Publications by authors named "Marjon van Slegtenhorst"

76 Publications

Missense and truncating variants in CHD5 in a dominant neurodevelopmental disorder with intellectual disability, behavioral disturbances, and epilepsy.

Hum Genet 2021 Jul 4;140(7):1109-1120. Epub 2021 May 4.

CHU Sainte-Justine Research Center, Montreal, QC, H3T 1C5, Canada.

Located in the critical 1p36 microdeletion region, the chromodomain helicase DNA-binding protein 5 (CHD5) gene encodes a subunit of the nucleosome remodeling and deacetylation (NuRD) complex required for neuronal development. Pathogenic variants in six of nine chromodomain (CHD) genes cause autosomal dominant neurodevelopmental disorders, while CHD5-related disorders are still unknown. Thanks to GeneMatcher and international collaborations, we assembled a cohort of 16 unrelated individuals harboring heterozygous CHD5 variants, all identified by exome sequencing. Twelve patients had de novo CHD5 variants, including ten missense and two splice site variants. Three familial cases had nonsense or missense variants segregating with speech delay, learning disabilities, and/or craniosynostosis. One patient carried a frameshift variant of unknown inheritance due to unavailability of the father. The most common clinical features included language deficits (81%), behavioral symptoms (69%), intellectual disability (64%), epilepsy (62%), and motor delay (56%). Epilepsy types were variable, with West syndrome observed in three patients, generalized tonic-clonic seizures in two, and other subtypes observed in one individual each. Our findings suggest that, in line with other CHD-related disorders, heterozygous CHD5 variants are associated with a variable neurodevelopmental syndrome that includes intellectual disability with speech delay, epilepsy, and behavioral problems as main features.
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http://dx.doi.org/10.1007/s00439-021-02283-2DOI Listing
July 2021

Biallelic Variants Are Associated With Mild Lissencephaly and Cerebellar Hypoplasia.

Neurol Genet 2021 Apr 21;7(2):e558. Epub 2021 Jan 21.

Department of Clinical Genetics (D.J.S., R.S., M.W., M.S., G.M.S.M.), ErasmusMC University Medical Center Rotterdam; Department of Child Neurology (M.C.Y.W.) and Department of Radiology (M.H.G.D.), Sophia Children's Hospital, ErasmusMC University Medical Center Rotterdam, the Netherlands; Department of Pediatrics (W.B.D.), University of Washington; Department of Neurology (W.B.D.), University of Washington, Seattle; Center for Integrative Brain Research (W.B.D.), Seattle Children's Research Institute, WA; Department of Human Genetics (W.B.D.), University of Minnesota, Minneapolis; Department of Radiology and Biomedical Imaging (A.J.B.), University of California, San Francisco; and ENCORE Expertise Center for Neurodevelopmental Disorders (M.C.Y.W., M.H.G.D., G.M.S.M.), ErasmusMC University Medical Center, Rotterdam, the Netherlands.

Objective: We aimed to identify pathogenic variants in a girl with epilepsy, developmental delay, cerebellar ataxia, oral motor difficulty, and structural brain abnormalities with the use of whole-exome sequencing.

Methods: Whole-exome trio analysis and molecular functional studies were performed in addition to the clinical findings and neuroimaging studies.

Results: Brain MRI showed mild pachygyria, hypoplasia of the cerebellar vermis, and abnormal foliation of the cerebellar vermis, suspected for a variant in one of the genes of the Reelin pathway. Trio whole-exome sequencing and additional functional studies were performed to identify the pathogenic variants. Trio whole-exome sequencing revealed compound heterozygous splice variants in , both affecting the highly conserved functional phosphotyrosine-binding domain. Expression studies in patient-derived cells showed loss of normal transcripts, confirming pathogenicity.

Conclusions: We conclude that these variants are very likely causally related to the cerebral phenotype and propose to consider loss-of-function variants in patients with RELN-like cortical malformations.
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http://dx.doi.org/10.1212/NXG.0000000000000558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830234PMC
April 2021

Missense variants in DPYSL5 cause a neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities.

Am J Hum Genet 2021 May 23;108(5):951-961. Epub 2021 Apr 23.

Service de Génétique, Centre Hospitalier Universitaire, 86021 Poitiers, France; Equipe d'Accueil 3808, Université de Poitiers, 86034 Poitiers, France.

The collapsin response mediator protein (CRMP) family proteins are intracellular mediators of neurotrophic factors regulating neurite structure/spine formation and are essential for dendrite patterning and directional axonal pathfinding during brain developmental processes. Among this family, CRMP5/DPYSL5 plays a significant role in neuronal migration, axonal guidance, dendrite outgrowth, and synapse formation by interacting with microtubules. Here, we report the identification of missense mutations in DPYSL5 in nine individuals with brain malformations, including corpus callosum agenesis and/or posterior fossa abnormalities, associated with variable degrees of intellectual disability. A recurrent de novo p.Glu41Lys variant was found in eight unrelated patients, and a p.Gly47Arg variant was identified in one individual from the first family reported with Ritscher-Schinzel syndrome. Functional analyses of the two missense mutations revealed impaired dendritic outgrowth processes in young developing hippocampal primary neuronal cultures. We further demonstrated that these mutations, both located in the same loop on the surface of DPYSL5 monomers and oligomers, reduced the interaction of DPYSL5 with neuronal cytoskeleton-associated proteins MAP2 and βIII-tubulin. Our findings collectively indicate that the p.Glu41Lys and p.Gly47Arg variants impair DPYSL5 function on dendritic outgrowth regulation by preventing the formation of the ternary complex with MAP2 and βIII-tubulin, ultimately leading to abnormal brain development. This study adds DPYSL5 to the list of genes implicated in brain malformation and in neurodevelopmental disorders.
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http://dx.doi.org/10.1016/j.ajhg.2021.04.004DOI Listing
May 2021

De novo Leu619Pro variant causes a new channelopathy characterised by giant cell lesions of the jaws and skull, skeletal abnormalities and polyneuropathy.

J Med Genet 2021 Mar 8. Epub 2021 Mar 8.

Department of Oral Surgery and Pathology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil

Background: Pathogenic germline variants in ransient eceptor otential anilloid 4 ation hannel () lead to channelopathies, which are phenotypically diverse and heterogeneous disorders grossly divided in neuromuscular disorders and skeletal dysplasia. We recently reported in sporadic giant cell lesions of the jaws (GCLJs) novel, somatic, heterozygous, gain-of-function mutations in , at Met713.

Methods: Here we report two unrelated women with a de novo germline p.Leu619Pro variant and an overlapping systemic disorder affecting all organs individually described in TRPV4 channelopathies.

Results: From an early age, both patients had several lesions of the nervous system including progressive polyneuropathy, and multiple aggressive giant cell-rich lesions of the jaws and craniofacial/skull bones, and other skeletal lesions. One patient had a relatively milder disease phenotype possibly due to postzygotic somatic mosaicism. Indeed, the p.Leu619Pro variant was present at a lower frequency (variant allele frequency (VAF)=21.6%) than expected for a heterozygous variant as seen in the other proband, and showed variable regional frequency in the GCLJ (VAF ranging from 42% to 10%). In silico structural analysis suggests that the gain-of-function p.Leu619Pro alters the ion channel activity leading to constitutive ion leakage.

Conclusion: Our findings define a novel polysystemic syndrome due to germline p.Leu619Pro and further extend the spectrum of channelopathies. They further highlight the convergence of mutations on different organ systems leading to complex phenotypes which are further mitigated by possible post-zygotic mosaicism. Treatment of this disorder is challenging, and surgical intervention of the GCLJ worsens the lesions, suggesting the future use of MEK inhibitors and TRPV4 antagonists as therapeutic modalities for unmet clinical needs.
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http://dx.doi.org/10.1136/jmedgenet-2020-107427DOI Listing
March 2021

SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females.

Am J Hum Genet 2021 03 16;108(3):502-516. Epub 2021 Feb 16.

Division of Medical Genetics, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA 15224, USA.

Deletion 1p36 (del1p36) syndrome is the most common human disorder resulting from a terminal autosomal deletion. This condition is molecularly and clinically heterogeneous. Deletions involving two non-overlapping regions, known as the distal (telomeric) and proximal (centromeric) critical regions, are sufficient to cause the majority of the recurrent clinical features, although with different facial features and dysmorphisms. SPEN encodes a transcriptional repressor commonly deleted in proximal del1p36 syndrome and is located centromeric to the proximal 1p36 critical region. Here, we used clinical data from 34 individuals with truncating variants in SPEN to define a neurodevelopmental disorder presenting with features that overlap considerably with those of proximal del1p36 syndrome. The clinical profile of this disease includes developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI, especially in females. SPEN also emerges as a relevant gene for del1p36 syndrome by co-expression analyses. Finally, we show that haploinsufficiency of SPEN is associated with a distinctive DNA methylation episignature of the X chromosome in affected females, providing further evidence of a specific contribution of the protein to the epigenetic control of this chromosome, and a paradigm of an X chromosome-specific episignature that classifies syndromic traits. We conclude that SPEN is required for multiple developmental processes and SPEN haploinsufficiency is a major contributor to a disorder associated with deletions centromeric to the previously established 1p36 critical regions.
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http://dx.doi.org/10.1016/j.ajhg.2021.01.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008487PMC
March 2021

TAOK1 is associated with neurodevelopmental disorder and essential for neuronal maturation and cortical development.

Hum Mutat 2021 Apr 1;42(4):445-459. Epub 2021 Mar 1.

Department of Pediatrics, SIU School of Medicine, Springfield, Illinois, USA.

Thousand and one amino-acid kinase 1 (TAOK1) is a MAP3K protein kinase, regulating different mitogen-activated protein kinase pathways, thereby modulating a multitude of processes in the cell. Given the recent finding of TAOK1 involvement in neurodevelopmental disorders (NDDs), we investigated the role of TAOK1 in neuronal function and collected a cohort of 23 individuals with mostly de novo variants in TAOK1 to further define the associated NDD. Here, we provide evidence for an important role for TAOK1 in neuronal function, showing that altered TAOK1 expression levels in the embryonic mouse brain affect neural migration in vivo, as well as neuronal maturation in vitro. The molecular spectrum of the identified TAOK1 variants comprises largely truncating and nonsense variants, but also missense variants, for which we provide evidence that they can have a loss of function or dominant-negative effect on TAOK1, expanding the potential underlying causative mechanisms resulting in NDD. Taken together, our data indicate that TAOK1 activity needs to be properly controlled for normal neuronal function and that TAOK1 dysregulation leads to a neurodevelopmental disorder mainly comprising similar facial features, developmental delay/intellectual disability and/or variable learning or behavioral problems, muscular hypotonia, infant feeding difficulties, and growth problems.
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http://dx.doi.org/10.1002/humu.24176DOI Listing
April 2021

Deciphering the premature mortality in PIGA-CDG - An untold story.

Epilepsy Res 2021 Feb 9;170:106530. Epub 2020 Dec 9.

Department of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Centre, Dianalund, Denmark; Department for Regional Health Services, University of Southern Denmark, Odense, Denmark.

Objective: Congenital disorder of glycosylation (CDG) due to a defective phosphatidylinositol glycan anchor biosynthesis class A protein (PIGA) is a severe X-linked developmental and epileptic encephalopathy. Seizures are often treatment refractory, and patients have intellectual disability and global developmental delay. Previous reports have suggested that patients with PIGA-CDG have a high risk of premature mortality. This study aimed to evaluate the observed high mortality and the causes of death in PIGA-CDG patients.

Methods: We reviewed the literature and collected additional unpublished patients through an international network.

Results: In total, we reviewed the data of 88 patients of whom 30 patients born alive were deceased, and the overall mortality before the age of 20 years was 30 % (26/88). Age at death ranged from 15 days to 48 years of life. The median age at death was two years and more than half of the patients deceased in early childhood. The PIGA-specific mortality rate/1000 person-years was 44.9/1000 person-years (95 %, CI 31.4-64.3). There were no cases of definite or probable sudden unexpected death in epilepsy (SUDEP) and half of the patients died due to respiratory failure (15/30, 50 %) or possible SUDEP (3/30, 10 %). Three patients (10 %) died from severe cardiomyopathy, liver failure and gastrointestinal bleeding, respectively. The cause of death was unclassified in nine patients (30 %). Autopsies were rarely performed and the true cause of death remains unknown for the majority of patients.

Significance: Our data indicate an increased risk of premature death in patients with PIGA-CDG when compared to most monogenic developmental and epileptic encephalopathies.
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http://dx.doi.org/10.1016/j.eplepsyres.2020.106530DOI Listing
February 2021

Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect.

Nat Genet 2021 02 25;53(2):128-134. Epub 2021 Jan 25.

Department of Epidemiology and Biostatistics, Imperial College London, London, UK.

The heart muscle diseases hypertrophic (HCM) and dilated (DCM) cardiomyopathies are leading causes of sudden death and heart failure in young, otherwise healthy, individuals. We conducted genome-wide association studies and multi-trait analyses in HCM (1,733 cases), DCM (5,521 cases) and nine left ventricular (LV) traits (19,260 UK Biobank participants with structurally normal hearts). We identified 16 loci associated with HCM, 13 with DCM and 23 with LV traits. We show strong genetic correlations between LV traits and cardiomyopathies, with opposing effects in HCM and DCM. Two-sample Mendelian randomization supports a causal association linking increased LV contractility with HCM risk. A polygenic risk score explains a significant portion of phenotypic variability in carriers of HCM-causing rare variants. Our findings thus provide evidence that polygenic risk score may account for variability in Mendelian diseases. More broadly, we provide insights into how genetic pathways may lead to distinct disorders through opposing genetic effects.
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http://dx.doi.org/10.1038/s41588-020-00762-2DOI Listing
February 2021

Isobutyryl-CoA dehydrogenase deficiency associated with autism in a girl without an alternative genetic diagnosis by trio whole exome sequencing: A case report.

Mol Genet Genomic Med 2021 02 11;9(2):e1595. Epub 2021 Jan 11.

Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, the Netherlands.

Background: Isobutyryl-CoA dehydrogenase (IBD) is a mitochondrial enzyme catalysing the third step in the degradation of the essential branched-chain amino acid valine and is encoded by ACAD8. ACAD8 mutations lead to isobutyryl-CoA dehydrogenase deficiency (IBDD), which is identified by increased C4-acylcarnitine levels. Affected individuals are either asymptomatic or display a variety of symptoms during infancy, including speech delay, cognitive impairment, failure to thrive, hypotonia, and emesis.

Methods: Here, we review all previously published IBDD patients and describe a girl diagnosed with IBDD who was presenting with autism as the main disease feature.

Results: To assess whether a phenotype-genotype correlation exists that could explain the development or absence of clinical symptoms in IBDD, we compared CADD scores, in silico mutation predictions, LoF tolerance scores and C4-acylcarnitine levels between symptomatic and asymptomatic individuals. Statistical analysis of these parameters did not establish significant differences amongst both groups.

Conclusion: As in our proband, trio whole exome sequencing did not establish an alternative secondary genetic diagnosis for autism, and reported long-term follow-up of IBDD patients is limited, it is possible that autism spectrum disorders could be one of the disease-associated features. Further long-term follow-up is suggested in order to delineate the full clinical spectrum associated with IBDD.
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http://dx.doi.org/10.1002/mgg3.1595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8077115PMC
February 2021

The potential diagnostic yield of whole exome sequencing in pregnancies complicated by fetal ultrasound anomalies.

Acta Obstet Gynecol Scand 2021 Jun 28;100(6):1106-1115. Epub 2020 Dec 28.

Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, the Netherlands.

Introduction: The aim of this retrospective cohort study was to determine the potential diagnostic yield of prenatal whole exome sequencing in fetuses with structural anomalies on expert ultrasound scans and normal chromosomal microarray results.

Material And Methods: In the period 2013-2016, 391 pregnant women with fetal ultrasound anomalies who received normal chromosomal microarray results, were referred for additional genetic counseling and opted for additional molecular testing pre- and/or postnatally. Most of the couples received only a targeted molecular test and in 159 cases (40.7%) whole exome sequencing (broad gene panels or open exome) was performed. The results of these molecular tests were evaluated retrospectively, regardless of the time of the genetic diagnosis (prenatal or postnatal).

Results: In 76 of 391 fetuses (19.4%, 95% CI 15.8%-23.6%) molecular testing provided a genetic diagnosis with identification of (likely) pathogenic variants. In the majority of cases (91.1%, 73/76) the (likely) pathogenic variant would be detected by prenatal whole exome sequencing analysis.

Conclusions: Our retrospective cohort study shows that prenatal whole exome sequencing, if offered by a clinical geneticist, in addition to chromosomal microarray, would notably increase the diagnostic yield in fetuses with ultrasound anomalies and would allow early diagnosis of a genetic disorder irrespective of the (incomplete) fetal phenotype.
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http://dx.doi.org/10.1111/aogs.14053DOI Listing
June 2021

BICRA, a SWI/SNF Complex Member, Is Associated with BAF-Disorder Related Phenotypes in Humans and Model Organisms.

Am J Hum Genet 2020 12 23;107(6):1096-1112. Epub 2020 Nov 23.

Division of Clinical Genetics, Children's Mercy Hospital, University of Missouri-Kansas City School of Medicine, Kansas City, MO 64108, USA.

SWI/SNF-related intellectual disability disorders (SSRIDDs) are rare neurodevelopmental disorders characterized by developmental disability, coarse facial features, and fifth digit/nail hypoplasia that are caused by pathogenic variants in genes that encode for members of the SWI/SNF (or BAF) family of chromatin remodeling complexes. We have identified 12 individuals with rare variants (10 loss-of-function, 2 missense) in the BICRA (BRD4 interacting chromatin remodeling complex-associated protein) gene, also known as GLTSCR1, which encodes a subunit of the non-canonical BAF (ncBAF) complex. These individuals exhibited neurodevelopmental phenotypes that include developmental delay, intellectual disability, autism spectrum disorder, and behavioral abnormalities as well as dysmorphic features. Notably, the majority of individuals lack the fifth digit/nail hypoplasia phenotype, a hallmark of most SSRIDDs. To confirm the role of BICRA in the development of these phenotypes, we performed functional characterization of the zebrafish and Drosophila orthologs of BICRA. In zebrafish, a mutation of bicra that mimics one of the loss-of-function variants leads to craniofacial defects possibly akin to the dysmorphic facial features seen in individuals harboring putatively pathogenic BICRA variants. We further show that Bicra physically binds to other non-canonical ncBAF complex members, including the BRD9/7 ortholog, CG7154, and is the defining member of the ncBAF complex in flies. Like other SWI/SNF complex members, loss of Bicra function in flies acts as a dominant enhancer of position effect variegation but in a more context-specific manner. We conclude that haploinsufficiency of BICRA leads to a unique SSRIDD in humans whose phenotypes overlap with those previously reported.
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http://dx.doi.org/10.1016/j.ajhg.2020.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820627PMC
December 2020

Warsaw Breakage Syndrome associated DDX11 helicase resolves G-quadruplex structures to support sister chromatid cohesion.

Nat Commun 2020 08 27;11(1):4287. Epub 2020 Aug 27.

Section of Oncogenetics, Cancer Center Amsterdam and Department of Clinical Genetics, Amsterdam University Medical Centers, De Boelelaan 1118, 1081, HV, Amsterdam, the Netherlands.

Warsaw Breakage Syndrome (WABS) is a rare disorder related to cohesinopathies and Fanconi anemia, caused by bi-allelic mutations in DDX11. Here, we report multiple compound heterozygous WABS cases, each displaying destabilized DDX11 protein and residual DDX11 function at the cellular level. Patient-derived cell lines exhibit sensitivity to topoisomerase and PARP inhibitors, defective sister chromatid cohesion and reduced DNA replication fork speed. Deleting DDX11 in RPE1-TERT cells inhibits proliferation and survival in a TP53-dependent manner and causes chromosome breaks and cohesion defects, independent of the expressed pseudogene DDX12p. Importantly, G-quadruplex (G4) stabilizing compounds induce chromosome breaks and cohesion defects which are strongly aggravated by inactivation of DDX11 but not FANCJ. The DNA helicase domain of DDX11 is essential for sister chromatid cohesion and resistance to G4 stabilizers. We propose that DDX11 is a DNA helicase protecting against G4 induced double-stranded breaks and concomitant loss of cohesion, possibly at DNA replication forks.
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http://dx.doi.org/10.1038/s41467-020-18066-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7452896PMC
August 2020

Impact of sex on timing and clinical outcome of septal myectomy for obstructive hypertrophic cardiomyopathy.

Int J Cardiol 2021 01 22;323:133-139. Epub 2020 Aug 22.

Department of Cardiology, Thoraxcenter, Erasmus MC, University Medical Center Rotterdam, 3015GD Rotterdam, The Netherlands.

Background: Sex disparities are common in hypertrophic cardiomyopathy (HCM). Previous research has shown that at time of myectomy, women are older, have greater impairment of diastolic function and more advanced cardiac remodeling. The clinical impact of these differences is unknown.

Method: This study included 162 HCM patients (61% men) who underwent septal myectomy. Time to treatment was calculated in relation to symptom onset and diagnosis. Pre- and post-operative echocardiographic data were collected. Sex differences were assessed at baseline and in time-to-event survival analyses for the composite endpoint of all-cause mortality, cardiac transplantation, re-intervention and aborted sudden cardiac death.

Results: Women were generally older at time of myectomy (57 vs. 49 years, p < 0.01), with similar time to treatment as measured from symptom onset (2.3 [1.3-6.0] vs. 2.8 [1.1-5.3] years, p > 0.05), but a shorter time since diagnosis compared to men (2.6 [1.2-7.0] vs. 4.3 [2.4-8.3] years, p = 0.02). Mean wall thickness and left atrial diameter were the same for men and women, but were higher in women when correcting for body surface area (absolute: 20 vs. 19 mm, 48 vs 46 mm, p ≥ 0.05; corrected: 9.7 vs. 11.2 mm/m, 23.4 vs. 26.3 mm/m, p < 0.01). After 5.9 [3.0-9.1] years, 15% of men and 8% of women had reached the composite endpoint (p > 0.05).

Conclusion: In conclusion, although women present later in life and seem to have more advanced disease on echocardiography, time until myectomy was similar and clinical outcomes after myectomy are favourable for both men and women.
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http://dx.doi.org/10.1016/j.ijcard.2020.08.059DOI Listing
January 2021

Variants in SCAF4 Cause a Neurodevelopmental Disorder and Are Associated with Impaired mRNA Processing.

Am J Hum Genet 2020 09 29;107(3):544-554. Epub 2020 Jul 29.

University of South Dakota, Sanford School of Medicine, Sioux Falls, SD 57105, USA.

RNA polymerase II interacts with various other complexes and factors to ensure correct initiation, elongation, and termination of mRNA transcription. One of these proteins is SR-related CTD-associated factor 4 (SCAF4), which is important for correct usage of polyA sites for mRNA termination. Using exome sequencing and international matchmaking, we identified nine likely pathogenic germline variants in SCAF4 including two splice-site and seven truncating variants, all residing in the N-terminal two thirds of the protein. Eight of these variants occurred de novo, and one was inherited. Affected individuals demonstrated a variable neurodevelopmental disorder characterized by mild intellectual disability, seizures, behavioral abnormalities, and various skeletal and structural anomalies. Paired-end RNA sequencing on blood lymphocytes of SCAF4-deficient individuals revealed a broad deregulation of more than 9,000 genes and significant differential splicing of more than 2,900 genes, indicating an important role of SCAF4 in mRNA processing. Knockdown of the SCAF4 ortholog CG4266 in the model organism Drosophila melanogaster resulted in impaired locomotor function, learning, and short-term memory. Furthermore, we observed an increased number of active zones in larval neuromuscular junctions, representing large glutamatergic synapses. These observations indicate a role of CG4266 in nervous system development and function and support the implication of SCAF4 in neurodevelopmental phenotypes. In summary, our data show that heterozygous, likely gene-disrupting variants in SCAF4 are causative for a variable neurodevelopmental disorder associated with impaired mRNA processing.
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http://dx.doi.org/10.1016/j.ajhg.2020.06.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477272PMC
September 2020

Left-ventricular outflow tract acceleration time is associated with symptoms in patients with obstructive hypertrophic cardiomyopathy.

J Ultrasound 2020 Jul 25. Epub 2020 Jul 25.

Department of Cardiology, Thoraxcenter, Erasmus MC, University Medical Center Rotterdam, Dr. Molewaterplein 40, Post Office box: 2040, 3015 GD, Rotterdam, The Netherlands.

Aims: Not all obstructive hypertrophic cardiomyopathy (HCM) patients are symptomatic. The relation between obstructive HCM and symptoms is not well understood. The hypothesis of this study is that left-ventricular outflow tract (LVOT) acceleration time (AT) is associated with symptoms.

Methods: We included 187 patients (61% men, mean age 55 ± 14 years) with obstructive HCM, defined as a maximal wall thickness ≥ 15 mm and a resting or provoked LVOT peak gradient ≥ 30 mmHg. Peak velocity (PV), left-ventricular (LV) ejection time (ET), and AT (the time between LVOT flow onset and the moment of PV) were measured on continuous-wave (CW) Doppler tracings. Logistic and Cox proportional hazard regression analyses were used to evaluate the relation between symptoms [New York Heart Association (NYHA) class ≥ II] and echocardiographic measurements, including AT. Reproducibility was assessed using the intraclass correlation coefficient (ICC).

Results: Symptomatic patients were more often female and had higher mean AT values. Logistic regression demonstrated a significant association between AT and symptomatic status (odds ratio 1.31 per 10 ms, p < 0.01) after adjustment for sex, negative inotropes, PV, LVOT diameter, and diastolic dysfunction. AT was independently associated with symptoms and septal reduction during follow-up (hazard ratio 1.09 per 10 ms, p < 0.05). The ICC was 0.98 with a mean difference of 0.28 ± 8.4 ms.

Conclusion: In obstructive HCM patients, increased AT is significantly related to symptoms after adjustment for sex, negative inotropes, PV, LVOT diameter, and diastolic dysfunction, and is associated with the symptomatic status during follow-up. AT represents an easily measured echocardiographic variable with excellent inter-reader reproducibility.
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http://dx.doi.org/10.1007/s40477-020-00513-3DOI Listing
July 2020

Rare variants in the GABA receptor subunit ε identified in patients with a wide spectrum of epileptic phenotypes.

Mol Genet Genomic Med 2020 09 25;8(9):e1388. Epub 2020 Jun 25.

Junior Research Group, Genetics of Childhood Brain Malformations, Faculty VI-School of Medicine and Health Sciences, University of Oldenburg, Oldenburg, Germany.

Background: Epilepsy belongs to a group of chronic and highly heterogeneous brain disorders. Many types of epilepsy and epileptic syndromes are caused by genetic factors. The neural amino acid y-aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the mammalian central nervous system. It regulates activity of channel pores by binding to transmembrane GABA-receptors (GABRs). The GABRs are heteropentamers assembled from different receptor subunits (α1-6, β1-3, γ1-3, δ, ε, θ, π, and ρ1-3). Several epileptic disorders are caused by mutations in genes encoding single GABRs.

Methods: We applied trio- and single-whole exome sequencing to search for genetic sequence variants associated with a wide range of epileptic phenotypes accompanied by intellectual disability and/or global developmental delay in the investigated patients.

Results: We identified four hemizygous sequence variants in the GABA receptor subunit ε gene (GABRE), including one nonsense (NM_004961.3: c.399C>A, p.Tyr133*), two missense variants (NM_004961.3: c.664G>A, p.Glu222Lys; NM_004961.3: c.1045G>A, p.Val349Ile), and one variant affecting the translation initiation codon (NM_004961.3: c.1A>G, p.Met1?) in four unrelated families.

Conclusion: Our clinical and molecular genetic findings suggest that GABRE is a likely candidate gene for epilepsy. Nevertheless, functional studies are necessary to better understand pathogenicity of the GABRE-mutations and their associations with epileptic phenotypes.
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http://dx.doi.org/10.1002/mgg3.1388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507344PMC
September 2020

Expanding the clinical and genetic spectrum of ALPK3 variants: Phenotypes identified in pediatric cardiomyopathy patients and adults with heterozygous variants.

Am Heart J 2020 07 21;225:108-119. Epub 2020 Apr 21.

Bruce Lefroy Centre for Genetic Health Research, Murdoch Children's Research Institute, Victoria, Australia; Department of Pediatrics, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Victoria, Australia; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Victoria, Australia.

Introduction: Biallelic damaging variants in ALPK3, encoding alpha-protein kinase 3, cause pediatric-onset cardiomyopathy with manifestations that are incompletely defined.

Methods And Results: We analyzed clinical manifestations of damaging biallelic ALPK3 variants in 19 pediatric patients, including nine previously published cases. Among these, 11 loss-of-function (LoF) variants, seven compound LoF and deleterious missense variants, and one homozygous deleterious missense variant were identified. Among 18 live-born patients, 8 exhibited neonatal dilated cardiomyopathy (44.4%; 95% CI: 21.5%-69.2%) that subsequently transitioned into ventricular hypertrophy. The majority of patients had extracardiac phenotypes, including contractures, scoliosis, cleft palate, and facial dysmorphisms. We observed no association between variant type or location, disease severity, and/or extracardiac manifestations. Myocardial histopathology showed focal cardiomyocyte hypertrophy, subendocardial fibroelastosis in patients under 4 years of age, and myofibrillar disarray in adults. Rare heterozygous ALPK3 variants were also assessed in adult-onset cardiomyopathy patients. Among 1548 Dutch patients referred for initial genetic analyses, we identified 39 individuals with rare heterozygous ALPK3 variants (2.5%; 95% CI: 1.8%-3.4%), including 26 missense and 10 LoF variants. Among 149 U.S. patients without pathogenic variants in 83 cardiomyopathy-related genes, we identified six missense and nine LoF ALPK3 variants (10.1%; 95% CI: 5.7%-16.1%). LoF ALPK3 variants were increased in comparison to matched controls (Dutch cohort, P = 1.6×10; U.S. cohort, P = 2.2×10).

Conclusion: Biallelic damaging ALPK3 variants cause pediatric cardiomyopathy manifested by DCM transitioning to hypertrophy, often with poor contractile function. Additional extracardiac features occur in most patients, including musculoskeletal abnormalities and cleft palate. Heterozygous LoF ALPK3 variants are enriched in adults with cardiomyopathy and may contribute to their cardiomyopathy. Adults with ALPK3 LoF variants therefore warrant evaluations for cardiomyopathy.
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http://dx.doi.org/10.1016/j.ahj.2020.03.023DOI Listing
July 2020

Lessons learned from 40 novel PIGA patients and a review of the literature.

Epilepsia 2020 06 26;61(6):1142-1155. Epub 2020 May 26.

Division of Genetic and Genomic Medicine, Nationwide Children's Hospital, Columbus, Ohio, USA.

Objective: To define the phenotypic spectrum of phosphatidylinositol glycan class A protein (PIGA)-related congenital disorder of glycosylation (PIGA-CDG) and evaluate genotype-phenotype correlations.

Methods: Our cohort encompasses 40 affected males with a pathogenic PIGA variant. We performed a detailed phenotypic assessment, and in addition, we reviewed the available clinical data of 36 previously published cases and assessed the variant pathogenicity using bioinformatical approaches.

Results: Most individuals had hypotonia, moderate to profound global developmental delay, and intractable seizures. We found that PIGA-CDG spans from a pure neurological phenotype at the mild end to a Fryns syndrome-like phenotype. We found a high frequency of cardiac anomalies including structural anomalies and cardiomyopathy, and a high frequency of spontaneous death, especially in childhood. Comparative bioinformatical analysis of common variants, found in the healthy population, and pathogenic variants, identified in affected individuals, revealed a profound physiochemical dissimilarity of the substituted amino acids in variant constrained regions of the protein.

Significance: Our comprehensive analysis of the largest cohort of published and novel PIGA patients broadens the spectrum of PIGA-CDG. Our genotype-phenotype correlation facilitates the estimation on pathogenicity of variants with unknown clinical significance and prognosis for individuals with pathogenic variants in PIGA.
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http://dx.doi.org/10.1111/epi.16545DOI Listing
June 2020

Diagnostic Cardiovascular Magnetic Resonance Imaging Criteria in Noncompaction Cardiomyopathy and the Yield of Genetic Testing.

Can J Cardiol 2021 Mar 21;37(3):433-442. Epub 2020 May 21.

Department of Cardiology, Erasmus Medical Centre, University Medical Centre Rotterdam, Rotterdam, The Netherlands; Department of Radiology and Nuclear Medicine, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, The Netherlands. Electronic address:

Background: Noncompaction cardiomyopathy (NCCM) is characterized by a thickened myocardial wall with excessive trabeculations of the left ventricle, and ∼30% is explained by a (likely) pathogenic variant [(L)PV] in a cardiomyopathy gene. Diagnosing an (L)PV is important because it allows accurate identification of which relatives are at risk and helps predicting prognosis. The goal of this study was to assess which specific clinical and morphologic characteristics of the myocardium may predict an (L)PV and which of the cardiovascular magnetic resonance (CMR) diagnostic criteria for NCCM can best be used for that purpose.

Methods: Sixty-two patients with NCCM, diagnosed by means of echocardiographic Jenni criteria, underwent CMR imaging that was evaluated according the Petersen, Stacey, Jacquier, Captur, and Choi diagnostic CMR criteria for NCCM. Patients also underwent DNA testing and were stratified according to having an (L)PV.

Results: Thirty-three patients (53%) with NCCM had an (L)PV. The apical and mid-lateral segments were the dominant locations for meeting Petersen and/or Stacey criteria. Correlation between different CMR criteria varied from moderate to very strong. In multivariate binary logistic regression analysis with CMR and non-CMR parameters, independent positive predictors for an (L)PV were familial cardiomyopathy, trabecular mass, and meeting Petersen criteria in ≥ 2 out of 3 long-axis views, whereas left bundle branch block and hypertension were negative predictors. The receiver operating characteristic curve of this multivariate model had an area under the curve of 0.89 (95% confidence interval 0.82-0.97).

Conclusions: CMR criteria together with family history help to distinguish those patients in whom an (L)PV can be identified, consequently leading to referral for genetic diagnostics and cascade screening.
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http://dx.doi.org/10.1016/j.cjca.2020.05.021DOI Listing
March 2021

Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy.

Nat Commun 2020 01 30;11(1):595. Epub 2020 Jan 30.

Department of Pediatrics, Department of Neurology, & the Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Developmental epileptic encephalopathies are devastating disorders characterized by intractable epileptic seizures and developmental delay. Here, we report an allelic series of germline recessive mutations in UGDH in 36 cases from 25 families presenting with epileptic encephalopathy with developmental delay and hypotonia. UGDH encodes an oxidoreductase that converts UDP-glucose to UDP-glucuronic acid, a key component of specific proteoglycans and glycolipids. Consistent with being loss-of-function alleles, we show using patients' primary fibroblasts and biochemical assays, that these mutations either impair UGDH stability, oligomerization, or enzymatic activity. In vitro, patient-derived cerebral organoids are smaller with a reduced number of proliferating neuronal progenitors while mutant ugdh zebrafish do not phenocopy the human disease. Our study defines UGDH as a key player for the production of extracellular matrix components that are essential for human brain development. Based on the incidence of variants observed, UGDH mutations are likely to be a frequent cause of recessive epileptic encephalopathy.
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http://dx.doi.org/10.1038/s41467-020-14360-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6992768PMC
January 2020

Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases.

Acta Neuropathol 2020 03 9;139(3):415-442. Epub 2019 Dec 9.

Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

Developmental and/or epileptic encephalopathies (DEEs) are a group of devastating genetic disorders, resulting in early-onset, therapy-resistant seizures and developmental delay. Here we report on 22 individuals from 15 families presenting with a severe form of intractable epilepsy, severe developmental delay, progressive microcephaly, visual disturbance and similar minor dysmorphisms. Whole exome sequencing identified a recurrent, homozygous variant (chr2:64083454A > G) in the essential UDP-glucose pyrophosphorylase (UGP2) gene in all probands. This rare variant results in a tolerable Met12Val missense change of the longer UGP2 protein isoform but causes a disruption of the start codon of the shorter isoform, which is predominant in brain. We show that the absence of the shorter isoform leads to a reduction of functional UGP2 enzyme in neural stem cells, leading to altered glycogen metabolism, upregulated unfolded protein response and premature neuronal differentiation, as modeled during pluripotent stem cell differentiation in vitro. In contrast, the complete lack of all UGP2 isoforms leads to differentiation defects in multiple lineages in human cells. Reduced expression of Ugp2a/Ugp2b in vivo in zebrafish mimics visual disturbance and mutant animals show a behavioral phenotype. Our study identifies a recurrent start codon mutation in UGP2 as a cause of a novel autosomal recessive DEE syndrome. Importantly, it also shows that isoform-specific start-loss mutations causing expression loss of a tissue-relevant isoform of an essential protein can cause a genetic disease, even when an organism-wide protein absence is incompatible with life. We provide additional examples where a similar disease mechanism applies.
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http://dx.doi.org/10.1007/s00401-019-02109-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035241PMC
March 2020

De novo CLTC variants are associated with a variable phenotype from mild to severe intellectual disability, microcephaly, hypoplasia of the corpus callosum, and epilepsy.

Genet Med 2020 04 28;22(4):797-802. Epub 2019 Nov 28.

Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center (Radboudumc), Nijmegen, The Netherlands.

Purpose: To delineate the genotype-phenotype correlation in individuals with likely pathogenic variants in the CLTC gene.

Methods: We describe 13 individuals with de novo CLTC variants. Causality of variants was determined by using the tolerance landscape of CLTC and computer-assisted molecular modeling where applicable. Phenotypic abnormalities observed in the individuals identified with missense and in-frame variants were compared with those with nonsense or frameshift variants in CLTC.

Results: All de novo variants were judged to be causal. Combining our data with that of 14 previously reported affected individuals (n = 27), all had intellectual disability (ID), ranging from mild to moderate/severe, with or without additional neurologic, behavioral, craniofacial, ophthalmologic, and gastrointestinal features. Microcephaly, hypoplasia of the corpus callosum, and epilepsy were more frequently observed in individuals with missense and in-frame variants than in those with nonsense and frameshift variants. However, this difference was not significant.

Conclusions: The wide phenotypic variability associated with likely pathogenic CLTC variants seems to be associated with allelic heterogeneity. The detailed clinical characterization of a larger cohort of individuals with pathogenic CLTC variants is warranted to support the hypothesis that missense and in-frame variants exert a dominant-negative effect, whereas the nonsense and frameshift variants would result in haploinsufficiency.
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http://dx.doi.org/10.1038/s41436-019-0703-yDOI Listing
April 2020

TGDS pathogenic variants cause Catel-Manzke syndrome without hyperphalangy.

Am J Med Genet A 2020 03 25;182(3):431-436. Epub 2019 Nov 25.

Institute of Medical Genetics and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany.

Catel-Manzke syndrome, also known as micrognathia-digital-syndrome, is a rare autosomal recessive disorder characterized by the combination of the two cardinal features Pierre-Robin sequence and bilateral hyperphalangy leading to ulnar clinodactyly (ulnar curvature of the phalanges) and radial deviation (radial angulation at the metacarpophalangeal joint) of the index fingers. Individuals without one of these major hallmarks or with additional hand malformations have been described as atypical or Catel-Manzke-like syndrome. Biallelic TGDS pathogenic variants have thus far been detected in eight individuals with typical Catel-Manzke syndrome and in one fetus with additional features. Here we report on two individuals with TGDS pathogenic variants who presented with mild radial deviation and ulnar clinodactyly of the index fingers but without radiologic signs of hyperphalangy. Furthermore, both individuals have disproportionate short stature, a feature that has not yet been associated with Catel-Manzke syndrome. Our data broaden the phenotypic spectrum of TGDS-associated Catel-Manzke syndrome and expand the indication for diagnostic testing.
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http://dx.doi.org/10.1002/ajmg.a.61419DOI Listing
March 2020

TMX2 Is a Crucial Regulator of Cellular Redox State, and Its Dysfunction Causes Severe Brain Developmental Abnormalities.

Am J Hum Genet 2019 12 14;105(6):1126-1147. Epub 2019 Nov 14.

Department of Neuromuscular Disorders, University College London Institute of Neurology, Queen Square, London WC1N 3BG, UK.

The redox state of the neural progenitors regulates physiological processes such as neuronal differentiation and dendritic and axonal growth. The relevance of endoplasmic reticulum (ER)-associated oxidoreductases in these processes is largely unexplored. We describe a severe neurological disorder caused by bi-allelic loss-of-function variants in thioredoxin (TRX)-related transmembrane-2 (TMX2); these variants were detected by exome sequencing in 14 affected individuals from ten unrelated families presenting with congenital microcephaly, cortical polymicrogyria, and other migration disorders. TMX2 encodes one of the five TMX proteins of the protein disulfide isomerase family, hitherto not linked to human developmental brain disease. Our mechanistic studies on protein function show that TMX2 localizes to the ER mitochondria-associated membranes (MAMs), is involved in posttranslational modification and protein folding, and undergoes physical interaction with the MAM-associated and ER folding chaperone calnexin and ER calcium pump SERCA2. These interactions are functionally relevant because TMX2-deficient fibroblasts show decreased mitochondrial respiratory reserve capacity and compensatory increased glycolytic activity. Intriguingly, under basal conditions TMX2 occurs in both reduced and oxidized monomeric form, while it forms a stable dimer under treatment with hydrogen peroxide, recently recognized as a signaling molecule in neural morphogenesis and axonal pathfinding. Exogenous expression of the pathogenic TMX2 variants or of variants with an in vitro mutagenized TRX domain induces a constitutive TMX2 polymerization, mimicking an increased oxidative state. Altogether these data uncover TMX2 as a sensor in the MAM-regulated redox signaling pathway and identify it as a key adaptive regulator of neuronal proliferation, migration, and organization in the developing brain.
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http://dx.doi.org/10.1016/j.ajhg.2019.10.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904804PMC
December 2019

Loss of SMPD4 Causes a Developmental Disorder Characterized by Microcephaly and Congenital Arthrogryposis.

Am J Hum Genet 2019 10 5;105(4):689-705. Epub 2019 Sep 5.

Department of Human Genetics, Division of Developmental Biology Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, MLC 7016, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati, College of Medicine, 3333 Burnet Ave., ML 4006, Cincinnati, OH 45229, USA.

Sphingomyelinases generate ceramide from sphingomyelin as a second messenger in intracellular signaling pathways involved in cell proliferation, differentiation, or apoptosis. Children from 12 unrelated families presented with microcephaly, simplified gyral pattern of the cortex, hypomyelination, cerebellar hypoplasia, congenital arthrogryposis, and early fetal/postnatal demise. Genomic analysis revealed bi-allelic loss-of-function variants in SMPD4, coding for the neutral sphingomyelinase-3 (nSMase-3/SMPD4). Overexpression of human Myc-tagged SMPD4 showed localization both to the outer nuclear envelope and the ER and additionally revealed interactions with several nuclear pore complex proteins by proteomics analysis. Fibroblasts from affected individuals showed ER cisternae abnormalities, suspected for increased autophagy, and were more susceptible to apoptosis under stress conditions, while treatment with siSMPD4 caused delayed cell cycle progression. Our data show that SMPD4 links homeostasis of membrane sphingolipids to cell fate by regulating the cross-talk between the ER and the outer nuclear envelope, while its loss reveals a pathogenic mechanism in microcephaly.
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http://dx.doi.org/10.1016/j.ajhg.2019.08.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817560PMC
October 2019

Biallelic Variants in , Encoding a Cytosolic Targeting Factor of Tail-Anchored Proteins, Cause Rapidly Progressive Pediatric Cardiomyopathy.

Circ Genom Precis Med 2019 09 28;12(9):397-406. Epub 2019 Aug 28.

Department of Clinical Genetics (J.M.A.V., M.v.d.B., H.C.v.d.L., L.M.A.v.U., M.H.-W., M.A.v.S., M.W.W., F.W.V., R.M.W.H., T.J.v.H., I.M.B.H.v.d.L.), Erasmus MC, University Medical Center Rotterdam.

Background: Pediatric cardiomyopathies are a clinically and genetically heterogeneous group of heart muscle disorders associated with high morbidity and mortality. Although knowledge of the genetic basis of pediatric cardiomyopathy has improved considerably, the underlying cause remains elusive in a substantial proportion of cases.

Methods: Exome sequencing was used to screen for the causative genetic defect in a pair of siblings with rapidly progressive dilated cardiomyopathy and death in early infancy. Protein expression was assessed in patient samples, followed by an in vitro tail-anchored protein insertion assay and functional analyses in zebrafish.

Results: We identified compound heterozygous variants in the highly conserved gene (arsA arsenite transporter, ATP-binding, homolog), which encodes an ATPase required for post-translational membrane insertion of tail-anchored proteins. The c.913C>T variant on the paternal allele is predicted to result in a premature stop codon p.(Gln305*), and likely explains the decreased protein expression observed in myocardial tissue and skin fibroblasts. The c.488T>C variant on the maternal allele results in a valine to alanine substitution at residue 163 (p.Val163Ala). Functional studies showed that this variant leads to protein misfolding as well as less effective tail-anchored protein insertion. Loss of in zebrafish resulted in reduced cardiac contractility and early lethality. In contrast to wild-type mRNA, injection of either mutant mRNA failed to rescue this phenotype.

Conclusions: Biallelic variants in cause severe pediatric cardiomyopathy and early death. Our findings point toward a critical role of the tail-anchored membrane protein insertion pathway in vertebrate cardiac function and disease.
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http://dx.doi.org/10.1161/CIRCGEN.119.002507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205403PMC
September 2019

Holoprosencephaly, orofacial cleft, and frontonaso-orbital encephaloceles: Genetic evaluation of a possible new syndrome.

Am J Med Genet A 2019 11 28;179(11):2170-2177. Epub 2019 Jul 28.

Institute of Education and Research, Santa Casa Belo Horizonte, Belo Horizonte, Minas Gerais, Brazil.

Here we report on a Brazilian child who presented semilobar holoprosencephaly, frontonasal encephaloceles and bilateral cleft lip and palate. Malformations also included agenesis of the corpus callosum, abnormal cortical gyres, dilation of the aqueduct, bilateral endolymphatic sac, bilateral cystic cocci-vestibular malformation, and a cribriform defect. The 3D TC craniofacial images showed abnormal frontonasal transition region, with a bone bifurcation, and partial agenesis of nasal bone. The trunk and upper and lower limbs were normal. To our knowledge, this rare association of holoprocensephaly with frontonaso-orbital encephaloceles without limb anomalies has never been reported before. Karyotype was normal. SNP-array showed no copy-number alterations but revealed 25% of regions of homozygosity (ROH) with normal copy number, indicating a high coefficient of inbreeding, which significantly increases the risk for an autosomal recessive disorder. Whole exome sequencing analysis did not reveal any pathogenic or likely pathogenic variants. We discuss the possible influence of two variants of uncertain significance found within the patient's ROHs. First, a missense p.(Gly394Ser) in PCSK9, a gene involved in the regulation of plasma low-density lipoprotein cholesterol. Second, an inframe duplication p.(Ala75_Ala81dup) in SP8, a zinc-finger transcription factor that regulates signaling centers during craniofacial development. Further studies and/or the identification of other patients with a similar phenotype will help elucidate the genetic etiology of this complex case.
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http://dx.doi.org/10.1002/ajmg.a.61305DOI Listing
November 2019

Genetic variants in the KDM6B gene are associated with neurodevelopmental delays and dysmorphic features.

Am J Med Genet A 2019 07 23;179(7):1276-1286. Epub 2019 May 23.

Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands.

Lysine-specific demethylase 6B (KDM6B) demethylates trimethylated lysine-27 on histone H3. The methylation and demethylation of histone proteins affects gene expression during development. Pathogenic alterations in histone lysine methylation and demethylation genes have been associated with multiple neurodevelopmental disorders. We have identified a number of de novo alterations in the KDM6B gene via whole exome sequencing (WES) in a cohort of 12 unrelated patients with developmental delay, intellectual disability, dysmorphic facial features, and other clinical findings. Our findings will allow for further investigation in to the role of the KDM6B gene in human neurodevelopmental disorders.
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http://dx.doi.org/10.1002/ajmg.a.61173DOI Listing
July 2019

Mortality Risk Associated With Truncating Founder Mutations in Titin.

Circ Genom Precis Med 2019 05;12(5):e002436

Department of Genetics (M.J., A.F.B., A.S.U., H.K.P.v.A., E.A.M.H., D.D.), University Medical Center Utrecht, Utrecht University, the Netherlands.

Background Truncating titin variants (TTNtv) are the most prevalent genetic cause of dilated cardiomyopathy, found in ≤25% of familial cases. Moreover, TTNtv associated with dilated cardiomyopathy are estimated to be present in 0.5% of the general population. The prognosis of asymptomatic carriers of TTNtv is poorly understood because TTNtv are associated with a highly variable phenotype. We aim to assess the natural history and clinical relevance of TTNtv by analyzing standardized mortality ratios (SMR) in multigenerational pedigrees and in close relatives of present-day patients. Methods Haplotype and genealogical analyses were performed on 3 recurrent TTNtv. Subsequently, the family tree mortality ratio method was used to compare all-cause mortality of subjects at an a priori 50% risk of carrying TTNtv to the general Dutch population. SMRs were stratified for sex, age, and calendar period. Subgroups were compared with Poisson regression. Similarly, SMRs were calculated in parents of 128 present-day dilated cardiomyopathy probands with TTNtv using the reverse parent-offspring method. Results The TTNtv were established as founder mutations and traced to 18th century ancestors. In 20 522 person-years, overall mortality was not significantly increased (SMR, 1.06; 95% CI, 0.95-1.18; P=0.162). However, mortality was significantly increased in subjects living after 1965 (SMR, 1.27; 95% CI, 1.04-1.53; P=0.009) and aged ≥60 years (SMR, 1.17; 95% CI, 1.01-1.35; P=0.02). The reverse parent-offspring analysis showed overall excess mortality (SMR, 1.26; 95% CI, 1.07-1.48; P=0.003), driven by subjects aged ≥60 years. Conclusions The natural history of the analyzed TTNtv shows a relatively mild disease course with significant excess mortality in elderly patients. With increasing life expectancy, TTNtv-associated morbidity and mortality will likely become more prevalent.
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http://dx.doi.org/10.1161/CIRCGEN.118.002436DOI Listing
May 2019

Variants in DOCK3 cause developmental delay and hypotonia.

Eur J Hum Genet 2019 08 11;27(8):1225-1234. Epub 2019 Apr 11.

Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA.

The DOCK3 gene encodes the Dedicator of cytokinesis 3 (DOCK3) protein, which belongs to the family of guanine nucleotide exchange factors and is expressed almost exclusively in the brain and spinal cord. We used whole exome sequencing (WES) to investigate the molecular cause of developmental delay and hypotonia in three unrelated probands. WES identified truncating and splice site variants in Patient 1 and compound heterozygous and homozygous missense variants in Patients 2 and 3, respectively. We studied the effect of the three missense variants in vitro by using site-directed mutagenesis and pull-down assay and show that the induction of Rac1 activation was significantly lower in DOCK3 mutant cells compared with wild type human DOCK3 (P < 0.05). We generated a protein model to further examine the effect of the two missense variants within or adjacent to the DHR-2 domain in DOCK3 and this model supports pathogenicity. Our results support a loss of function mechanism but the data on the patients with missense variants should be cautiously interpreted because of the variability of the phenotypes and limited number of cases. Prior studies have described DOCK3 bi-allelic loss of function variants in two families with ataxia, hypotonia, and developmental delay. Here, we report on three patients with DOCK3-related developmental delay, wide-based or uncoordinated gait, and hypotonia, further supporting DOCK3's role in a neurodevelopmental syndrome and expanding the spectrum of phenotypic and genotypic variability.
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http://dx.doi.org/10.1038/s41431-019-0397-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777627PMC
August 2019