Publications by authors named "Christina Fagerberg"

49 Publications

Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders.

Genome Med 2021 Apr 19;13(1):63. Epub 2021 Apr 19.

The Atwal Clinic: Genomic & Personalized Medicine, Jacksonville, FL, USA.

Background: With the increasing number of genomic sequencing studies, hundreds of genes have been implicated in neurodevelopmental disorders (NDDs). The rate of gene discovery far outpaces our understanding of genotype-phenotype correlations, with clinical characterization remaining a bottleneck for understanding NDDs. Most disease-associated Mendelian genes are members of gene families, and we hypothesize that those with related molecular function share clinical presentations.

Methods: We tested our hypothesis by considering gene families that have multiple members with an enrichment of de novo variants among NDDs, as determined by previous meta-analyses. One of these gene families is the heterogeneous nuclear ribonucleoproteins (hnRNPs), which has 33 members, five of which have been recently identified as NDD genes (HNRNPK, HNRNPU, HNRNPH1, HNRNPH2, and HNRNPR) and two of which have significant enrichment in our previous meta-analysis of probands with NDDs (HNRNPU and SYNCRIP). Utilizing protein homology, mutation analyses, gene expression analyses, and phenotypic characterization, we provide evidence for variation in 12 HNRNP genes as candidates for NDDs. Seven are potentially novel while the remaining genes in the family likely do not significantly contribute to NDD risk.

Results: We report 119 new NDD cases (64 de novo variants) through sequencing and international collaborations and combined with published clinical case reports. We consider 235 cases with gene-disruptive single-nucleotide variants or indels and 15 cases with small copy number variants. Three hnRNP-encoding genes reach nominal or exome-wide significance for de novo variant enrichment, while nine are candidates for pathogenic mutations. Comparison of HNRNP gene expression shows a pattern consistent with a role in cerebral cortical development with enriched expression among radial glial progenitors. Clinical assessment of probands (n = 188-221) expands the phenotypes associated with HNRNP rare variants, and phenotypes associated with variation in the HNRNP genes distinguishes them as a subgroup of NDDs.

Conclusions: Overall, our novel approach of exploiting gene families in NDDs identifies new HNRNP-related disorders, expands the phenotypes of known HNRNP-related disorders, strongly implicates disruption of the hnRNPs as a whole in NDDs, and supports that NDD subtypes likely have shared molecular pathogenesis. To date, this is the first study to identify novel genetic disorders based on the presence of disorders in related genes. We also perform the first phenotypic analyses focusing on related genes. Finally, we show that radial glial expression of these genes is likely critical during neurodevelopment. This is important for diagnostics, as well as developing strategies to best study these genes for the development of therapeutics.
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http://dx.doi.org/10.1186/s13073-021-00870-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056596PMC
April 2021

Total number of reads affects the accuracy of fetal fraction estimates in NIPT.

Mol Genet Genomic Med 2021 Mar 9:e1653. Epub 2021 Mar 9.

Clinical Genome Center & Human Genetics, Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.

Background: Sufficient fetal fraction (FF) is crucial for quality control of NIPT (Non-Invasive Prenatal Test) results. Different factors influencing bioinformatic estimation of FF should be considered when implementing NIPT. To what extent the total number of sequencing reads influences FF estimate has been unexplored. In this study, to test the robustness of SeqFF FF estimation and provide additional recommendations for NIPT analysis quality control, we compared the SeqFF FF estimates with two other methods and investigated how the number of sequencing reads and FF level affects the accuracy and precision of FF estimates.

Methods: WGS data of 516 NIPT samples from a prenatal screening program was obtained. Sample data were randomly downsampled by the read count, and FF was calculated by SeqFF software. Then, the outcome was compared with FF estimates from SNP- and chrY-based methods. FF estimated with different read counts and FF levels were compared with FF at 30 M reads as a reference.

Results: SeqFF FF highly correlates with SNP- and chrY-based FF estimates. Raising read count from 2 M to 10 M drastically increased the accuracy of FF estimates. After adding more reads, we saw a further improvement in FF accuracy, reaching a plateau at 20 M reads. Precision of SeqFF FF estimate is independent of FF level in the sample.

Conclusion: SeqFF is a robust method for FF estimation for both genders and for any FF level in range 2-13%. Accuracy of FF estimates highly depends on the read count. We recommend using no less than 10 M reads to achieve accurate FF estimates for NIPT analysis in clinical settings.
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http://dx.doi.org/10.1002/mgg3.1653DOI Listing
March 2021

Disruption of RFX family transcription factors causes autism, attention-deficit/hyperactivity disorder, intellectual disability, and dysregulated behavior.

Genet Med 2021 Mar 3. Epub 2021 Mar 3.

Division of Medical Genetics, Nemours/A.I. DuPont Hospital for Children, Wilmington, DE, USA.

Purpose: We describe a novel neurobehavioral phenotype of autism spectrum disorder (ASD), intellectual disability, and/or attention-deficit/hyperactivity disorder (ADHD) associated with de novo or inherited deleterious variants in members of the RFX family of genes. RFX genes are evolutionarily conserved transcription factors that act as master regulators of central nervous system development and ciliogenesis.

Methods: We assembled a cohort of 38 individuals (from 33 unrelated families) with de novo variants in RFX3, RFX4, and RFX7. We describe their common clinical phenotypes and present bioinformatic analyses of expression patterns and downstream targets of these genes as they relate to other neurodevelopmental risk genes.

Results: These individuals share neurobehavioral features including ASD, intellectual disability, and/or ADHD; other frequent features include hypersensitivity to sensory stimuli and sleep problems. RFX3, RFX4, and RFX7 are strongly expressed in developing and adult human brain, and X-box binding motifs as well as RFX ChIP-seq peaks are enriched in the cis-regulatory regions of known ASD risk genes.

Conclusion: These results establish a likely role of deleterious variation in RFX3, RFX4, and RFX7 in cases of monogenic intellectual disability, ADHD and ASD, and position these genes as potentially critical transcriptional regulators of neurobiological pathways associated with neurodevelopmental disease pathogenesis.
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http://dx.doi.org/10.1038/s41436-021-01114-zDOI Listing
March 2021

Histone H3.3 beyond cancer: Germline mutations in cause a previously unidentified neurodegenerative disorder in 46 patients.

Sci Adv 2020 Dec 2;6(49). Epub 2020 Dec 2.

Institut für Neurogenomik, Helmholtz Zentrum München, Munich, Germany.

Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A () or with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of all 37 variants demonstrated clear disruptions in interactions with DNA, other histones, and histone chaperone proteins. Patient histone posttranslational modifications (PTMs) analysis revealed notably aberrant local PTM patterns distinct from the somatic lysine mutations that cause global PTM dysregulation. RNA sequencing on patient cells demonstrated up-regulated gene expression related to mitosis and cell division, and cellular assays confirmed an increased proliferative capacity. A zebrafish model showed craniofacial anomalies and a defect in Foxd3-derived glia. These data suggest that the mechanism of germline mutations are distinct from cancer-associated somatic histone mutations but may converge on control of cell proliferation.
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http://dx.doi.org/10.1126/sciadv.abc9207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821880PMC
December 2020

Trisomy 8 mosaicism in the placenta: A Danish cohort study of 37 cases and a literature review.

Prenat Diagn 2021 Mar 18;41(4):409-421. Epub 2020 Dec 18.

Center for Fetal Diagnostics, Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark.

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.
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http://dx.doi.org/10.1002/pd.5875DOI Listing
March 2021

National data on the early clinical use of non-invasive prenatal testing in public and private healthcare in Denmark 2013-2017.

Acta Obstet Gynecol Scand 2021 May 24;100(5):884-892. Epub 2021 Feb 24.

Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark.

Introduction: In Denmark, non-invasive prenatal testing (NIPT) has been used since 2013. We aimed to evaluate the early clinical use of NIPT in Danish public and private healthcare settings before NIPT became an integrated part of the national guidelines on prenatal screening and diagnosis in 2017.

Material And Methods: NIPT data were collected between March 2013 and June 2017 from national public registries and private providers. Results from follow-up samples (chorionic villi, amniotic fluid, postnatal blood or fetal tissue) were included from The Danish Cytogenetics Central Registry and indications and outcome from The Danish Fetal Medicine Database.

Results: A total of 3936 NIPT results were included in the study from public hospitals (n = 3463, 88.0%) and private clinics (n = 473, 12.0%). The total number of prenatal tests was 19 713 during the study period: 20% were NIPT analyses (n = 3936) and 80% invasive procedures (n = 15 777). Twenty-five percent of NIPTs in the private clinics were performed before gestational week 11 , whereas NIPT in public settings was used only after combined first trimester screening (P < .001). Regardless of indication, the national public sensitivity was 96.9% (95% CI 82.0%-99.8%) for trisomy 21, 100% (95% CI 46.3%-100%) for trisomy 18, 100% (95% CI 5.5%-100%) for trisomy 13, and 87.0% (95% CI 74.5%-92.4%) for any fetal chromosomal aberration. Forty-seven true-positive NIPT results included cases of common aneuplodies (trisomy 21, n = 31; trisomy 18, n = 5; and trisomy 13, n = 1), sex chromosomal aberrations (n = 7) and atypical chromosomal aberrations (n = 3). One false-negative NIPT result occurred (trisomy 21). Of 47 cases, 21 (45%) cases with a true-positive NIPT result resulted in live births by choice; 11 of these children had Down and 4 had Edwards syndrome.

Conclusions: The total number of NIPT analyses was low compared with the number of invasive procedures in the implementation period. In contrast to the generally high termination rate after a positive result following invasive testing in Denmark, a high proportion of true-positive NIPT results from the public setting resulted in live births. NIPT may be an important risk-free alternative to invasive testing for a minority of women in the public setting who wish to use prenatal genetic testing for information only and not for reproductive decision-making.
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http://dx.doi.org/10.1111/aogs.14052DOI Listing
May 2021

NCKAP1 Disruptive Variants Lead to a Neurodevelopmental Disorder with Core Features of Autism.

Am J Hum Genet 2020 11;107(5):963-976

Service of Endocrinology, Diabetology, and Metabolism, Lausanne University Hospital, Lausanne 1011, Switzerland.

NCKAP1/NAP1 regulates neuronal cytoskeletal dynamics and is essential for neuronal differentiation in the developing brain. Deleterious variants in NCKAP1 have been identified in individuals with autism spectrum disorder (ASD) and intellectual disability; however, its clinical significance remains unclear. To determine its significance, we assemble genotype and phenotype data for 21 affected individuals from 20 unrelated families with predicted deleterious variants in NCKAP1. This includes 16 individuals with de novo (n = 8), transmitted (n = 6), or inheritance unknown (n = 2) truncating variants, two individuals with structural variants, and three with potentially disruptive de novo missense variants. We report a de novo and ultra-rare deleterious variant burden of NCKAP1 in individuals with neurodevelopmental disorders which needs further replication. ASD or autistic features, language and motor delay, and variable expression of intellectual or learning disability are common clinical features. Among inherited cases, there is evidence of deleterious variants segregating with neuropsychiatric disorders. Based on available human brain transcriptomic data, we show that NCKAP1 is broadly and highly expressed in both prenatal and postnatal periods and demostrate enriched expression in excitatory neurons and radial glias but depleted expression in inhibitory neurons. Mouse in utero electroporation experiments reveal that Nckap1 loss of function promotes neuronal migration during early cortical development. Combined, these data support a role for disruptive NCKAP1 variants in neurodevelopmental delay/autism, possibly by interfering with neuronal migration early in cortical development.
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http://dx.doi.org/10.1016/j.ajhg.2020.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674997PMC
November 2020

Bi-allelic Loss-of-Function Variants in NUP188 Cause a Recognizable Syndrome Characterized by Neurologic, Ocular, and Cardiac Abnormalities.

Am J Hum Genet 2020 05 9;106(5):623-631. Epub 2020 Apr 9.

Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA 98195, USA; Seattle Children's Hospital, Seattle, WA 98105, USA; Brotman Baty Institute for Precision Medicine, Seattle, WA 98195, USA. Electronic address:

Nucleoporins (NUPs) are an essential component of the nuclear-pore complex, which regulates nucleocytoplasmic transport of macromolecules. Pathogenic variants in NUP genes have been linked to several inherited human diseases, including a number with progressive neurological degeneration. We present six affected individuals with bi-allelic truncating variants in NUP188 and strikingly similar phenotypes and clinical courses, representing a recognizable genetic syndrome; the individuals are from four unrelated families. Key clinical features include congenital cataracts, hypotonia, prenatal-onset ventriculomegaly, white-matter abnormalities, hypoplastic corpus callosum, congenital heart defects, and central hypoventilation. Characteristic dysmorphic features include small palpebral fissures, a wide nasal bridge and nose, micrognathia, and digital anomalies. All affected individuals died as a result of respiratory failure, and five of them died within the first year of life. Nuclear import of proteins was decreased in affected individuals' fibroblasts, supporting a possible disease mechanism. CRISPR-mediated knockout of NUP188 in Drosophila revealed motor deficits and seizure susceptibility, partially recapitulating the neurological phenotype seen in affected individuals. Removal of NUP188 also resulted in aberrant dendrite tiling, suggesting a potential role of NUP188 in dendritic development. Two of the NUP188 pathogenic variants are enriched in the Ashkenazi Jewish population in gnomAD, a finding we confirmed with a separate targeted population screen of an international sampling of 3,225 healthy Ashkenazi Jewish individuals. Taken together, our results implicate bi-allelic loss-of-function NUP188 variants in a recessive syndrome characterized by a distinct neurologic, ophthalmologic, and facial phenotype.
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http://dx.doi.org/10.1016/j.ajhg.2020.03.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212259PMC
May 2020

A new 1p36.13-1p36.12 microdeletion syndrome characterized by learning disability, behavioral abnormalities, and ptosis.

Clin Genet 2020 06 1;97(6):927-932. Epub 2020 Apr 1.

Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.

Two 1p36 contiguous gene deletion syndromes are known so far: the terminal 1p36 deletion syndrome and a 1p36 deletion syndrome with a critical region located more proximal at 1p36.23-1p36.22. We present even more proximally located overlapping deletions from seven individuals, with the smallest region of overlap comprising 1 Mb at 1p36.13-1p36.12 (chr1:19077793-20081292 (GRCh37/hg19)) defining a new contiguous gene deletion syndrome. The characteristic features of this new syndrome are learning disability or mild intellectual disability, speech delay, behavioral abnormalities, and ptosis. The genes UBR4 and CAPZB are considered the most likely candidate genes for the features of this new syndrome.
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http://dx.doi.org/10.1111/cge.13739DOI Listing
June 2020

Novel phenotype of syndromic premature ovarian insufficiency associated with TP63 molecular defect.

Clin Genet 2020 05 24;97(5):779-784. Epub 2020 Feb 24.

Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.

There is growing evidence that TP63 is associated with isolated as well as syndromic premature ovarian insufficiency (POI). We report two adolescent sisters diagnosed with undetectable ovaries, uterine hypoplasia, and mammary gland hypoplasia. A novel paternally inherited nonsense variant in TP63 [NM_003722.4 c.1927C > T,p.(Arg643*)] in exon 14 was identified by exome sequencing. One of the syndromes linked to TP63 is limb mammary syndrome (LMS), an autosomal dominant inherited disorder characterized by ectrodactyly, hypoplasia of mammary-gland and nipple, lacrimal duct stenosis, nail dysplasia, dental anomalies, cleft palate and/or cleft lip and absence of skin and hair defects. The TP63 variant segregated with symptoms of LMS in the family, however, no affected individual had limb defects. The phenotype reported here represents a novel syndromic phenotype associated with TP63. Reported cases with TP63 associated POI are reviewed.
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http://dx.doi.org/10.1111/cge.13725DOI Listing
May 2020

Choline transporter-like 1 deficiency causes a new type of childhood-onset neurodegeneration.

Brain 2020 01;143(1):94-111

Department of Human Health and Nutritional Sciences, University of Guelph, Canada.

Cerebral choline metabolism is crucial for normal brain function, and its homoeostasis depends on carrier-mediated transport. Here, we report on four individuals from three families with neurodegenerative disease and homozygous frameshift mutations (Asp517Metfs*19, Ser126Metfs*8, and Lys90Metfs*18) in the SLC44A1 gene encoding choline transporter-like protein 1. Clinical features included progressive ataxia, tremor, cognitive decline, dysphagia, optic atrophy, dysarthria, as well as urinary and bowel incontinence. Brain MRI demonstrated cerebellar atrophy and leukoencephalopathy. Moreover, low signal intensity in globus pallidus with hyperintensive streaking and low signal intensity in substantia nigra were seen in two individuals. The Asp517Metfs*19 and Ser126Metfs*8 fibroblasts were structurally and functionally indistinguishable. The most prominent ultrastructural changes of the mutant fibroblasts were reduced presence of free ribosomes, the appearance of elongated endoplasmic reticulum and strikingly increased number of mitochondria and small vesicles. When chronically treated with choline, those characteristics disappeared and mutant ultrastructure resembled healthy control cells. Functional analysis revealed diminished choline transport yet the membrane phosphatidylcholine content remained unchanged. As part of the mechanism to preserve choline and phosphatidylcholine, choline transporter deficiency was implicated in impaired membrane homeostasis of other phospholipids. Choline treatments could restore the membrane lipids, repair cellular organelles and protect mutant cells from acute iron overload. In conclusion, we describe a novel childhood-onset neurometabolic disease caused by choline transporter deficiency with autosomal recessive inheritance.
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http://dx.doi.org/10.1093/brain/awz376DOI Listing
January 2020

[Endometrioid adenocarcinoma with a co-existing non-gestational choriocarcinoma in uterus].

Ugeskr Laeger 2019 Nov;181(47)

This is a case report of a 56-year-old woman with a history of postmenopausal bleeding, who presented with an endometrioid adenocarcinoma and a co-existing non-gestational choriocarcinoma. We performed robotic assisted hysterectomy, bilateral oophorectomy and pelvic lymphadectomy, and histopathologic examination revealed a malignant tumour showing an endometrioid adenocarcinoma grade 2 with a minor component of choriocarcinoma incorporated into the adenocarcinoma. We compared data from exome sequencing of DNA from tumour and blood to show, that the choriocarcinoma component was most likely non-gestational.
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November 2019

De Novo Missense Variants in FBXW11 Cause Diverse Developmental Phenotypes Including Brain, Eye, and Digit Anomalies.

Am J Hum Genet 2019 09 8;105(3):640-657. Epub 2019 Aug 8.

Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.

The identification of genetic variants implicated in human developmental disorders has been revolutionized by second-generation sequencing combined with international pooling of cases. Here, we describe seven individuals who have diverse yet overlapping developmental anomalies, and who all have de novo missense FBXW11 variants identified by whole exome or whole genome sequencing and not reported in the gnomAD database. Their phenotypes include striking neurodevelopmental, digital, jaw, and eye anomalies, and in one individual, features resembling Noonan syndrome, a condition caused by dysregulated RAS signaling. FBXW11 encodes an F-box protein, part of the Skp1-cullin-F-box (SCF) ubiquitin ligase complex, involved in ubiquitination and proteasomal degradation and thus fundamental to many protein regulatory processes. FBXW11 targets include β-catenin and GLI transcription factors, key mediators of Wnt and Hh signaling, respectively, critical to digital, neurological, and eye development. Structural analyses indicate affected residues cluster at the surface of the loops of the substrate-binding domain of FBXW11, and the variants are predicted to destabilize the protein and/or its interactions. In situ hybridization studies on human and zebrafish embryonic tissues demonstrate FBXW11 is expressed in the developing eye, brain, mandibular processes, and limb buds or pectoral fins. Knockdown of the zebrafish FBXW11 orthologs fbxw11a and fbxw11b resulted in embryos with smaller, misshapen, and underdeveloped eyes and abnormal jaw and pectoral fin development. Our findings support the role of FBXW11 in multiple developmental processes, including those involving the brain, eye, digits, and jaw.
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http://dx.doi.org/10.1016/j.ajhg.2019.07.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731360PMC
September 2019

De Novo Heterozygous POLR2A Variants Cause a Neurodevelopmental Syndrome with Profound Infantile-Onset Hypotonia.

Am J Hum Genet 2019 08 25;105(2):283-301. Epub 2019 Jul 25.

Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Oncode Institute, 3584 CT Utrecht, the Netherlands.

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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http://dx.doi.org/10.1016/j.ajhg.2019.06.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6699192PMC
August 2019

PEDIA: prioritization of exome data by image analysis.

Genet Med 2019 12 5;21(12):2807-2814. Epub 2019 Jun 5.

National Research and Applied Medicine Centre 'Mother and Child'', Minsk, Belarus.

Purpose: Phenotype information is crucial for the interpretation of genomic variants. So far it has only been accessible for bioinformatics workflows after encoding into clinical terms by expert dysmorphologists.

Methods: Here, we introduce an approach driven by artificial intelligence that uses portrait photographs for the interpretation of clinical exome data. We measured the value added by computer-assisted image analysis to the diagnostic yield on a cohort consisting of 679 individuals with 105 different monogenic disorders. For each case in the cohort we compiled frontal photos, clinical features, and the disease-causing variants, and simulated multiple exomes of different ethnic backgrounds.

Results: The additional use of similarity scores from computer-assisted analysis of frontal photos improved the top 1 accuracy rate by more than 20-89% and the top 10 accuracy rate by more than 5-99% for the disease-causing gene.

Conclusion: Image analysis by deep-learning algorithms can be used to quantify the phenotypic similarity (PP4 criterion of the American College of Medical Genetics and Genomics guidelines) and to advance the performance of bioinformatics pipelines for exome analysis.
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http://dx.doi.org/10.1038/s41436-019-0566-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6892739PMC
December 2019

A novel PDGFRB sequence variant in a family with a mild form of primary familial brain calcification: a case report and a review of the literature.

BMC Neurol 2019 Apr 12;19(1):60. Epub 2019 Apr 12.

Department of Clinical Genetics, Odense University Hospital, J. B. Winsløvs Vej 4, DK-5000, Odense, Denmark.

Background: Primary familial brain calcification is a rare autosomal dominant or recessive neurodegenerative disease, characterized by bilateral brain calcifications in different areas of the brain. It is a clinically heterogeneous disease and patients are reported to exhibit a wide spectrum of neurological and psychiatric symptoms. Mutations in five genes have been identified so far including SLC20A2, PDGFRB, PDGFB, XPR1, and MYORG. PDGFRB encodes the platelet-derived growth factor receptor-beta, and is expressed in neurons, vascular smooth muscle cells and pericytes. Patients with a PDGFRB mutation seem to exhibit a milder phenotype and milder brain calcification on brain imaging than patients with SLC20A2 and PDGFB mutations. However, this is based on a few observations so far.

Case Presentation: We present a Danish family with bilateral brain calcifications and mild clinical symptoms of primary familial brain calcification, segregating with a novel PDGFRB sequence variant: c.1834G > A; p.(Gly612Arg), detected by whole exome sequencing. The variant results in physiochemical changes at the amino acid level, and affects a highly conserved nucleotide as well as amino acid. It is located in the tyrosine kinase domain of PDGFRβ. Segregation analysis and in silico analyses predicted the missense variant to be disease causing.

Conclusion: Our study confirms that PDGFRB mutation carriers in general have a mild clinical phenotype, and basal ganglia calcifications can be detected by a CT scan, also in asymptomatic mutation carriers.
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http://dx.doi.org/10.1186/s12883-019-1292-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6460731PMC
April 2019

Deletions and loss-of-function variants in TP63 associated with orofacial clefting.

Eur J Hum Genet 2019 07 8;27(7):1101-1112. Epub 2019 Mar 8.

Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.

We aimed to identify novel deletions and variants of TP63 associated with orofacial clefting (OFC). Copy number variants were assessed in three OFC families using microarray analysis. Subsequently, we analyzed TP63 in a cohort of 1072 individuals affected with OFC and 706 population-based controls using molecular inversion probes (MIPs). We identified partial deletions of TP63 in individuals from three families affected with OFC. In the OFC cohort, we identified several TP63 variants predicting to cause loss-of-function alleles, including a frameshift variant c.569_576del (p.(Ala190Aspfs*5)) and a nonsense variant c.997C>T (p.(Gln333*)) that introduces a premature stop codon in the DNA-binding domain. In addition, we identified the first missense variants in the oligomerization domain c.1213G>A (p.(Val405Met)), which occurred in individuals with OFC. This variant was shown to abrogate oligomerization of mutant p63 protein into oligomeric complexes, and therefore likely represents a loss-of-function allele rather than a dominant-negative. All of these variants were inherited from an unaffected parent, suggesting reduced penetrance of such loss-of-function alleles. Our data indicate that loss-of-function alleles in TP63 can also give rise to OFC as the main phenotype. We have uncovered the dosage-dependent functions of p63, which were previously rejected.
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http://dx.doi.org/10.1038/s41431-019-0370-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777535PMC
July 2019

Correction: The ARID1B spectrum in 143 patients: from nonsyndromic intellectual disability to Coffin-Siris syndrome.

Genet Med 2019 Sep;21(9):2160-2161

University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.

The original version of this Article contained an error in the spelling of the author Pleuntje J. van der Sluijs, which was incorrectly given as Eline (P. J.) van der Sluijs. This has now been corrected in both the PDF and HTML versions of the Article.
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http://dx.doi.org/10.1038/s41436-018-0368-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752317PMC
September 2019

Mosaic MECP2 variants in males with classical Rett syndrome features, including stereotypical hand movements.

Clin Genet 2019 03 7;95(3):403-408. Epub 2018 Dec 7.

Kennedy Center, Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

Rett syndrome is rarely suspected in males because of the X-linked dominant inheritance. In the literature, only six male patients have been reported with methyl-CpG-binding protein 2 (MECP2) mosaicism. Next-generation sequencing (NGS) methods have enabled better detection of somatic mosaicism compared to conventional Sanger sequencing; however, mosaics can still be difficult to detect. We present clinical and molecular findings in two males mosaic for a pathogenic MECP2 variant. Both have been reexamined using deep sequencing of DNA isolated from four different cell tissues (blood, muscle, fibroblasts and oral mucosa). Deep sequencing of the different tissues revealed that the variants were present in all tissues. In one patient, the molecular diagnosis could only be established by reexamination after a normal whole exome sequencing, and the other case is an example of reverse genetic diagnostics. Rett syndrome should be considered in males with neurodevelopmental delay and stereotypical hand movements. Subsequent to clinical diagnosis males should be investigated with NGS-based technologies of MECP2 with high read depth and a low threshold for variant calls. If the initial analysis on full blood derived DNA fails to confirm the suspicion, we recommend repeating the analysis on another tissue, preferentially fibroblasts to increase the diagnostic yield.
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http://dx.doi.org/10.1111/cge.13473DOI Listing
March 2019

The ARID1B spectrum in 143 patients: from nonsyndromic intellectual disability to Coffin-Siris syndrome.

Genet Med 2019 06 8;21(6):1295-1307. Epub 2018 Nov 8.

University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.

Purpose: Pathogenic variants in ARID1B are one of the most frequent causes of intellectual disability (ID) as determined by large-scale exome sequencing studies. Most studies published thus far describe clinically diagnosed Coffin-Siris patients (ARID1B-CSS) and it is unclear whether these data are representative for patients identified through sequencing of unbiased ID cohorts (ARID1B-ID). We therefore sought to determine genotypic and phenotypic differences between ARID1B-ID and ARID1B-CSS. In parallel, we investigated the effect of different methods of phenotype reporting.

Methods: Clinicians entered clinical data in an extensive web-based survey.

Results: 79 ARID1B-CSS and 64 ARID1B-ID patients were included. CSS-associated dysmorphic features, such as thick eyebrows, long eyelashes, thick alae nasi, long and/or broad philtrum, small nails and small or absent fifth distal phalanx and hypertrichosis, were observed significantly more often (p < 0.001) in ARID1B-CSS patients. No other significant differences were identified.

Conclusion: There are only minor differences between ARID1B-ID and ARID1B-CSS patients. ARID1B-related disorders seem to consist of a spectrum, and patients should be managed similarly. We demonstrated that data collection methods without an explicit option to report the absence of a feature (such as most Human Phenotype Ontology-based methods) tended to underestimate gene-related features.
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http://dx.doi.org/10.1038/s41436-018-0330-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752273PMC
June 2019

De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.

Am J Hum Genet 2018 11 18;103(5):666-678. Epub 2018 Oct 18.

Division of Genetics and Metabolism, Phoenix Children's Hospital, Phoenix, AZ 85016, USA.

Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on EEG, and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the α-subunit of the voltage-gated Ca2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. Most of the 14, partially recurring, variants cluster within the cytoplasmic ends of all four S6 segments, which form the presumed Ca2.3 channel activation gate. Functional analysis of several S6 variants revealed consistent gain-of-function effects comprising facilitated voltage-dependent activation and slowed inactivation. Another variant located in the domain II S4-S5 linker results in facilitated activation and increased current density. Five participants achieved seizure freedom on the anti-epileptic drug topiramate, which blocks R-type calcium channels. We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders.
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http://dx.doi.org/10.1016/j.ajhg.2018.09.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6216110PMC
November 2018

Homozygosity for Arg1142Gln causes congenital myopathy with variable disease expression.

Neurol Genet 2018 Oct 19;4(5):e267. Epub 2018 Sep 19.

Department of Neurology (C.K.S., D.G.), Odense University Hospital; and Department of Clinical Research (C.K.S., D.G.), Faculty of Health Sciences, University of Southern Denmark, Odense; Department of Biomedical Sciences (F.D., N.S., B.H.B.), Faculty of Health and Medical Sciences, University of Copenhagen; Department of Clinical Genetics (C.F.), Odense University Hospital; and Copenhagen Neuromuscular Center, Department of Neurology (J.V.), Rigshospitalet, University of Copenhagen, Denmark.

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http://dx.doi.org/10.1212/NXG.0000000000000267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6167177PMC
October 2018

Is MED13L-related intellectual disability a recognizable syndrome?

Eur J Med Genet 2019 Feb 27;62(2):129-136. Epub 2018 Jun 27.

Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.

Introduction: MED13L-related intellectual disability is characterized by moderate intellectual disability (ID), speech impairment, and dysmorphic facial features. We present 8 patients with MED13L-related intellectual disability and review the literature for phenotypical and genetic aspects of previously described patients.

Materials And Methods: In the search for genetic aberrations in individuals with ID, two of the patients were identified by chromosomal microarray analysis, and five by exome sequencing. One of the individuals, suspected of MED13L-related intellectual disability, based on clinical features, was identified by Sanger sequencing.

Results: All 8 individuals had de novo MED13L aberrations, including two intragenic microdeletions, two frameshift, three nonsense variants, and one missense variant. Phenotypically, they all had intellectual disability, speech and motor delay, and features of the mouth (open mouth appearance, macroglossia, and/or macrostomia). Two individuals were diagnosed with autism, and one had autistic features. One had complex congenital heart defect, and one had persistent foramen ovale. The literature was reviewed with respect to clinical and dysmorphic features, and genetic aberrations.

Conclusions: Even if most clinical features of MED13L-related intellectual disability are rather non-specific, the syndrome may be suspected in some individuals based on the association of developmental delay, speech impairment, bulbous nasal tip, and macroglossia, macrostomia, or open mouth appearance.
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http://dx.doi.org/10.1016/j.ejmg.2018.06.014DOI Listing
February 2019

Risks and Recommendations in Prenatally Detected De Novo Balanced Chromosomal Rearrangements from Assessment of Long-Term Outcomes.

Am J Hum Genet 2018 06 24;102(6):1090-1103. Epub 2018 May 24.

Wilhelm Johannsen Centre for Functional Genome Research, Department of Cellular and Molecular Medicine, University of Copenhagen, 2200 Copenhagen N, Denmark; Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, 2100 Copenhagen O, Denmark. Electronic address:

The 6%-9% risk of an untoward outcome previously established by Warburton for prenatally detected de novo balanced chromosomal rearrangements (BCRs) does not account for long-term morbidity. We performed long-term follow-up (mean 17 years) of a registry-based nationwide cohort of 41 individuals carrying a prenatally detected de novo BCR with normal first trimester screening/ultrasound scan. We observed a significantly higher frequency of neurodevelopmental and/or neuropsychiatric disorders than in a matched control group (19.5% versus 8.3%, p = 0.04), which was increased to 26.8% upon clinical follow-up. Chromosomal microarray of 32 carriers revealed no pathogenic imbalances, illustrating a low prognostic value when fetal ultrasound scan is normal. In contrast, mate-pair sequencing revealed disrupted genes (ARID1B, NPAS3, CELF4), regulatory domains of known developmental genes (ZEB2, HOXC), and complex BCRs associated with adverse outcomes. Seven unmappable autosomal-autosomal BCRs with breakpoints involving pericentromeric/heterochromatic regions may represent a low-risk group. We performed independent phenotype-aware and blinded interpretation, which accurately predicted benign outcomes (specificity = 100%) but demonstrated relatively low sensitivity for prediction of the clinical outcome in affected carriers (sensitivity = 45%-55%). This sensitivity emphasizes the challenges associated with prenatal risk prediction for long-term morbidity in the absence of phenotypic data given the still immature annotation of the morbidity genome and poorly understood long-range regulatory mechanisms. In conclusion, we upwardly revise the previous estimates of Warburton to a morbidity risk of 27% and recommend sequencing of the chromosomal breakpoints as the first-tier diagnostic test in pregnancies with a de novo BCR.
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http://dx.doi.org/10.1016/j.ajhg.2018.04.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5992120PMC
June 2018

Prostaglandin E -EP receptor subtype gene deletion in mother and son impairs platelet aggregation.

Br J Haematol 2019 03 13;184(5):851-853. Epub 2018 Mar 13.

Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark.

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http://dx.doi.org/10.1111/bjh.15196DOI Listing
March 2019

[Review of a new subtype of hereditary angio-oedema with normal complement C1-inhibitor].

Ugeskr Laeger 2018 02;180(6)

Hereditary angio-oedema (HAE) is a rare, potentially fatal disease characterized by recurrent swelling of skin and mucosa. Besides HAE with quantitative (type I) or qualitative (type II) deficiency of complement C1-inhibitor (C1-INH), a new subtype of HAE is now described with normal levels of C1-INH. This subtype is possibly underdiagnosed, and a treatment regimen and general knowledge about the condition is still in its infancy. The purpose of this article is to inform Danish doctors about the disease to identify more Danish patients.
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February 2018

Chromosomal Aberrations in Monozygotic and Dizygotic Twins Versus Singletons in Denmark During 1968-2009.

Twin Res Hum Genet 2017 06 9;20(3):216-225. Epub 2017 May 9.

Department of Clinical Genetics,Odense University Hospital,Odense C,Denmark.

Background: Hall (Embryologic development and monozygotic twinning. Acta Geneticae Medicae et Gemellologiae, Vol. 45, 1996, pp. 53-57) hypothesized that chromosomal aberrations can lead to monozygotic (MZ) twinning. However, twinning and chromosomal aberrations increase prenatal mortality and could reduce the prevalence of chromosomal aberrations in live-born twins. We compared prevalence proportion ratios (PPR) of chromosomal aberrations and trisomy 21 (T21) in live-born twins versus singletons born in Denmark during 1968-2009.

Methods: We linked the Danish Twin Registry and a 5% random sample of all singletons to the Danish Cytogenetic Central Register and calculated PPR adjusted for maternal age for MZ, dizygotic (DZ), and all twins versus singletons. Zygosity was based on questionnaires or genetic markers.

Results: No overall difference in risk of chromosomal aberrations or T21 in twins versus singletons was found. PPR in MZ and DZ twins was 0.87 (95% CI [0.60, 1.27]) and 1.05 (95% CI [0.88, 1.27]), respectively. For T21 there was a tendency to a lower prevalence in MZ twins compared to singletons (PPR: 0.29, 95% CI [0.07, 1.14]), whereas PPR was significantly increased in DZ twins (1.62, 95% CI [1.20, 2.19]). The observed proportion of MZ twin pairs among twin pairs with aberrations (0.22, 95% CI [0.16, 0.28]) was significantly lower than the proportion expected from the Weinberg method (0.32, 95% CI [CI, 0.26, 0.39]).

Conclusion: Based on databases providing complete national coverage on twins with chromosomal aberrations, we found no overall difference in risk of chromosomal aberrations or T21 in twins versus singletons. Around conception twins may have an increased risk of chromosomal aberrations, but loss of especially MZ embryos could lead to similar risk among live-born twins and singletons.
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http://dx.doi.org/10.1017/thg.2017.17DOI Listing
June 2017

Clinical characteristics and real-life diagnostic approaches in all Danish children with hereditary angioedema.

Orphanet J Rare Dis 2017 03 16;12(1):55. Epub 2017 Mar 16.

Department of Dermatology and Allergy Centre, Odense University Hospital, Odense, Denmark.

Background: With a potentially early onset, hereditary angioedema (HAE) requires special knowledge also in infancy and early childhood. In children from families with HAE, the diagnosis should be confirmed or refuted early, which can be difficult. Studies of childhood HAE and the diagnostic approaches are limited. Our aim was to investigate the entire Danish cohort of children with HAE and non-HAE children of HAE patients for diagnostic approaches and clinical characteristics.

Results: We included 41 children: 22 with HAE and 19 non-HAE. Of the HAE children, 14 were symptomatic-median age at onset was 4 [1-11] years. The first attack was peripheral in 8/14 children and abdominal in 6/14 children, i.e. no one had their first attacks in the upper airways. Most children had less than one attack per month. All of the symptomatic children had been treated with tranexamic acid and/or C1 inhibitor concentrate. Unlike in other countries, androgens were not used in our pediatric cohort. Home therapy with C1 inhibitor concentrate was established in 9 cases: 6 children were trained in self-administration and 3 children were treated by parents. Of the children, 10 had been diagnosed by symptoms, including 3 without family history-median age of diagnosis among these children was 5.35 [2-13.2] years. In 31 children, HAE was diagnosed or refuted before symptoms by blood samples. In 23 of these children, complement values were investigated, and in 9 cases genetic testing was added to the complement measurements. In 8 children recently investigated, genetic testing was first choice. Cord blood was used for complement measurements in 9 children and for genetic testing in 4 children. Results of complement measurements were equivocal in several cases, especially in the cord blood samples, and the sensitivity of low complement C4 for the diagnosis of HAE was 75%.

Conclusions: We investigated clinical characteristics in all Danish children with HAE. The rate of home therapy was high and androgens had been avoided. Complement values were often equivocal, especially in cord blood samples. Consequently, we have changed diagnostic practice to early genetic testing in children where the family mutation is known.
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http://dx.doi.org/10.1186/s13023-017-0604-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5356294PMC
March 2017

Biallelic mutations in the 3' exonuclease TOE1 cause pontocerebellar hypoplasia and uncover a role in snRNA processing.

Nat Genet 2017 Mar 16;49(3):457-464. Epub 2017 Jan 16.

Department of Pediatrics, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada.

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.
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http://dx.doi.org/10.1038/ng.3762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5325768PMC
March 2017