Objective
About 3% of newborns show malformations, with about 20% of the affected having genetic causes. Clarification of genetic diseases in postnatal diagnostics was significantly improved with ...high‐throughput sequencing, in particular through whole exome sequencing covering all protein‐coding regions. Here, we aim to extend the use of this technology to prenatal diagnostics.
Method
Between 07/2018 and 10/2020, 500 pregnancies with fetal ultrasound abnormalities were analyzed after genetic counseling as part of prenatal diagnostics using WES of the fetus and parents.
Results
Molecular genetic findings could explain ultrasound abnormalities in 38% of affected fetuses. In 47% of these, disease‐causing de novo variants were found. Pathogenic variants in genes with autosomal recessive or X‐linked inheritance were detected in more than one‐third (70/189 = 37%). The latter are associated with increased probability of recurrence, making their detection important for further pregnancies. Average time from sample receipt to report was 12 days in the recent cases.
Conclusion
Trio exome sequencing is a useful addition to prenatal diagnostics due to its high diagnostic yield and short processing time (comparable to chromosome analysis). It covers a wide spectrum of genetic changes. Comprehensive interdisciplinary counseling before and after diagnostics is indispensable.
Key points
What's already known about this topic?
It is known that about 20% of malformations in newborns can be associated with genetic causes.
Whole‐exome sequencing, and especially trio exome sequencing, is an established and successful method in postnatal genetic diagnostics. Diagnostic yield for trio exome sequencing is around 37%.
What does this study add?
We show that trio exome sequencing is a fast and comprehensive method in prenatal diagnostics with diagnostic yield similar to that of postnatal trio exome sequencing.
We provide case solution rates for different phenotypic observations from 19% for abnormalities of internal organs up to 52% for skeletal malformations.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The genomic and clinical landscape of fetal akinesia Pergande, Matthias; Motameny, Susanne; Özdemir, Özkan ...
Genetics in medicine,
March 2020, 2020-03-00, 20200301, 2020-03-01, Volume:
22, Issue:
3
Journal Article
Peer reviewed
Open access
Fetal akinesia has multiple clinical subtypes with over 160 gene associations, but the genetic etiology is not yet completely understood.
In this study, 51 patients from 47 unrelated families were ...analyzed using next-generation sequencing (NGS) techniques aiming to decipher the genomic landscape of fetal akinesia (FA).
We have identified likely pathogenic gene variants in 37 cases and report 41 novel variants. Additionally, we report putative pathogenic variants in eight cases including nine novel variants. Our work identified 14 novel disease–gene associations for fetal akinesia: ADSSL1, ASAH1, ASPM, ATP2B3,EARS2, FBLN1, PRG4, PRICKLE1, ROR2, SETBP1, SCN5A, SCN8A, and ZEB2. Furthermore, a sibling pair harbored a homozygous copy-number variant inTNNT1, an ultrarare congenital myopathy gene that has been linked to arthrogryposis via Gene Ontology analysis.
Our analysis indicates that genetic defects leading to primary skeletal muscle diseases might have been underdiagnosed, especially pathogenic variants in RYR1. We discuss three novel putative fetal akinesia genes: GCN1,IQSEC3 and RYR3. Of those, IQSEC3, andRYR3 had been proposed as neuromuscular disease–associated genes recently, and our findings endorse them as FA candidate genes. By combining NGS with deep clinical phenotyping, we achieved a 73% success rate of solved cases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
•Locus heterogeneity in neurodevelopmental disorders complicates genetic diagnosis.•We report phenotypically similar siblings with intra-familial locus heterogeneity.•Comprehensive genetics may ...overcome the diagnostic pitfall of locus heterogeneity.
Correct diagnosis of children presenting with developmental delay and intellectual disability remains challenging due to the complex and heterogeneous etiology. High throughput sequencing technologies like exome sequencing have become more commonly available and are significantly improving genetic testing. We present two siblings – a 14-year old male and an 8-year old female patient – with a similar clinical phenotype that was characterized by combined developmental delay primarily affecting speech, mild to moderate intellectual disability, behavioral abnormalities, and autism spectrum disorder, but with no congenital anomalies. The sister showed additional muscular hypotonia and more pronounced dysmorphic features compared to her brother. Both parents had psychiatric disorders and mild to moderate intellectual disability. A common genetic etiology in the siblings was suspected. Metabolic, psychological and neuroradiological examinations were complemented by basic genetic testing including chromosome analysis and array comparative genomics hybridization analysis (CGH), followed by exome sequencing and combined data analysis of the family. Exome sequencing identified two different underlying genetic conditions: in the sister, a maternally inherited pathogenic variant c.1661C > T, p.Pro554Leu in SLC6A8 (NM_005629.4) was identified causing cerebral creatine deficiency syndrome 1 (MIM #300352) which was confirmed by MR spectroscopy and treated accordingly. In the brother, a paternally inherited 16p13.11 duplication was identified by exome sequencing and considered to be likely associated with his and possibly his father’s phenotype. The 16p13.11 duplication had been previously identified in an array CGH but had not been prioritized due to the lack of segregation in the siblings. In conclusion, we report a case of intra-familial locus heterogeneity of developmental delay in two siblings. We advocate for the need of unbiased and comprehensive genetic testing to provide accurate diagnosis despite locus heterogeneity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Dystonia is a prevalent, heterogeneous movement disorder characterized by involuntarily abnormal postures. Biomarkers of dystonia are notoriously lacking. Here, a biomarker is reported for histone ...lysine methyltransferase (KMT2B)-deficient dystonia, a leading subtype among the individually rare monogenic dystonias. It was derived by applying a support vector machine to an episignature of 113 DNA CpG sites, which, in blood cells, showed significant epigenome-wide association with KMT2B deficiency and at least 1× log-fold change of methylation. This classifier was accurate both when tested on the general population and on samples with various other deficiencies of the epigenetic machinery, thus allowing for definitive evaluation of variants of uncertain significance and identifying patients who may profit from deep brain stimulation, a highly successful treatment in KMT2B-deficient dystonia. Methylation was increased in KMT2B deficiency at all 113 CpG sites. The coefficients of variation of the normalized methylation levels at these sites also perfectly classified the samples with KMT2B-deficient dystonia. Moreover, the mean of the normalized methylation levels correlated well with the age at onset of dystonia (P = 0.003)-being lower in samples with late or incomplete penetrance-thus serving as a predictor of disease onset and severity. Similarly, it may also function in monitoring the recently envisioned treatment of KMT2B deficiency by inhibition of DNA methylation.
Individuals with autism spectrum disorder (ASD) exhibit an increased burden of de novo mutations (DNMs) in a broadening range of genes. While these studies have implicated hundreds of genes in ASD ...pathogenesis, which DNMs cause functional consequences in vivo remains unclear. We functionally test the effects of ASD missense DNMs using Drosophila through “humanization” rescue and overexpression-based strategies. We examine 79 ASD variants in 74 genes identified in the Simons Simplex Collection and find 38% of them to cause functional alterations. Moreover, we identify GLRA2 as the cause of a spectrum of neurodevelopmental phenotypes beyond ASD in 13 previously undiagnosed subjects. Functional characterization of variants in ASD candidate genes points to conserved neurobiological mechanisms and facilitates gene discovery for rare neurodevelopmental diseases.
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•We generate and characterize >300 (TG4 and cDNA) Drosophila mutants and transgenics•Humanization and overexpression strategies to functionally assess ASD variants in vivo•ASD variant data in flies help identify GLRA2-related neurodevelopmental disorders•Basic and clinical collaboration facilitates variant testing and disease gene discovery
Marcogliese et al. generate >300 Drosophila mutants and use complementary rescue-based and overexpression approaches to study the function of de novo missense variants found in autism. They find that 38% of missense changes have functional consequences and identify variants in GLRA2 that cause a variable neurological disorder.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Objective
Epilepsy is common in patients with PIGN diseases due to biallelic variants; however, limited epilepsy phenotyping data have been reported. We describe the epileptology of PIGN ...encephalopathy.
Methods
We recruited patients with epilepsy due to biallelic PIGN variants and obtained clinical data regarding age at seizure onset/offset and semiology, development, medical history, examination, electroencephalogram, neuroimaging, and treatment. Seizure and epilepsy types were classified.
Results
Twenty six patients (13 female) from 26 families were identified, with mean age 7 years (range = 1 month to 21 years; three deceased). Abnormal development at seizure onset was present in 25 of 26. Developmental outcome was most frequently profound (14/26) or severe (11/26). Patients presented with focal motor (12/26), unknown onset motor (5/26), focal impaired awareness (1/26), absence (2/26), myoclonic (2/26), myoclonic–atonic (1/26), and generalized tonic–clonic (2/26) seizures. Twenty of 26 were classified as developmental and epileptic encephalopathy (DEE): 55% (11/20) focal DEE, 30% (6/20) generalized DEE, and 15% (3/20) combined DEE. Six had intellectual disability and epilepsy (ID+E): two generalized and four focal epilepsy. Mean age at seizure onset was 13 months (birth to 10 years), with a lower mean onset in DEE (7 months) compared with ID+E (33 months). Patients with DEE had drug‐resistant epilepsy, compared to 4/6 ID+E patients, who were seizure‐free. Hyperkinetic movement disorder occurred in 13 of 26 patients. Twenty‐seven of 34 variants were novel. Variants were truncating (n = 7), intronic and predicted to affect splicing (n = 7), and missense or inframe indels (n = 20, of which 11 were predicted to affect splicing). Seven variants were recurrent, including p.Leu311Trp in 10 unrelated patients, nine with generalized seizures, accounting for nine of the 11 patients in this cohort with generalized seizures.
Significance
PIGN encephalopathy is a complex autosomal recessive disorder associated with a wide spectrum of epilepsy phenotypes, typically with substantial profound to severe developmental impairment.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
PurposeFetal akinesia has multiple clinical subtypes with over 160 gene associations, but the genetic etiology is not yet completely understood.MethodsIn this study, 51 patients from 47 unrelated ...families were analyzed using next-generation sequencing (NGS) techniques aiming to decipher the genomic landscape of fetal akinesia (FA).ResultsWe have identified likely pathogenic gene variants in 37 cases and report 41 novel variants. Additionally, we report putative pathogenic variants in eight cases including nine novel variants. Our work identified 14 novel disease–gene associations for fetal akinesia: ADSSL1, ASAH1, ASPM, ATP2B3,EARS2, FBLN1, PRG4, PRICKLE1, ROR2, SETBP1, SCN5A, SCN8A, and ZEB2. Furthermore, a sibling pair harbored a homozygous copy-number variant inTNNT1, an ultrarare congenital myopathy gene that has been linked to arthrogryposis via Gene Ontology analysis.ConclusionOur analysis indicates that genetic defects leading to primary skeletal muscle diseases might have been underdiagnosed, especially pathogenic variants in RYR1. We discuss three novel putative fetal akinesia genes: GCN1,IQSEC3 and RYR3. Of those, IQSEC3, andRYR3 had been proposed as neuromuscular disease–associated genes recently, and our findings endorse them as FA candidate genes. By combining NGS with deep clinical phenotyping, we achieved a 73% success rate of solved cases.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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