which in turn proved more helpful than information provided by geneticists (2·5 [1·44–4·31]; p=0·001).Interpretation:Psychiatric comorbidity is a common feature of rare genomic disorders, but the paucity of suitable information available from clinical specialists suggests families are not optimally informed about these challenges. Wider implementation of genomic testing in general medicine should include adequate training in genetic counselling to ensure best practice in communicating and explaining complex test results supported by comprehensive, family-oriented information.Funding:The Waterloo Foundation: Changing Minds Programme (506296); The Medical Research Council (MRC) Research Grant: Intellectual Disability and Mental Health: Assessing Genomic Impact on Neurodevelopment (MR/N022572/1).

Antenatal diagnosis and pre-implantation genetic testing

2018 ◽  
Author(s):  
Frances Flinter
Keyword(s):  
Prenatal Diagnosis ◽  
Genetic Testing ◽  
Molecular Level ◽  
Antenatal Diagnosis ◽  
Genetic Diagnosis ◽  
Recurrence Risk ◽  
Antenatal Screening ◽  
Ultrasound Scan ◽  
Specific Diagnosis ◽  
Non Invasive

Routine pregnancy screening (e.g. ultrasound scan) may lead unexpectedly to the identification of an underlying renal problem whose aetiology may not be apparent immediately. It is important to recognize genetic causes so that associated problems in other organs can be anticipated and the recurrence risk for future pregnancies established. Specific diagnosis at a cytogenetic or molecular level may be essential if the options of early prenatal diagnosis or pre-implantation genetic diagnosis are to be available to the couple in future pregnancies. This chapter discusses the topics of antenatal screening, prenatal diagnosis (including invasive and non-invasive diagnosis and counselling) and intervention, and pre-implantation genetic diagnosis.

scholarly journals Genetics of neuromuscular fetal akinesia in the genomics era

2018 ◽  
Vol 55 (8) ◽  
pp. 505-514 ◽  
Author(s):  
Sarah Jane Beecroft ◽  
Marcus Lombard ◽  
David Mowat ◽  
Catriona McLean ◽  
Anita Cairns ◽  
...  
Keyword(s):  
Clinical Utility ◽  
Disease Gene ◽  
Genetic Diagnosis ◽  
Recurrence Risk ◽  
Population Based ◽  
Disease Genes ◽  
Neuromuscular System ◽  
Mendelian Genetics ◽  
Planning Decisions ◽  
Disease Gene Discovery

Fetal hypokinesia or akinesia encompasses a broad spectrum of disorders, united by impaired movement in utero. Often, the underlying aetiology is genetic in origin, affecting part of the neuromuscular system. The affordable and high-throughput nature of next-generation DNA sequencing has led to an explosion in disease gene discovery across rare diseases, including fetal akinesias. A genetic diagnosis has clinical utility as it may affect management and prognosis and informs recurrence risk, facilitating family planning decisions. More broadly, knowledge of disease genes increasingly allows population-based preconception carrier screening, which has reduced the incidence of recessive diseases in several populations. Despite gains in knowledge of the genetics of fetal akinesia, many families lack a genetic diagnosis. In this review, we describe the developments in Mendelian genetics of neuromuscular fetal akinesia in the genomics era. We examine genetic diagnoses with neuromuscular causes, specifically including the lower motor neuron, peripheral nerve, neuromuscular junction and muscle.

scholarly journals Exome sequencing in patients with antiepileptic drug exposure and complex phenotypes

2019 ◽  
Vol 105 (4) ◽  
pp. 384-389 ◽  
Author(s):  
Adam Jackson ◽  
Heather Ward ◽  
Rebecca Louise Bromley ◽  
Charulata Deshpande ◽  
Pradeep Vasudevan ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Copy Number ◽  
Developmental Disorders ◽  
Drug Exposure ◽  
Genetic Disorders ◽  
Copy Number Variants ◽  
Copy Number Variant ◽  
In Utero ◽  
Developmental Problems ◽  
Number Of Children

IntroductionFetal anticonvulsant syndrome (FACS) describes the pattern of physical and developmental problems seen in those children exposed to certain antiepileptic drugs (AEDs) in utero. The diagnosis of FACS is a clinical one and so excluding alternative diagnoses such as genetic disorders is essential.MethodsWe reviewed the pathogenicity of reported variants identified on exome sequencing in the Deciphering Developmental Disorders (DDD) Study in 42 children exposed to AEDs in utero, but where a diagnosis other than FACS was suspected. In addition, we analysed chromosome microarray data from 10 patients with FACS seen in a Regional Genetics Service.ResultsSeven children (17%) from the DDD Study had a copy number variant or pathogenic variant in a developmental disorder gene which was considered to explain or partially explain their phenotype. Across the AED exposure types, variants were found in 2/15 (13%) valproate exposed cases and 3/14 (21%) carbamazepine exposed cases. No pathogenic copy number variants were identified in our local sample (n=10).ConclusionsThis study is the first of its kind to analyse the exomes of children with developmental disorders who were exposed to AEDs in utero. Though we acknowledge that the results are subject to bias, a significant number of children were identified with alternate diagnoses which had an impact on counselling and management. We suggest that consideration is given to performing whole exome sequencing as part of the diagnostic work-up for children exposed to AEDs in utero.

Magnetic resonance imaging versus ultrasonography for the in utero evaluation of central nervous system anomalies

2010 ◽  
Vol 6 (4) ◽  
pp. 340-345 ◽  
Author(s):  
Pierpaolo Peruzzi ◽  
Rebecca J. Corbitt ◽  
Corey Raffel
Keyword(s):  
Magnetic Resonance Imaging ◽  
Prenatal Diagnosis ◽  
Mr Imaging ◽  
False Negative ◽  
In Utero ◽  
Resonance Imaging ◽  
Fetal Ultrasonography ◽  
Negative Results ◽  
False Negative Results ◽  
Fetal Mr

Object The use of fetal MR imaging for the in utero evaluation of pathological conditions of the CNS is widely accepted as an adjunct to fetal ultrasonography studies. Magnetic resonance imaging is thought to characterize CNS anomalies better, and to provide a more exact diagnosis and accurate prognosis. The purpose of this study was to determine the role of and indications for fetal MR imaging in evaluating fetuses with different CNS abnormalities that were seen initially on prenatal sonograms. Methods Over a 3-year period, fetuses with prior sonographic evidence of CNS abnormalities who consequently received prenatal MR imaging at Columbus Nationwide Children's Hospital within 2 weeks of the fetal ultrasonography study were included in this study. For each patient, radiological reports from both studies were reviewed, analyzed, and compared with the findings at postnatal imaging or physical examination. Results of the 2 modalities were then compared in terms of diagnostic accuracy. Results Twenty-six fetuses were included in this study on the basis of an in utero sonogram showing a CNS anomaly. Their gestational age ranged from 17 to 35 weeks, with a mean of 25 weeks at the time of fetal ultrasonography. Hydrocephalus was identified in 16 fetuses, 6 had evidence of a spinal dysraphic defect, 2 had holoprosencephaly, 1 had an encephalocele, and 1 had multiple body abnormalities requiring detailed CNS evaluation. Twenty-five of the fetuses were correctly evaluated as having abnormal CNS findings on both fetal ultrasonography and fetal MR imaging. Fetal ultrasonography provided a correct prenatal diagnosis in 20 cases, whereas fetal MR imaging was correct in 22 cases. There were 9 cumulative false-positive results for fetal ultrasonography and 7 for fetal MR imaging, whereas for false-negative results there were a total of 34 and 19, respectively. Conclusions Fetal MR imaging is more sensitive in detecting fetal CNS abnormalities, but its ability to provide a correct prenatal diagnosis is only marginally superior to fetal ultrasonography. Moreover, fetal MR imaging is not exempt from misdiagnosis, and still shows a significantly high rate of false-negative results. Particularly for spinal dysraphic defects, fetal MR imaging does not seem to add important diagnostic or prognostic details when compared with fetal ultrasonography.

scholarly journals Information and genetic counselling for psychiatric risks in children with rare genomic disorders

2019 ◽  
Author(s):  
Andrew Cuthbert ◽  
Aimee Challenger ◽  
Jeremy Hall ◽  
Marianne BM van den Bree
Keyword(s):  
Genetic Counselling ◽  
Online Survey ◽  
Genomic Medicine ◽  
Genetic Diagnosis ◽  
Single Nucleotide Variants ◽  
Full Spectrum ◽  
Face To Face ◽  
Professional Information ◽  
Genomic Disorders ◽  
Psychiatric Manifestations

AbstractPurposeGenomic medicine has transformed the diagnosis of neurodevelopmental disorders. Evidence of increased psychiatric comorbidity associated with genomic copy number and single nucleotide variants (CNV and SNV) may not be fully considered when providing genetic counselling. We explored parents’ experiences of genetics services and how they obtained information concerning psychiatric manifestations.MethodsParents of children diagnosed with genomic variants completed an online survey exploring, (i) how they experienced the genetic diagnosis, and (ii) how they acquired information about psychiatric, developmental and physical manifestations.ResultsTwo-hundred and 86 respondents completed the survey. Thirty percent were unsatisfied with receiving genetic diagnoses. Satisfaction was predicted if communication was by geneticists (p = 0.004); provided face-to-face (p = 0.003); clearly explained (p < 0.001); and accompanied by support (p = 0.017). Parents obtained psychiatric information from non-professional sources more often than developmental (ϕ 0.26, p < 0.001) and physical manifestations (ϕ 0.21, p = 0.003), which mostly came from health professionals. Information from support organisations was more helpful than from geneticists (odds ratio [OR] 21.0, 95% CI 5.1 – 86.8, p < 0.001); paediatricians (OR 11.0, 1.4 – 85.2, p = 0.004); and internet sites (OR 15.5, 3.7 – 64.8, p < 0.001).ConclusionA paucity of professional information about psychiatric risks after genetic diagnosis may impede early diagnosis and intervention for children with high genotypic risks. Planned integration of genomic testing into mainstream services should include genetic counselling training to address the full spectrum of developmental, physical and psychiatric manifestations and timely provision of high-quality information.

scholarly journals Rare variants in the genetic background modulate the expressivity of neurodevelopmental disorders

2018 ◽  
Author(s):  
Lucilla Pizzo ◽  
Matthew Jensen ◽  
Andrew Polyak ◽  
Jill A. Rosenfeld ◽  
Katrin Mannik ◽  
...  
Keyword(s):  
Family History ◽  
Genetic Background ◽  
Rare Variants ◽  
De Novo ◽  
Genetic Diagnosis ◽  
Clinical Information ◽  
Disease Genes ◽  
Complete Evaluation ◽  
Rare Cnvs ◽  
Complex Disorders

AbstractPurposeTo assess the contribution of rare variants in the genetic background towards variability of neurodevelopmental phenotypes in individuals with rare copy-number variants (CNVs) and gene-disruptive mutations.MethodsWe analyzed quantitative clinical information, exome-sequencing, and microarray data from 757 probands and 233 parents and siblings who carry disease-associated mutations.ResultsThe number of rare secondary mutations in functionally intolerant genes (second-hits) correlated with the expressivity of neurodevelopmental phenotypes in probands with 16p12.1 deletion (n=23, p=0.004) and in probands with autism carrying gene-disruptive mutations (n=184, p=0.03) compared to their carrier family members. Probands with 16p12.1 deletion and a strong family history presented more severe clinical features (p=0.04) and higher burden of second-hits compared to those with mild/no family history (p=0.001). The number of secondary variants also correlated with the severity of cognitive impairment in probands carrying pathogenic rare CNVs (n=53) or de novo mutations in disease genes (n=290), and negatively correlated with head size among 80 probands with 16p11.2 deletion. These second-hits involved known disease-associated genes such as SETD5, AUTS2, and NRXN1, and were enriched for genes affecting cellular and developmental processes.ConclusionAccurate genetic diagnosis of complex disorders will require complete evaluation of the genetic background even after a candidate gene mutation is identified.

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