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  • 1
    Language: English
    In: Molecular syndromology, 2014-08, Vol.5 (5), p.201-211
    Description: Fibrodysplasia ossificans progressiva (FOP, MIM 135100) is a rare autosomal dominant genetic disorder and the most disabling condition of heterotopic (extraskeletal) ossification in humans. Mutations in the ACVR1 gene (MIM 102576) were identified as a genetic cause of FOP [Shore et al., 2006]. Most patients with FOP have the same recurrent single nucleotide change c.617G〉A, p.R206H in the ACVR1 gene. Furthermore, 11 other mutations in the ACVR1 gene have been described as a cause of FOP. Here, we review phenotypic and molecular findings of 130 cases of FOP reported in the literature from 1982 to April 2014 and discuss possible genotype-phenotype correlations in FOP patients.
    Subject(s): ACVR1 ; FOP ; Great toe malformations ; Heterotopic ossifications ; Progressive immobility ; Review ; Review Article
    ISSN: 1661-8769
    E-ISSN: 1661-8777
    Source: PubMed Central
    Source: Karger Journals Archiv (DFG Nationallizenzen)
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  • 2
    Language: English
    In: Epilepsia (Copenhagen), 2014, Vol.55 (4), p.e25-9
    Description: Epilepsy is a phenotypically and genetically highly heterogeneous disorder with 〉200 genes linked to inherited forms of the disease. To identify the underlying genetic cause in a patient with intractable seizures, optic atrophy, severe intellectual disability (ID), brain abnormalities, and muscular hypotonia, we performed exome sequencing in a 5-year-old girl and her unaffected parents. In the patient, we detected a novel, de novo missense mutation in the SCN2A (c.5645G〉T; p.R1882L) gene encoding the alphaII -subunit of the voltage-gated sodium channel Nav 1.2. A literature review revealed 33 different SCN2A mutations in 14 families with benign forms of epilepsy and in 21 cases with severe phenotypes. Although almost all benign mutations were inherited, the majority of severe mutations occurred de novo. Of interest, de novo SCN2A mutations have also been reported in five patients without seizures but with ID (n = 3) and/or autism (n = 3). In the present study, we successfully used exome sequencing to detect a de novo mutation in a genetically heterogeneous disorder with epilepsy and ID. Using this approach, we expand the phenotypic spectrum of SCN2A mutations. Our own and literature data indicate that SCN2A-linked severe phenotypes are more likely to be caused by de novo mutations. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.
    Subject(s): Abnormalities ; Brain ; Brain - abnormalities ; Child, Preschool ; Epilepsy ; Epileptic encephalopathy ; Exome - genetics ; Female ; Genetic aspects ; Humans ; Intellectual disability ; Intellectual Disability - complications ; Intellectual Disability - diagnosis ; Intellectual Disability - genetics ; Muscle Hypotonia - complications ; Muscle Hypotonia - diagnosis ; Muscle Hypotonia - genetics ; Mutation, Missense - genetics ; NAV1.2 Voltage-Gated Sodium Channel - genetics ; Optic atrophy ; Optic Atrophy - complications ; Optic Atrophy - diagnosis ; Optic Atrophy - genetics ; Phenotype ; Rett‐like syndrome ; Seizures (Medicine) ; Seizures - complications ; Seizures - diagnosis ; Seizures - genetics ; Sodium channel
    ISSN: 0013-9580
    E-ISSN: 1528-1167
    Source: Wiley Online Library All Backfiles
    Source: Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
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  • 3
    Language: English
    In: Human mutation, 2017-08, Vol.38 (8), p.942-946
    Description: Ocular coloboma (OC) is a defect in optic fissure closure and is a common cause of severe congenital visual impairment. Bilateral OC is primarily genetically determined and shows marked locus heterogeneity. Whole‐exome sequencing (WES) was used to analyze 12 trios (child affected with OC and both unaffected parents). This identified de novo mutations in 10 different genes in eight probands. Three of these genes encoded proteins associated with actin cytoskeleton dynamics: ACTG1, TWF1, and LCP1. Proband‐only WES identified a second unrelated individual with isolated OC carrying the same ACTG1 allele, encoding p.(Pro70Leu). Both individuals have normal neurodevelopment with no extra‐ocular signs of Baraitser–Winter syndrome. We found this mutant protein to be incapable of incorporation into F‐actin. The LCP1 and TWF1 variants each resulted in only minor disturbance of actin interactions, and no further plausibly causative variants were identified in these genes on resequencing 380 unrelated individuals with OC. Ocular coloboma (OC) is a defect in optic fissure closure and a common cause of severe congenital visual impairment. We identified de novo mutations in 10 different genes in eight unrelated individuals with isolated OC, using whole exome sequencing. Three of these genes encoded proteins associated with actin cytoskeleton dynamics and the mutations impacted on normal actin function. Only mutations in ACTG1 were recurrent among a larger cohort upon targeted re‐sequencing, suggesting that to accurately determine all of the disease‐accolated loci for this important eye malformation, sequencing of many more families is required.
    Subject(s): ACTG1 ; Actin ; Actins - genetics ; Analysis ; Animals ; Brief Report ; Brief Reports ; Coloboma - etiology ; Coloboma - genetics ; Cytoskeleton ; eye development ; Eye diseases ; Female ; Genetic aspects ; Genetic disorders ; Humans ; Male ; Mice ; Microfilament Proteins - genetics ; Muscle proteins ; Mutation ; Mutation - genetics ; ocular coloboma ; Protein-Tyrosine Kinases - genetics ; Proteins ; tissue fusion
    ISSN: 1059-7794
    E-ISSN: 1098-1004
    Source: Hellenic Academic Libraries Link
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  • 4
    Language: English
    In: American journal of medical genetics. Part A, 2017-05, Vol.173 (5), p.1400-1405
    Description: Simpson–Golabi–Behmel syndrome (SGBS) is characterized by multiple congenital abnormalities, pre/postnatal overgrowth, distinctive craniofacial features intellectual disability (ID) of variable degree, and an increased risk for embryonal tumors. SGBS is X‐linked recessive and caused by deletions, duplications, and point mutations in GPC3, encoding a membrane associated cell surface heparan sulfate proteoglycan named glypican 3. GPC3 plays essential roles in the regulation of cell growth signaling and cell division. Here, we report on a family with three affected cousins who show variable clinical signs of SGBS and ID. Initial microarray‐CGH revealed a deletion of approximately 30–50 kb that includes at least one exon of GPC3. By subsequent Sanger sequencing of genomic DNA we could map the chromosomal break points to define a deletion size of 43,617 bp including exons 5 and 6 of the GPC3 gene. RT‐PCR analysis on RNA derived from whole blood could further confirm the deletion of both exons on transcript level. This loss of two exons results in a frameshift and a premature stop of translation. Based on our results we have established a breakpoint spanning PCR that could identify the mutation in the mothers and grandmother of the patients. Thus, we provided a molecular test that allows accurate genetic counselling and prenatal diagnosis for this family.
    Subject(s): Abnormalities, Multiple - genetics ; Abnormalities, Multiple - physiopathology ; Arrhythmias, Cardiac - genetics ; Arrhythmias, Cardiac - physiopathology ; Cell division ; Cell surface ; Child ; Child, Preschool ; Chromosome Breakage ; Chromosome deletion ; DNA microarrays ; DNA sequencing ; Exons ; Exons - genetics ; Female ; Frameshift Mutation ; Genes ; Genes, X-Linked ; Genetic counselling ; Genetic Diseases, X-Linked - genetics ; Genetic Diseases, X-Linked - physiopathology ; Gigantism - genetics ; Gigantism - physiopathology ; Glypicans - genetics ; GPC3 ; GPC3 gene ; Heart Defects, Congenital - genetics ; Heart Defects, Congenital - physiopathology ; Heparan sulfate ; Heparan sulfate proteoglycans ; Humans ; Infant ; Intellectual disabilities ; Intellectual Disability - genetics ; Intellectual Disability - physiopathology ; Male ; Mutation ; organomegaly ; overgrowth ; Pedigree ; Phenotype ; Polymerase chain reaction ; Prenatal diagnosis ; Proteoglycans ; Sequence Deletion ; Simpson–Golabi–Behmel syndrome ; Transcription ; Tumors
    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, 2016-09, Vol.170A (9), p.2404-2407
    Description: Patients with Van der Woude syndrome typically present with cleft lip, cleft lip and palate, or with cleft palate only. In contrast to non‐syndromic cleft lip and/or palate, Van der Woude syndrome typically is characterized by bilateral, paramedian lower‐lip pits. Popliteal pterygium syndrome shares features with Van der Woude syndrome, but, in addition, is characterized by a popliteal pterygium, genital anomalies, cutaneous syndactyly of the fingers and the toes, and a characteristic pyramidal fold of skin overlying the nail of the hallux. In some patients oral synechiae or eyelid synechiae are present. Van der Woude Syndrome and Popliteal pterygium syndrome are autosomal dominantly inherited disorders caused by heterozygous mutations in IRF6. We present a three generation family with tremendous intrafamilial phenotypic variability. The newborn index patient had a diagnosis of Popliteal pterygium syndrome. The mother presented with a classic Van der Woude Syndrome, while the maternal grandfather had Van der Woude Syndrome as well as minor signs of Popliteal pterygium syndrome. In all three affecteds the known pathogenic mutation c.265A〉G, p.Lys89Glu in IRF6 was identified. While inter‐ as well as intra‐familial variability has been described in IRF6‐related disorders, the occurrence of a typical Van der Woude Syndrome without any other anomalies as well as a diagnosis of Popliteal pterygium syndrome in the same family is rare. © 2016 Wiley Periodicals, Inc.
    Subject(s): Abnormalities, Multiple - diagnosis ; Abnormalities, Multiple - genetics ; Adult ; Alleles ; Cleft Lip - diagnosis ; Cleft Lip - genetics ; Cleft Palate - diagnosis ; Cleft Palate - genetics ; Cysts - diagnosis ; Cysts - genetics ; Exons ; Eye Abnormalities - diagnosis ; Eye Abnormalities - genetics ; Female ; Fingers - abnormalities ; Genetic Association Studies ; Heterozygote ; Humans ; Infant, Newborn ; Interferon Regulatory Factors - genetics ; intrafamilial variability ; IRF6 ; Knee Joint - abnormalities ; Lip - abnormalities ; Lower Extremity Deformities, Congenital - diagnosis ; Lower Extremity Deformities, Congenital - genetics ; Male ; Mutation ; Pedigree ; Phenotype ; Popliteal pterygium syndrome ; Syndactyly - diagnosis ; Syndactyly - genetics ; Urogenital Abnormalities - diagnosis ; Urogenital Abnormalities - genetics ; Van der Woude syndrome
    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: Clinical and translational allergy, 2019, Vol.9 (1), p.9-n/a
    Description: Hereditary angioedema (HAE) is a life‐threatening disease characterized by recurrent episodes of subcutaneous and mucosal swellings and abdominal cramping. Corticosteroids and antihistamines, which are usually beneficial in histamine‐induced acquired angioedema, are not effective in HAE. Therefore, diagnosing HAE correctly is crucial for affected patients. We report a family from Northern Germany with six individuals suffering from recurrent swellings, indicating HAE. Laboratory tests and genetic diagnostics of the genes SERPING1, encoding C1 esterase inhibitor (C1‐INH), and F12, encoding coagulation factor XII, were unremarkable. In three affected and one yet unaffected member of the family, we were then able to identify the c.988A 〉 G (also termed c.1100A 〉 G) mutation in the plasminogen (PLG) gene, which has recently been described in several families with HAE. This mutation leads to a missense mutation with an amino acid exchange p.Lys330Glu in the kringle 3 domain of plasminogen. There was no direct relationship between the earlier described cases with this mutation and the family we report here. In all affected members of the family, the symptoms manifested in adulthood, with swellings of the face, tongue and larynx, including a fatal case of a 19 year‐old female individual. The frequency of the attacks was variable, ranging between once per year to once a month. In one individual, we also found decreased serum levels of plasminogen as well as coagulation factor XII. As previously reported in patients with PLG defects, icatibant proved to be very effective in controlling acute attacks, indicating an involvement of bradykinin in the pathogenesis.
    Subject(s): Allergy ; Angioneurotic edema ; Family ; Gene mutations ; Genes ; Histamine ; Icatibant ; Letter to the Editor ; Life Sciences & Biomedicine ; Science & Technology ; Thrombolytic drugs ; Tranexamic acid
    ISSN: 2045-7022
    E-ISSN: 2045-7022
    Source: BioMedCentral Open Access
    Source: Academic Search Ultimate
    Source: Web of Science - Science Citation Index Expanded - 2019〈img src="http://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" /〉
    Source: PubMed Central
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  • 7
    Language: English
    In: Journal of human genetics, 2017-11, Vol.62 (11), p.1005-1006
    Subject(s): Adult ; Age ; Amino Acid Sequence ; Body Dysmorphic Disorders - complications ; Body Dysmorphic Disorders - genetics ; Body Dysmorphic Disorders - pathology ; Casein Kinase II - genetics ; Child ; Congenital diseases ; Female ; Genetic Predisposition to Disease ; Genetics ; Genomics ; Humans ; Kinases ; Male ; Microcephaly ; Mutation ; Neurodevelopmental disorders ; Neurodevelopmental Disorders - complications ; Neurodevelopmental Disorders - genetics ; Neurodevelopmental Disorders - pathology ; Patients ; Pedigree ; Prognosis ; Proteins ; Sequence Homology
    ISSN: 1434-5161
    E-ISSN: 1435-232X
    Source: Alma/SFX Local Collection
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  • 8
    Language: English
    In: European journal of human genetics : EJHG, 2015-02, Vol.23 (2), p.180-188
    Description: The imprinted region on chromosome 14q32 harbors several maternally or paternally expressed genes as well as two DMRs (differentially methylated regions), the IG-DMR and the MEG3-DMR, which both act as imprinting control centers. Genetic aberrations affecting the imprinted gene cluster in 14q32 result in distinct phenotypes, known as maternal or paternal uniparental disomy 14 phenotypes (upd(14)mat, upd(14)pat). In both syndromes, three types of molecular alterations have been reported: uniparental disomy 14, deletions and epimutations. In contrast to uniparental disomy and epimutations, deletions affecting regulatory elements in 14q32 are associated with a high-recurrence risk. Based on two single deletion cases a functional hierarchy of the IG-DMR as a regulator for the methylation of the MEG3-DMR has been proposed. We have identified two novel deletions of maternal origin spanning the MEG3-DMR, but not the IG-DMR in patients with upd(14)pat syndrome, one de novo deletion of 165 kb and another deletion of 5.8 kb in two siblings. The 5.8 kb deletion was inherited from the phenotypically normal mother, who carries the deletion in a mosaic state on her paternal chromosome 14. The methylation at both DMRs was investigated by quantitative next generation bisulfite sequencing and revealed normal methylation patterns at the IG-DMR in all patients with the exception of certain CpG dinucleotides. Thus, we could confirm that deletions of the MEG3-DMR does not generally influence the methylation pattern of the IG-DMR, which strengthens the hypothesis of a hierarchical structure and distinct functional properties of the two DMRs.
    Subject(s): Adult ; Binding sites ; Bisulfite ; Chromosome 14 ; Chromosome deletion ; Chromosomes ; Chromosomes, Human, Pair 14 - genetics ; Clonal deletion ; CpG Islands ; DNA Methylation ; Epigenetics ; Female ; Gene Deletion ; Genes ; Genetics ; Genomic Imprinting ; Genotype & phenotype ; Humans ; Hypotheses ; Immunoglobulins ; Imprinting ; Infant ; Male ; Methylation ; Patients ; Pedigree ; Phenotypes ; Placenta ; Regulation ; Regulatory sequences ; RNA, Long Noncoding - genetics ; Uniparental disomy
    ISSN: 1018-4813
    E-ISSN: 1476-5438
    Source: Academic Search Ultimate
    Source: PubMed Central
    Source: Alma/SFX Local Collection
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  • 9
    Language: English
    In: Human mutation, 2010-01, Vol.31 (1), p.81-89
    Description: Werner mesomelic syndrome (WMS) is an autosomal dominant disorder with unknown molecular etiology characterized by hypo‐ or aplasia of the tibiae in addition to the preaxial polydactyly (PPD) of the hands and feet and/or five‐fingered hand with absence of thumbs. We show that point mutations of a specific nucleotide within the sonic hedgehog (SHH) regulatory region (ZRS) cause WMS. In a previously unpublished WMS family, we identified the causative G〉A transition at position 404 of the ZRS, and in six affected family members of a second WMS family we found a 404G〉C mutation of the ZRS. The 404G〉A ZRS mutation is known as the “Cuban mutation” of PPD type II (PPD2). Interestingly, the index patient of that family had tibial hypoplasia as well. These data provide the first evidence that WMS is caused by a specific ZRS mutation, which leads to strong ectopic SHH expression. In contrast, we show that complete duplications of the ZRS region lead to type Haas polysyndactyly or triphalangeal thumb‐polysyndactyly syndrome, but do not affect lower limb development. We suggest the term “ZRS‐associated syndromes” and a clinical subclassification for the continuum of limb malformations caused by different molecular alterations of the ZRS. Hum Mutat 30:1–9, 2009. © 2009 Wiley‐Liss, Inc.
    Subject(s): Adult ; Enhancer Elements, Genetic - genetics ; Female ; Finger Phalanges - abnormalities ; Genetic Predisposition to Disease ; Haas polysyndactyly ; Hedgehog Proteins - genetics ; Humans ; Limb Deformities, Congenital - genetics ; Male ; Point Mutation ; Polydactyly - genetics ; Syndactyly - genetics ; Syndrome ; Thumb - abnormalities ; Tibia - abnormalities ; triphalangeal thumb polysyndactyly syndrome ; WMS ; ZRS
    ISSN: 1059-7794
    E-ISSN: 1098-1004
    Source: Hellenic Academic Libraries Link
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  • 10
    Language: English
    In: Journal of human genetics, 2018-09, Vol.63 (9), p.997-1001
    Description: Approximately 1-3% of children have intellectual disability or global developmental delay. Heterozygous mutations have emerged as a major cause of different intellectual disability syndromes. In severely affected patients, reproductive fitness is impaired and mutations have usually arisen de novo. Massive parallel sequencing has been an effective means of diagnosing patients, especially those who carry a de novo mutation. The molecular diagnosis can be a way to shift from a more phenotype-driven management of the clinical signs to a more refined treatment based on genotype. Here, we report a novel dominantly inherited KAT6A missense variant in the C-terminal transactivation domain identified by exome sequencing in a girl and her father. Both had intellectual disability/developmental delay, short stature, microcephaly, and strabismus with the father being mildly affected. We here report the first inherited variant in KAT6A and suggest missense variants in KAT6A to be associated with an inheritable, milder clinical presentation compared to previously reported de novo, truncating mutations in this gene.
    Subject(s): Child ; Chromosome Disorders - genetics ; Developmental Disabilities - genetics ; Female ; Genes, Dominant ; Genotypes ; Histone Acetyltransferases - genetics ; Humans ; Intellectual disabilities ; Microcephaly ; Microcephaly - genetics ; Microencephaly ; Mutation ; Mutation, Missense ; Patients ; Phenotypes ; Reproductive fitness ; Strabismus
    ISSN: 1434-5161
    E-ISSN: 1435-232X
    Source: Alma/SFX Local Collection
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