Objective
To evaluate the risk of fetal involvement when trisomy 8 mosaicism (T8M) is detected in chorionic villus samples (CVS).
Methods
A retrospective descriptive study of registered pregnancies ...in Denmark with T8M in CVS identified through a database search and a review of published cases of T8M found through a systematic literature search and inclusion of cross references. Pregnancies with T8M in CVS and no additional numerical chromosomal aberrations were included.
Results
A total of 37 Danish cases and 60 published cases were included. T8M detected in a CVS was associated with fetal involvement in 18 out of 97 pregnancies (18.6% 95%CI: 11.4–27.7). Eight out of 70 (11.4% 95%CI: 5.1–21.3) interpreted prenatally to be confined placental mosaicism (CPM) were subsequently found to be true fetal mosaicisms (TFM).
Conclusion
T8M detected in CVS poses a significant risk of fetal involvement, and examination of amniotic fluid (AF) and/or fetal tissue should be offered. However, a normal result of AF still has a considerable residual risk of fetal involvement. Genetic counselling at an early gestational age is essential, and follow‐up ultrasonography should be performed to predict fetal involvement if possible.
We report a three-generation family with isolated Alport-like retinal abnormalities in the absence of lenticonus, hearing loss, kidney disease, and detectable molecular genetic defects in known ...Alport-related genes.
Clinical examination includes ocular biomicroscopy, fundus photography, optical coherence tomography, dipstick urinalysis, serum creatinine assessment, and molecular genetic analysis.
The proband, her mother, and her maternal grandmother had normal best-corrected visual acuity and normal visual fields in both eyes. The macula presented a petaloid stair-case profile with scarce vessels in both eyes of the proband and a flat temporal macula lacking a foveal avascular zone in her mother and her grandmother. No family member had renal symptoms, unexplained subnormal hearing, or lenticonus. Sequencing and MLPA found no defect in
,
, and
. Common SNPs around the genes ± 1Mb showed no segregation. Furthermore, none of the variants shared between the affected individuals in genes from a gene panel of genes relevant for ophthalmopathy nor whole exome- and genome sequencing explained the phenotype.
A new condition with two retinal Alport-like phenotypes was found. No abnormalities of the kidneys and lens were found, neither abnormalities of the type IV collagen genes related to Alport syndrome. Homology with retinal abnormalities seen in patients after surgical removal of the inner limiting membrane of the retina suggests that this is where the defect is located. We therefore suggest that the new retinal phenotypes and similar phenotypes can be described with the new definition "frail inner limiting membrane maculopathy."
Objective
To evaluate time of diagnosis of 22q11.2 deletion and 22q11.2 duplication as well as trisomies 21, 13, and 18 before and after introduction of a prenatal screening program including ...combined first‐trimester screening (cFTS) for the trisomies in Denmark in 2004.
Method
Cross‐sectional, population‐based register study employing The Danish Cytogenetic Central Register. Proportions of cases diagnosed 1998‐2004 and 2005‐2017 were compared before 14+0 and 22+0 weeks and birth (prenatal cases) or up to 1 or 10 years of age (postnatal cases).
Results
In total, 4562 cases were included. From 1998‐2004 to 2005‐2017, the proportion of 22q11.2 deletion cases identified prenatally increased from 4.3% (95% CI: 0.9‐12.0%) to 27.3% (21.2‐34.0%), while for 22q11.2 duplication an increase from 0/6 to 26/87 (prenatal cases/all cases) was observed. Similarly, proportions of trisomies 21, 13, and 18 detected before birth increased. A greater proportion of the studied conditions was identified earlier in pregnancy, but not generally earlier in the postnatal course.
Conclusion
Proportions of 22q11.2 deletion and 22q11.2 duplication identified prenatally increased after introduction of a prenatal screening program not aimed specifically to identify these conditions,. A greater proportion of all cases were detected earlier in pregnancy, but not earlier postnatally, following introduction of screening.
Disease causing variants in the Ryanodine receptor 1 (RYR1) gene are a common cause for congenital myopathy and for malignant hyperthermia susceptibility. We report a 17 year old boy with congenital ...muscle weakness progressing to a myasthenia like myopathy with muscle weakness, fatigability, ptosis, and ophthalmoplegia. Muscle biopsy showed predominance and atrophy of type 1 fibers. Whole-exome trio sequencing revealed three variants in the RYR1-gene in the patient: c.6721C > T,p.(Arg2241*) and c.2122G > A,p.(Asp708Asn) in cis position, and the c.325C > T,p.(Arg109Trp) variant in trans. Treatment with pyridostigmine improved symptoms. This case supports that a myasthenia like phenotype is part of the phenotypic spectrum of RYR1 related disorders, and that treatment with pyridostigmine can be beneficial for patients with this phenotype.
Deadenylases are best known for degrading the poly(A) tail during mRNA decay. The deadenylase family has expanded throughout evolution and, in mammals, consists of 12 Mg
-dependent 3'-end RNases with ...substrate specificity that is mostly unknown. Pontocerebellar hypoplasia type 7 (PCH7) is a unique recessive syndrome characterized by neurodegeneration and ambiguous genitalia. We studied 12 human families with PCH7, uncovering biallelic, loss-of-function mutations in TOE1, which encodes an unconventional deadenylase. toe1-morphant zebrafish displayed midbrain and hindbrain degeneration, modeling PCH-like structural defects in vivo. Surprisingly, we found that TOE1 associated with small nuclear RNAs (snRNAs) incompletely processed spliceosomal. These pre-snRNAs contained 3' genome-encoded tails often followed by post-transcriptionally added adenosines. Human cells with reduced levels of TOE1 accumulated 3'-end-extended pre-snRNAs, and the immunoisolated TOE1 complex was sufficient for 3'-end maturation of snRNAs. Our findings identify the cause of a neurodegenerative syndrome linked to snRNA maturation and uncover a key factor involved in the processing of snRNA 3' ends.
Introduction
Denmark was the first country in the world to implement a national, free‐for‐all offer of prenatal screening for Down syndrome to all pregnant women. It has a high uptake (>90%) compared ...to other countries. Thus, Denmark offers an interesting case for investigating the consequences of implementing comprehensive, national prenatal screening guidelines. The aim of this study was to describe the historical developments in invasive procedures, pre‐/postnatal diagnoses of Down syndrome and Down syndrome live births in the period 1973–2016 in Denmark.
Material and methods
Data on invasive procedures, pre‐ and postnatal Down syndrome diagnoses were retrieved from the Danish Cytogenetic Central Registry.
Results
From 1973 to 1993, screening based on maternal age and high‐risk indications resulted in a constant increase in invasive procedures. After the introduction of the triple test in 1994, invasive procedures decreased for the first time in 20 years. Following the introduction of an offer of combined screening to all pregnant women in 2004, the number of invasive procedures decreased markedly, while there was a concurrent increase in prenatal diagnoses of Down syndrome. Additionally, the number of Down syndrome live births decreased suddenly and significantly, but subsequently stabilized at 23–35 annual live births. Of these, the majority were diagnosed postnatally.
Conclusion
Though prenatal screening technologies constantly improve, it was the introduction of and adherence to national guidelines that resulted in marked shifts in screening procedures and outcome in Denmark.
Objective
This study aimed to assess the diagnostic yield of prenatal genetic testing using trio whole exome sequencing (WES) and trio whole genome sequencing (WGS) in pregnancies with fetal ...anomalies by comparing the results with conventional chromosomal microarray (CMA) analysis.
Methods
A total of 40 pregnancies with fetal anomalies or increased nuchal translucency (NT ≥ 5 mm) were included between the 12th and 21st week of gestation. Trio WES/WGS and CMA were performed in all cases.
Results
The trio WES/WGS analysis increased the diagnostic yield by 25% in cases with negative CMA results. Furthermore, all six chromosomal aberrations identified by CMA were independently detected by WES/WGS analysis. In total, 16 out of 40 cases obtained a genetic sequence variant, copy number variant, or aneuploidy explaining the phenotype, resulting in an overall WES/WGS diagnostic yield of 40%. WES analysis provided a more reliable identification of mosaic sequence variants than WGS because of its higher sequencing depth.
Conclusions
Prenatal WES/WGS proved to be powerful diagnostic tools for fetal anomalies, surpassing the diagnostic yield of CMA. They have the potential to serve as standalone methods for prenatal diagnosis. The study highlighted the limitations of WGS in accurately detecting mosaic variants, which is particularly relevant when analyzing chorionic villus samples.
Key points
What's already known about this topic?
Whole exome or genome sequencing (WES/WGS) increases the diagnostic yield compared to chromosomal microarray (CMA) alone.
Confined placental mosaicism (CPM) is observed at the sequence level, which may provide ambiguous results in CVS WES/WGS analysis.
What does this study add?
WES/WGS can be a stand‐alone prenatal test detecting both sequence variants and CNVs as well as chromosomal aneuploidies.
WES outperforms WGS in identifying mosaic sequence variants prenatally with high accuracy due to higher sequencing depth.
The study highlights the limitations of WGS in detecting mosaic variants compared with WES.
The RNA polymerase II complex (pol II) is responsible for transcription of all ∼21,000 human protein-encoding genes. Here, we describe sixteen individuals harboring de novo heterozygous variants in ...POLR2A, encoding RPB1, the largest subunit of pol II. An iterative approach combining structural evaluation and mass spectrometry analyses, the use of S. cerevisiae as a model system, and the assessment of cell viability in HeLa cells allowed us to classify eleven variants as probably disease-causing and four variants as possibly disease-causing. The significance of one variant remains unresolved. By quantification of phenotypic severity, we could distinguish mild and severe phenotypic consequences of the disease-causing variants. Missense variants expected to exert only mild structural effects led to a malfunctioning pol II enzyme, thereby inducing a dominant-negative effect on gene transcription. Intriguingly, individuals carrying these variants presented with a severe phenotype dominated by profound infantile-onset hypotonia and developmental delay. Conversely, individuals carrying variants expected to result in complete loss of function, thus reduced levels of functional pol II from the normal allele, exhibited the mildest phenotypes. We conclude that subtle variants that are central in functionally important domains of POLR2A cause a neurodevelopmental syndrome characterized by profound infantile-onset hypotonia and developmental delay through a dominant-negative effect on pol-II-mediated transcription of DNA.
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