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  • 1
    Language: English
    In: Nucleic acids research, 2019-07-02, Vol.47 (W1), p.W114-W120
    Description: MutationDistiller is a freely available online tool for user-driven analyses of Whole Exome Sequencing data. It offers a user-friendly interface aimed at clinicians and researchers, who are not necessarily bioinformaticians. MutationDistiller combines MutationTaster's pathogenicity predictions with a phenotype-based approach. Phenotypic information is not limited to symptoms included in the Human Phenotype Ontology (HPO), but may also comprise clinical diagnoses and the suspected mode of inheritance. The search can be restricted to lists of candidate genes (e.g. virtual gene panels) and by tissue-specific gene expression. The inclusion of GeneOntology (GO) and metabolic pathways facilitates the discovery of hitherto unknown disease genes. In a novel approach, we trained MutationDistiller's HPO-based prioritization on authentic genotype-phenotype sets obtained from ClinVar and found it to match or outcompete current prioritization tools in terms of accuracy. In the output, the program provides a list of potential disease mutations ordered by the likelihood of the affected genes to cause the phenotype. MutationDistiller provides links to gene-related information from various resources. It has been extensively tested by clinicians and their suggestions have been valued in many iterative cycles of revisions. The tool, a comprehensive documentation and examples are freely available at https://www.mutationdistiller.org/
    Subject(s): Biochemistry & Molecular Biology ; Databases, Genetic ; DNA - genetics ; Exome - genetics ; Genetic Diseases, Inborn - genetics ; Genetic Variation - genetics ; Humans ; Life Sciences & Biomedicine ; Mutation - genetics ; Phenotype ; Science & Technology ; Software ; User-Computer Interface ; Web Server Issue ; Whole Exome Sequencing
    ISSN: 0305-1048
    E-ISSN: 1362-4962
    Source: Web of Science - Science Citation Index Expanded - 2019〈img src="http://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" /〉
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 2
    Language: English
    In: Nucleic acids research, 2020-07-02, Vol.48 (W1), p.W162-W169
    Description: Abstract VarFish is a user-friendly web application for the quality control, filtering, prioritization, analysis, and user-based annotation of DNA variant data with a focus on rare disease genetics. It is capable of processing variant call files with single or multiple samples. The variants are automatically annotated with population frequencies, molecular impact, and presence in databases such as ClinVar. Further, it provides support for pathogenicity scores including CADD, MutationTaster, and phenotypic similarity scores. Users can filter variants based on these annotations and presumed inheritance pattern and sort the results by these scores. Variants passing the filter are listed with their annotations and many useful link-outs to genome browsers, other gene/variant data portals, and external tools for variant assessment. VarFish allows users to create their own annotations including support for variant assessment following ACMG-AMP guidelines. In close collaboration with medical practitioners, VarFish was designed for variant analysis and prioritization in diagnostic and research settings as described in the software's extensive manual. The user interface has been optimized for supporting these protocols. Users can install VarFish on their own in-house servers where it provides additional lab notebook features for collaborative analysis and allows re-analysis of cases, e.g. after update of genotype or phenotype databases.
    Subject(s): AcademicSubjects ; SCI00010 ; Web Server Issue
    ISSN: 0305-1048
    E-ISSN: 1362-4962
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 3
    Language: English
    In: Genetics in medicine, 2021-04, Vol.23 (4), p.679-688
    Description: This study aimed to identify the genetic cause of a new multiple congenital anomalies syndrome observed in three individuals from two unrelated families. Clinical assessment was conducted prenatally and at different postnatal stages. Genetic studies included exome sequencing (ES) combined with single-nucleotide polymorphism (SNP) array based homozygosity mapping and trio ES. Dermal fibroblasts were used for functional assays. A clinically recognizable syndrome characterized by severe developmental delay, variable brain anomalies, congenital heart defects, dysmorphic facial features, and a distinctive type of synpolydactyly with an additional hypoplastic digit between the fourth and fifth digits of hands and/or feet was identified. Additional features included eye abnormalities, hearing impairment, and electroencephalogram anomalies. ES detected different homozygous truncating variants in MAPKAPK5 in both families. Patient-derived cells showed no expression of MAPKAPK5 protein isoforms and reduced levels of the MAPKAPK5-interacting protein ERK3. F-actin recovery after latrunculin B treatment was found to be less efficient in patient-derived fibroblasts than in control cells, supporting a role of MAPKAPK5 in F-actin polymerization. Our data indicate that loss-of-function variants in MAPKAPK5 result in a severe developmental disorder and reveal a major role of this gene in human brain, heart, and limb development.
    Subject(s): Child ; Congenital diseases ; Developmental Disabilities - genetics ; Fibroblasts ; Humans ; Intracellular Signaling Peptides and Proteins - genetics ; Phenotype ; Protein Serine-Threonine Kinases - genetics ; Syndactyly - genetics
    ISSN: 1098-3600
    E-ISSN: 1530-0366
    Source: Alma/SFX Local Collection
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  • 4
    Language: English
    In: American journal of medical genetics. Part A, 2017-06, Vol.173 (6), p.1694-1697
    Description: Pierre–Robin sequence, radial deviation, and ulnar clinodactyly of the index fingers due to an additional phalangeal bone, as well as heart defects are the key features of Catel–Manzke syndrome. Although mutations in TGDS were identified as the cause of this disorder, the pathogenetic mechanism remains unknown. Here, we report on a fetus with severe heart defect, nuchal edema, talipes, Pierre–Robin sequence, and bilateral deviation and clinodactyly of the index and middle fingers. Pregnancy was terminated at the 22nd week of gestation. Postmortem radiographs showed hypoplasia and V‐shaped displacement of the second and third proximal phalanges of both hands as well as hypoplasia of the first metatarsals and the phalangeal bones of the halluces. The suggested diagnosis Catel–Manzke syndrome was confirmed by the detection of two compound heterozygous mutations in TGDS: The known variant c.298G〉T; p.(Ala100Ser) and the so far undescribed variant c.895G〉A; p.(Asp299Asn), located in the predicted substrate binding site of TGDS. This is the first report on the association of mutations in TGDS with additional anomalies of the middle fingers and halluces. We provide a detailed phenotypic characterization of the only fetus with molecularly confirmed Catel–Manzke syndrome, which is relevant for prenatal diagnosis. Our findings widen the phenotype spectrum caused by TGDS mutations and underline the phenotypic overlap with Temtamy preaxial brachydactyly syndrome. This improves our understanding of the prenatal development and the pathogenetic mechanism of Catel–Manzke syndrome.
    Subject(s): Abnormalities, Multiple - diagnosis ; Abnormalities, Multiple - genetics ; Abnormalities, Multiple - physiopathology ; atypical phenotype ; Brachydactyly ; Brachydactyly - diagnosis ; Brachydactyly - genetics ; Brachydactyly - physiopathology ; Catel–Manzke syndrome ; Clubfoot ; Deafness - diagnosis ; Deafness - genetics ; Deafness - physiopathology ; Edema ; Female ; fetal pathology ; Fetus - physiopathology ; Fetuses ; Fingers & toes ; Fingers - abnormalities ; Fingers - physiopathology ; Gestation ; Hand Deformities, Congenital - diagnosis ; Hand Deformities, Congenital - genetics ; Hand Deformities, Congenital - physiopathology ; Heart Defects, Congenital - genetics ; Heart Defects, Congenital - physiopathology ; Heterozygote ; Humans ; Hydro-Lyases - genetics ; Hypoplasia ; Intellectual Disability - diagnosis ; Intellectual Disability - genetics ; Intellectual Disability - physiopathology ; Mouth Abnormalities - diagnosis ; Mouth Abnormalities - genetics ; Mouth Abnormalities - physiopathology ; Mutation ; Pierre Robin Syndrome - diagnosis ; Pierre Robin Syndrome - genetics ; Pierre Robin Syndrome - physiopathology ; Pierre–Robin sequence ; Pregnancy ; Prenatal development ; Prenatal Diagnosis ; prenatal manifestation ; Radiography ; TGDS ; Tooth Abnormalities - diagnosis ; Tooth Abnormalities - genetics ; Tooth Abnormalities - physiopathology
    ISSN: 1552-4825
    E-ISSN: 1552-4833
    Source: Hellenic Academic Libraries Link
    Source: Wiley Online Library All Journals
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  • 5
    Language: English
    In: American journal of medical genetics. Part A, 2020-03, Vol.182 (3), p.431-436
    Description: 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.
    Subject(s): Abnormalities, Multiple - genetics ; Abnormalities, Multiple - physiopathology ; Adolescent ; Alleles ; Catel‐Manzke syndrome ; Child ; Child, Preschool ; Female ; Fetuses ; Hand Deformities, Congenital - diagnosis ; Hand Deformities, Congenital - genetics ; Hand Deformities, Congenital - physiopathology ; Hereditary diseases ; Humans ; Hydro-Lyases - genetics ; hyperphalangy ; Male ; Manzke dysostosis ; Mutation - genetics ; Pierre Robin Syndrome - diagnosis ; Pierre Robin Syndrome - genetics ; Pierre Robin Syndrome - physiopathology ; Pierre‐Robin sequence ; Polydactyly - genetics ; Polydactyly - physiopathology ; short stature ; TGDS
    ISSN: 1552-4825
    E-ISSN: 1552-4833
    Source: Hellenic Academic Libraries Link
    Source: Wiley Online Library All Journals
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  • 6
    Language: English
    In: Genetics in medicine, 2019-08-01, Vol.21 (8), p.1797-1807
    Description: Purpose: Haploinsufficiency of USP7, located at chromosome 16p13.2, has recently been reported in seven individuals with neurodevelopmental phenotypes, including developmental delay/intellectual disability (DD/ID), autism spectrum disorder (ASD), seizures, and hypogonadism. Further, USP7 was identified to critically incorporate into the MAGEL2-USP7-TRIM27 (MUST), such that pathogenic variants in USP7 lead to altered endosomal F-actin polymerization and dysregulated protein recycling. Methods: We report 16 newly identified individuals with heterozygous USP7 variants, identified by genome or exome sequencing or by chromosome microarray analysis. Clinical features were evaluated by review of medical records. Additional clinical information was obtained on the seven previously reported individuals to fully elucidate the phenotypic expression associated with USP7 haploinsufficiency. Results: The clinical manifestations of these 23 individuals suggest a syndrome characterized by DD/ID, hypotonia, eye anomalies,feeding difficulties, GERD, behavioral anomalies, and ASD, and more specific phenotypes of speech delays including a nonverbal phenotype and abnormal brain magnetic resonance image findings including white matter changes based on neuroradiologic examination. Conclusion: The consistency of clinical features among all individuals presented regardless of de novo USP7 variant type supports haploinsufficiency as a mechanism for pathogenesis and refines the clinical impact faced by affected individuals and caregivers.
    Subject(s): Adolescent ; Autism ; Autism Spectrum Disorder - genetics ; Autism Spectrum Disorder - physiopathology ; Behavior ; Child ; Child, Preschool ; Chromosome Deletion ; Chromosomes ; corpus callosum thinning ; DNA-Binding Proteins - genetics ; Family medical history ; Genetic counseling ; Genetics ; Genetics & Heredity ; Genetics(clinical) ; Genome, Human - genetics ; Genomes ; Genotype & phenotype ; Haploinsufficiency - genetics ; Hospitals ; Humans ; Infant ; Infant, Newborn ; Intellectual Disability - genetics ; Intellectual Disability - physiopathology ; Laboratories ; Language Development Disorders - genetics ; Language Development Disorders - physiopathology ; Life Sciences & Biomedicine ; Medical records ; Medicine ; neurodevelopment ; Neurodevelopmental Disorders - genetics ; Neurodevelopmental Disorders - physiopathology ; Nuclear Proteins - genetics ; Patients ; Pediatrics ; Phenotype ; Problem Behavior ; Proteins ; Proteins - genetics ; Science & Technology ; speech delay ; USP7 ; white matter paucity ; Whole Exome Sequencing
    ISSN: 1098-3600
    E-ISSN: 1530-0366
    Source: Web of Science - Science Citation Index Expanded - 2019〈img src="http://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" /〉
    Source: Alma/SFX Local Collection
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  • 7
    Language: English
    In: Genetics in medicine, 2021-06, Vol.23 (6), p.1050-1057
    Description: To expand the recent description of a new neurodevelopmental syndrome related to alterations in CDK19. Individuals were identified through international collaboration. Functional studies included autophosphorylation assays for CDK19 Gly28Arg and Tyr32His variants and in vivo zebrafish assays of the CDK19 and CDK19 . We describe 11 unrelated individuals (age range: 9 months to 14 years) with de novo missense variants mapped to the kinase domain of CDK19, including two recurrent changes at residues Tyr32 and Gly28. In vitro autophosphorylation and substrate phosphorylation assays revealed that kinase activity of protein was lower for p.Gly28Arg and higher for p.Tyr32His substitutions compared with that of the wild-type protein. Injection of CDK19 messenger RNA (mRNA) with either the Tyr32His or the Gly28Arg variants using in vivo zebrafish model significantly increased fraction of embryos with morphological abnormalities. Overall, the phenotype of the now 14 individuals with CDK19-related disorder includes universal developmental delay and facial dysmorphism, hypotonia (79%), seizures (64%), ophthalmologic anomalies (64%), and autism/autistic traits (56%). CDK19 de novo missense variants are responsible for a novel neurodevelopmental disorder. Both kinase assay and zebrafish experiments showed that the pathogenetic mechanism may be more diverse than previously thought.
    Subject(s): Animals ; Cloning ; Cyclin-Dependent Kinases - genetics ; Gain of Function Mutation ; Genetics ; Genomes ; Glycerol ; Hospitals ; Humans ; Infant ; Insects ; Intellectual disabilities ; Intellectual Disability ; Kinases ; Medicine ; Metabolism ; Mutation, Missense ; Neurodevelopmental Disorders ; Pediatrics ; Phosphorylation ; Proteins ; RNA polymerase ; Zebrafish - genetics
    ISSN: 1098-3600
    E-ISSN: 1530-0366
    Source: Alma/SFX Local Collection
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  • 8
    Language: English
    In: American journal of medical genetics. Part A, 2020-09, Vol.182 (9), p.2068-2076
    Description: Hand hyperphalangism leading to shortened index fingers with ulnar deviation, hallux valgus, mild facial dysmorphism and respiratory compromise requiring assisted ventilation are the key features of Chitayat syndrome. This condition results from the recurrent heterozygous missense variant NM_006494.2:c.266A〉G; p.(Tyr89Cys) in ERF on chromosome 19q13.2, encoding the ETS2 repressor factor (ERF) protein. The pathomechanism of Chitayat syndrome is unknown. To date, seven individuals with Chitayat syndrome and the recurrent pathogenic ERF variant have been reported in the literature. Here, we describe six additional individuals, among them only one presenting with a history of assisted ventilation, and the remaining presenting with variable pulmonary phenotypes, including one individual without any obvious pulmonary manifestations. Our findings widen the phenotype spectrum caused by the recurrent pathogenic variant in ERF, underline Chitayat syndrome as a cause of isolated skeletal malformations and therefore contribute to the improvement of diagnostic strategies in individuals with hand hyperphalangism.
    Subject(s): bronchomalacia ; Chitayat syndrome ; Chromosome 19 ; ERF ; Ets-2 protein ; hyperphalangism ; Phenotypes ; respiratory distress ; ulnar deviation ; Ventilation
    ISSN: 1552-4825
    E-ISSN: 1552-4833
    Source: Hellenic Academic Libraries Link
    Source: Wiley Online Library All Journals
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  • 9
    Language: English
    In: American journal of medical genetics. Part A, 2014-12, Vol.164A (12), p.3170-3175
    Description: Vici syndrome is a rare autosomal recessively inherited multisystem disorder characterized by agenesis of the corpus callosum, cataracts, cardiomyopathy, combined immunodeficiency, psychomotor delay, and hypopigmentation. Cullup et al. recently identified mutations in the gene EPG5 as the cause of Vici syndrome. EPG5 is involved in autophagy, an evolutionarily conserved lysosomal degradation process that is essential for cell homeostasis. Following the first description in 1988 by Vici et al., 24 other cases of Vici syndrome have been published with variable expression of the defining features. Here, we report on a further case of Vici syndrome with a homozygous truncating mutation of EPG5, identified by whole‐exome sequencing. The mutation in our patient is the first reported affecting the penultimate exon of EPG5 and presenting with typical clinical manifestations of Vici syndrome. Additionally, we present a detailed clinical analysis of Vici syndrome comprising all cases previously described in the literature. © 2014 Wiley Periodicals, Inc.
    Subject(s): Agenesis of Corpus Callosum - genetics ; Agenesis of Corpus Callosum - pathology ; agenesis of the corpus callosum ; agenesis of the corpus callosum, autophagy ; autophagy ; Base Sequence ; cardiomyopathy ; Cataract - genetics ; Cataract - pathology ; developmental delay ; EPG5 ; Exome - genetics ; Exons - genetics ; Fatal Outcome ; Genes, Recessive - genetics ; Humans ; hypopigmentation ; immunodeficiency ; Infant ; Iran ; Molecular Sequence Data ; Proteins - genetics ; Sequence Analysis, DNA ; Vici syndrome ; whole-exome sequencing
    ISSN: 1552-4825
    E-ISSN: 1552-4833
    Source: Hellenic Academic Libraries Link
    Source: Wiley Online Library All Journals
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  • 10
    Language: English
    In: American journal of medical genetics. Part A, 2017-05, Vol.173 (5), p.1251-1256
    Description: ZBTB18 has been proposed as candidate gene for microcephaly and abnormalities of the corpus callosum based on overlapping microdeletions of 1q43q44. More recently, de novo mutations of ZBTB18 have been identified in patients with syndromic and non‐syndromic intellectual disability. Heterozygous microdeletions of 15q13.3 encompassing the candidate gene CHRNA7 are associated with developmental delay or intellectual disability with speech problems, hypotonia, and seizures. They are characterized by significant variability and reduced penetrance. We report on a patient with a de novo ZBTB18 nonsense mutation and a de novo 15q13.3 microdeletion, both in a heterozygous state, identified by next generation sequencing and array‐CGH. The 6‐year‐old girl showed global developmental delay, absent speech, therapy‐refractory seizures, ataxia, muscular hypotonia, and discrete facial dysmorphisms. Almost all of these features have been reported for both genetic aberrations, but the severity could hardly been explained by the microdeletion 15q13.3 alone. We assume an additive effect of haploinsufficiency of ZBTB18 and CHRNA7 in our patient. Assembling the features of our patient and the published patients, we noted that only one of them showed mild anomalies of the corpus callosum. Moreover, we hypothesize that nonsense mutations of ZBTB18 are associated with a more severe phenotype than missense mutations. This report indicates that haploinsufficiency of additional genes beside ZBTB18 causes the high frequency of corpus callosum anomalies in patients with microdeletions of 1q43q44 and underlines the importance of an NGS‐based molecular diagnostic in complex phenotypes.
    Subject(s): 15q13.3 microdeletion syndrome ; 1q43q44 microdeletion ; agenesis of corpus callosum ; Agenesis of Corpus Callosum - genetics ; Agenesis of Corpus Callosum - physiopathology ; alpha7 Nicotinic Acetylcholine Receptor - genetics ; array CGH ; Ataxia ; Chromosome Deletion ; Chromosome Disorders - genetics ; Chromosome Disorders - pathology ; Chromosomes, Human, Pair 15 - genetics ; Codon, Nonsense ; Corpus callosum ; Corpus Callosum - physiopathology ; Female ; Genes ; Haploinsufficiency ; Haploinsufficiency - genetics ; Humans ; Intellectual disabilities ; Intellectual Disability - genetics ; Intellectual Disability - pathology ; Intellectual Disability - physiopathology ; Microencephaly ; Missense mutation ; Mutation ; Next-generation sequencing ; NGS panel diagnostic ; Nonsense mutation ; Patients ; Phenotypes ; Repressor Proteins - genetics ; Seizures ; Seizures - genetics ; Seizures - pathology ; Speech ; ZBTB18
    ISSN: 1552-4825
    E-ISSN: 1552-4833
    Source: Hellenic Academic Libraries Link
    Source: Wiley Online Library All Journals
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