Spinal muscular atrophy (SMA) is a leading inherited cause of infant death with a reported incidence of ~1 in 10,000 live births and is second to cystic fibrosis as a common, life-shortening ...autosomal recessive disorder. The American College of Medical Genetics has recommended population carrier screening for SMA, regardless of race or ethnicity, to facilitate informed reproductive options, although other organizations have cited the need for additional large-scale studies before widespread implementation. We report our data from carrier testing (n = 72,453) and prenatal diagnosis (n = 121) for this condition. Our analysis of large-scale population carrier screening data (n = 68,471) demonstrates the technical feasibility of high throughput testing and provides mutation carrier and allele frequencies at a level of accuracy afforded by large data sets. In our United States pan-ethnic population, the calculated a priori carrier frequency of SMA is 1/54 with a detection rate of 91.2%, and the pan-ethnic disease incidence is calculated to be 1/11,000. Carrier frequency and detection rates provided for six major ethnic groups in the United States range from 1/47 and 94.8% in the Caucasian population to 1/72 and 70.5% in the African American population, respectively. This collective experience can be utilized to facilitate accurate pre- and post-test counseling in the settings of carrier screening and prenatal diagnosis for SMA.
Objective
To examine parental experiences during pregnancies affected by Arthrogryposis Multiplex Congenita (AMC) by identifying commonalities, risk factors, and areas for improvement in detection ...rates, care protocols, and patient experience.
Study Design
An online survey was distributed via AMC support groups on Facebook. Topics included demographics, risk factors, parental recall of sonographic findings, delivery characteristics and neonatal findings. Responses were divided into antenatally detected cases (ADCs) and postnatally detected cases (PDCs). Quantitative responses were analyzed with the Fisher exact test. Qualitative data were analyzed with thematic analysis.
Results
The antenatal detection rate of arthrogryposis was 37%. Decreased fetal movement was reported by 53% and early bleeding by 21%. Sonographic findings in ADCs included clubfoot (83%), clenched hand (51%), decreased fetal movement (50%), elbow contracture (51%), and knee contracture (46%). Among ADCs, 29% delivered vaginally and 71% delivered by cesarean versus PDCs (44% vaginal, 56% cesarean). Neonatal intensive care unit admission rate was 63%. Bone fracture occurred in 9%. Detection led to a planned change in delivery mode in 33% and location in 50%. Among ADCs, 17% felt their concerns were not adequately addressed versus 43% of PDCs.
Conclusions
Antenatal detection of arthrogryposis was low. We propose enhanced screening criteria to aid prenatal diagnosis and promote utilization of more robust practice guidelines.
Key points
What is already known about this topic?
The antenatal detection rate of Arthrogryposis Multiplex Congenita (AMC) by ultrasound is low.
Risk factors include extrinsic (uterine/placental) factors and intrinsic (fetal neuromuscular and genetic) factors
Guidelines for prenatal care following prenatal detection have been proposed but are not yet routinely recommended
What does this study add?
Our data reproduce previous detection rates and risk factors and identify additional factors
Evaluation of fetal movement is an underappreciated tool in the detection of AMC
Antenatal detection impacts the mode, timing, and location of delivery
Parental experiences have not previously been reported and are important considerations for utilization of published care guidelines
In the nearly 60 years since prenatal diagnosis for genetic disease was first offered, the field of prenatal diagnosis has progressed far past rudimentary uterine puncture to provide fetal material ...to assess gender and interpret risk. Concurrent with the improvements in invasive fetal sampling came technological advances in cytogenetics and molecular biology that widened both the scope of genetic disorders that could be diagnosed and also the resolution at which the human genome could be interrogated. Nowadays, routine blood work available to all pregnant women can determine the risk for common chromosome abnormalities; chorionic villus sampling (CVS) and amniocentesis can be used to diagnose nearly all conditions with a known genetic cause; and the genome and/or exome of a fetus with multiple anomalies can be sequenced in an attempt to determine the underlying etiology. This chapter will discuss some of the major advances in prenatal sampling and prenatal diagnostic laboratory techniques that have occurred over the past six decades.
Non‐invasive prenatal testing (NIPT) is an emerging form of prenatal genetic testing that provides information about the genetic constitution of a foetus without the risk of pregnancy loss as a ...direct result of the test procedure. As with other prenatal tests, information from NIPT can help to make a decision about termination of pregnancy, plan contingencies for birth or prepare parents to raise a child with a genetic condition. NIPT can also be used by women and couples to test purely ‘for information’. Here, no particular action is envisaged following the test; it is motivated entirely by an interest in the result. The fact that NIPT can be performed without posing a risk to the pregnancy could give rise to an increase in such requests. In this paper, we examine the ethical aspects of using NIPT ‘purely for information’, including the competing interests of the prospective parents and the future child, and the acceptability of testing for ‘frivolous’ reasons. Drawing on several clinical scenarios, we claim that arguments about testing children for genetic conditions are relevant to this debate. In addition, we raise ethical concerns over the potential for objectification of the child. We conclude that, in most cases, using NIPT to test for adult‐onset conditions, carrier status or non‐serious traits presenting in childhood would be unacceptable.
Objective
To evaluate whether targeted sequencing and relative mutation dosage can be used to diagnose correctly inheritance of maternal β‐thalassaemia mutations in cell‐free DNA.
Design
Feasibility ...study using samples collected in a prenatal clinic.
Setting
South East Asia.
Population
Couples where both partners were known to be carriers of one of four common β‐thalassaemia mutations or an HbE mutation, and therefore at risk of carrying a fetus affected with β‐thalassaemia.
Methods
49 samples previously identified as having inherited a paternal β‐thalassaemia mutation were amplified using nested polymerase chain reaction (PCR), and then sequencing. Relative mutation dosage was used to classify the fetus as having inherited the wild‐type or mutant maternal allele.
Main outcome measures
Classification of the fetus as ‘unaffected’ (if the maternal wild‐type allele was inherited) or ‘affected’ with β‐thalassaemia (if the maternal mutant allele was inherited).
Results
A classification for inheritance of maternal allele was obtained in 48/49 samples (98.0%). A concordant call was made in 44/48 cases (91.7%): one false‐positive and three false‐negatives were obtained. Thus, we had an overall sensitivity of 87.5% 95% confidence interval (CI) 67.6–97.3% and a specificity of 95.8% (95% CI 78.9–99.9%) for inheritance of maternal genotype.
Conclusions
RMD for detection of inheritance of maternal β‐thalassaemia mutations has potential for clinical use. Our sequential approach could be applied to other single‐gene disorders.
Tweetable
NIPT for β‐thalassaemia achieved using nested‐PCR followed by relative mutation dosage.
Tweetable
NIPT for β‐thalassaemia achieved using nested‐PCR followed by relative mutation dosage.
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