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  • 1
    Language: English
    In: The New England journal of medicine, 2015-07-23, Vol.373 (4), p.349-356
    Description: Analysis of a family, some of the members of which have marked growth restriction, showed that the affected members carry a variant of IGF2 . It would therefore appear that IGF-II affects prenatal and postnatal growth. IGF-II is a peptide hormone and a member of the IGF family. IGF-I and IGF-II regulate somatic growth and cell proliferation by binding and activating the IGF-I receptor (IGF-IR). Although both are expressed during fetal development, IGF-II is thought to have a major effect on embryonic growth, with IGF-I becoming predominant after birth. 1 , 2 Studies of mice have supported a major role for the IGF receptor pathway in growth: knockout of Igf1 , Igf2 , or Igf1r results in growth retardation, whereas overexpression of Igf2 results in overgrowth. 3 , 4 In humans, mutations in IGF1 and in IGF1R have been implicated . . .
    Subject(s): Abridged Index Medicus ; Codon, Nonsense ; Fathers ; Female ; Fetal Growth Retardation - genetics ; Gene mutations ; Genes ; Genetics ; Genomes ; Genotype & phenotype ; Growth Disorders - genetics ; Growth factors ; Human growth ; Humans ; Imprinting ; Infant, Newborn ; Insulin ; Insulin-like growth factor I ; Insulin-like growth factor II ; Insulin-Like Growth Factor II - deficiency ; Insulin-Like Growth Factor II - genetics ; Male ; Mutation ; Pathogenicity ; Pedigree ; Phenotype ; Phenotypes ; Research ; Silver-Russell Syndrome - genetics ; Somatotropin
    ISSN: 0028-4793
    E-ISSN: 1533-4406
    Source: Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
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  • 2
    Language: English
    In: Nature genetics, 2012, Vol.44 (8), p.934-940
    Description: Megalencephaly-capillary malformation (MCAP) and megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndromes are sporadic overgrowth disorders associated with markedly enlarged brain size and other recognizable features. We performed exome sequencing in 3 families with MCAP or MPPH, and our initial observations were confirmed in exomes from 7 individuals with MCAP and 174 control individuals, as well as in 40 additional subjects with megalencephaly, using a combination of Sanger sequencing, restriction enzyme assays and targeted deep sequencing. We identified de novo germline or postzygotic mutations in three core components of the phosphatidylinositol 3-kinase (PI3K)-AKT pathway. These include 2 mutations in AKT3, 1 recurrent mutation in PIK3R2 in 11 unrelated families with MPPH and 15 mostly postzygotic mutations in PIK3CA in 23 individuals with MCAP and 1 with MPPH. Our data highlight the central role of PI3K-AKT signaling in vascular, limb and brain development and emphasize the power of massively parallel sequencing in a challenging context of phenotypic and genetic heterogeneity combined with postzygotic mosaicism.
    Subject(s): Abnormalities ; Biological and medical sciences ; Brain ; Class I Phosphatidylinositol 3-Kinases ; Complex syndromes ; Exome ; Fundamental and applied biological sciences. Psychology ; Gene mutations ; Genetic aspects ; Genetics of eukaryotes. Biological and molecular evolution ; Germ-Line Mutation ; Health aspects ; Humans ; Hydrocephalus - enzymology ; Hydrocephalus - genetics ; Hydrocephalus - pathology ; Malformations of Cortical Development - enzymology ; Malformations of Cortical Development - genetics ; Malformations of Cortical Development - pathology ; Malformations of the nervous system ; Medical genetics ; Medical sciences ; Megalencephaly - enzymology ; Megalencephaly - genetics ; Megalencephaly - pathology ; Mutation ; Mutation, Missense ; Neurology ; Phosphatidylinositol 3-Kinases - genetics ; Physiological aspects ; Protein kinases ; Proto-Oncogene Proteins c-akt - genetics ; Research ; Risk factors ; Syndrome
    ISSN: 1061-4036
    E-ISSN: 1546-1718
    Source: Academic Search Ultimate
    Source: Alma/SFX Local Collection
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  • 3
    Language: English
    In: Molecular psychiatry, 2019-07-01, Vol.24 (7), p.1027-1039
    Description: Autosomal recessive (AR) gene defects are the leading genetic cause of intellectual disability (ID) in countries with frequent parental consanguinity, which account for about 1/7th of the world population. Yet, compared to autosomal dominant de novo mutations, which are the predominant cause of ID in Western countries, the identification of AR-ID genes has lagged behind. Here, we report on whole exome and whole genome sequencing in 404 consanguineous predominantly Iranian families with two or more affected offspring. In 219 of these, we found likely causative variants, involving 77 known and 77 novel AR-ID (candidate) genes, 21 X-linked genes, as well as 9 genes previously implicated in diseases other than ID. This study, the largest of its kind published to date, illustrates that high-throughput DNA sequencing in consanguineous families is a superior strategy for elucidating the thousands of hitherto unknown gene defects underlying AR-ID, and it sheds light on their prevalence.
    Subject(s): Adult ; Biochemistry & Molecular Biology ; Consanguinity ; DNA sequencing ; Exome - genetics ; Family ; Female ; Genes ; Genes, Recessive - genetics ; Genetic aspects ; Genomes ; Genomics ; High-Throughput Nucleotide Sequencing - methods ; Homozygote ; Humans ; Intellectual Disability - genetics ; Iran ; Life Sciences & Biomedicine ; Male ; Medical research ; Medicine, Experimental ; Middle Aged ; Mutation - genetics ; Neurosciences ; Neurosciences & Neurology ; Nucleotide sequencing ; Pedigree ; Protein Interaction Maps - genetics ; Psychiatry ; Science & Technology ; Whole Exome Sequencing - methods ; Whole Genome Sequencing - methods
    ISSN: 1359-4184
    E-ISSN: 1476-5578
    Source: Web of Science - Science Citation Index Expanded - 2019〈img src="http://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" /〉
    Source: Nature Journals Online
    Source: Alma/SFX Local Collection
    Source: Web of Science - Social Sciences Citation Index – 2019〈img src="http://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" /〉
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  • 4
    Language: English
    In: Genetics in medicine, 2018-01, Vol.20 (1), p.98-108
    Description: PurposeThe study aimed at widening the clinical and genetic spectrum and assessing genotype-phenotype associations in FOXG1 syndrome due to FOXG1 variants.MethodsWe compiled 30 new and 53 reported patients with a heterozygous pathogenic or likely pathogenic variant in FOXG1. We grouped patients according to type and location of the variant. Statistical analysis of molecular and clinical data was performed using Fisher's exact test and a nonparametric multivariate test.ResultsAmong the 30 new patients, we identified 19 novel FOXG1 variants. Among the total group of 83 patients, there were 54 variants: 20 frameshift (37%), 17 missense (31%), 15 nonsense (28%), and 2 in-frame variants (4%). Frameshift and nonsense variants are distributed over all FOXG1 protein domains; missense variants cluster within the conserved forkhead domain. We found a higher phenotypic variability than previously described. Genotype-phenotype association revealed significant differences in psychomotor development and neurological features between FOXG1 genotype groups. More severe phenotypes were associated with truncating FOXG1 variants in the N-terminal domain and the forkhead domain (except conserved site 1) and milder phenotypes with missense variants in the forkhead conserved site 1.ConclusionsThese data may serve for improved interpretation of new FOXG1 sequence variants and well-founded genetic counseling.
    Subject(s): Child ; Child, Preschool ; DNA Mutational Analysis ; Female ; Forkhead Transcription Factors - genetics ; Genetic Association Studies ; Genetic counseling ; Genetic Variation ; Genotype ; Genotype & phenotype ; Humans ; Magnetic Resonance Imaging ; Male ; Nerve Tissue Proteins - genetics ; Phenotype ; Polymorphism, Single Nucleotide ; Rett Syndrome - diagnosis ; Rett Syndrome - genetics
    ISSN: 1098-3600
    E-ISSN: 1530-0366
    Source: Alma/SFX Local Collection
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  • 5
    Language: English
    In: Journal of medical genetics, 2011-11, Vol.48 (11), p.741-751
    Description: BackgroundHeterozygous mutations in the CASK gene in Xp11.4 have been shown to be associated with a distinct brain malformation phenotype in females, including disproportionate pontine and cerebellar hypoplasia.MethodsThe study characterised the CASK alteration in 20 new female patients by molecular karyotyping, fluorescence in situ hybridisation, sequencing, reverse transcriptase (RT) and/or quantitative real-time PCR. Clinical and brain imaging data of a total of 25 patients were reviewed.Results11 submicroscopic copy number alterations, including nine deletions of ∼11 kb to 4.5 Mb and two duplications, all covering (part of) CASK, four splice, four nonsense, and one 1 bp deletion are reported. These heterozygous CASK mutations most likely lead to a null allele. Brain imaging consistently showed diffuse brainstem and cerebellar hypoplasia with a dilated fourth ventricle, but of remarkably varying degrees. Analysis of 20 patients in this study, and five previously reported patients, revealed a core clinical phenotype comprising severe developmental delay/intellectual disability, severe postnatal microcephaly, often associated with growth retardation, (axial) hypotonia with or without hypertonia of extremities, optic nerve hypoplasia, and/or other eye abnormalities. A recognisable facial phenotype emerged, including prominent and broad nasal bridge and tip, small or short nose, long philtrum, small chin, and/or large ears.ConclusionsThese findings define the phenotypic spectrum associated with CASK loss-of-function mutations. The combination of developmental and brain imaging features together with mild facial dysmorphism is highly suggestive of this disorder and should prompt subsequent testing of the CASK gene.
    Subject(s): academic medicine ; Base Sequence ; Biological and medical sciences ; Biomarkers - metabolism ; Brain - metabolism ; Brain - pathology ; Brain - physiopathology ; CASK ; Child ; Child, Preschool ; chromosomal ; clinical genetics ; Cohort Studies ; copy-number ; developmental ; diagnostics ; diagnostics tests ; epigenetics ; epilepsy and seizures ; Female ; Fundamental and applied biological sciences. Psychology ; Gene Dosage ; Gene Duplication ; Gene mutations ; General aspects. Genetic counseling ; Genetic Association Studies ; genetic screening/counselling ; Genetic Variation ; genetics ; Genetics of eukaryotes. Biological and molecular evolution ; Genotype ; Guanylate Kinases - genetics ; Heterozygote ; Humans ; In Situ Hybridization, Fluorescence ; Infant ; intellectual disability ; Intellectual Disability - diagnosis ; Intellectual Disability - genetics ; Intellectual Disability - physiopathology ; Karyotyping ; Medical genetics ; Medical sciences ; microcephaly ; Microcephaly - diagnosis ; Microcephaly - genetics ; Microcephaly - physiopathology ; Molecular and cellular biology ; molecular genetics ; Molecular Sequence Data ; Neuroimaging ; neurology ; neurosciences ; other neurology ; Phenotype ; pontocerebellar hypoplasia ; Real-Time Polymerase Chain Reaction ; Research ; Sequence Deletion ; visual development ; X linked mental retardation
    ISSN: 0022-2593
    E-ISSN: 1468-6244
    Source: Hellenic Academic Libraries Link
    Source: BMJ Journals - NESLi2
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  • 6
    Language: English
    In: American journal of medical genetics. Part A, 2021-02, Vol.185 (2), p.517-527
    Description: Bone dysplasias (osteochondrodysplasias) are a large group of conditions associated with short stature, skeletal disproportion, and radiographic abnormalities of skeletal elements. Nearly all are genetic in origin. We report a series of seven children with similar findings of chondrodysplasia and growth failure following early hematopoietic stem cell transplantation (HSCT) for pediatric non‐oncologic disease: hemophagocytic lymphohistiocytosis or HLH (five children, three with biallelic HLH‐associated variants [in PRF1 and UNC13D] and one with HLH secondary to visceral Leishmaniasis), one child with severe combined immunodeficiency and one with Omenn syndrome (both children had biallelic RAG1 pathogenic variants). All children had normal growth and no sign of chondrodysplasia at birth and prior to their primary disease. After HSCT, all children developed growth failure, with standard deviation scores for height at or below −3. Radiographically, all children had changes in the spine, metaphyses and epiphyses, compatible with a spondyloepimetaphyseal dysplasia. Genomic sequencing failed to detect pathogenic variants in genes associated with osteochondrodysplasias. We propose that such chondrodysplasia with growth failure is a novel, rare, but clinically important complication following early HSCT for non‐oncologic pediatric diseases. The pathogenesis is unknown but could possibly involve loss or perturbation of the cartilage‐bone stem cell population.
    Subject(s): Analysis ; Bone diseases ; Child development ; chondrodysplasia ; Dysplasia ; Growth ; hematopoietic stem cell transplantation ; Hematopoietic stem cells ; Leishmaniasis ; Medicin och hälsovetenskap ; phenocopy ; skeletal dysplasia ; Stem cells ; Transplantation
    ISSN: 1552-4825
    ISSN: 1552-4833
    E-ISSN: 1552-4833
    Source: Hellenic Academic Libraries Link
    Source: Alma/SFX Local Collection
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  • 7
    Language: English
    In: Clinical genetics, 2021-08, Vol.100 (2), p.187-200
    Description: Mutations affecting the transcriptional regulator Ankyrin Repeat Domain 11 (ANKRD11) are mainly associated with the multisystem developmental disorder known as KBG syndrome, but have also been identified in individuals with Cornelia de Lange syndrome (CdLS) and other developmental disorders caused by variants affecting different chromatin regulators. The extensive functional overlap of these proteins results in shared phenotypical features, which complicate the assessment of the clinical diagnosis. Additionally, re‐evaluation of individuals at a later age occasionally reveals that the initial phenotype has evolved toward clinical features more reminiscent of a developmental disorder different from the one that was initially diagnosed. For this reason, variants in ANKRD11 can be ascribed to a broader class of disorders that fall within the category of the so‐called chromatinopathies. In this work, we report on the clinical characterization of 23 individuals with variants in ANKRD11. The subjects present primarily with developmental delay, intellectual disability and dysmorphic features, and all but two received an initial clinical diagnosis of either KBG syndrome or CdLS. The number and the severity of the clinical signs are overlapping but variable and result in a broad spectrum of phenotypes, which could be partially accounted for by the presence of additional molecular diagnoses and distinct pathogenic mechanisms. ​
    Subject(s): Abnormalities, Multiple - etiology ; Abnormalities, Multiple - genetics ; Adolescent ; ANKRD11 ; Birth defects ; Bone Diseases, Developmental - etiology ; Bone Diseases, Developmental - genetics ; Child ; Child, Preschool ; chromatinopathies ; Cornelia de Lange syndrome (CdLS) ; developmental disorders ; Face - abnormalities ; Facies ; Female ; Humans ; Intellectual Disability - etiology ; Intellectual Disability - genetics ; KBG syndrome (KBGS) ; Male ; Mutation ; Pedigree ; Proteins ; Repressor Proteins - genetics ; Tooth Abnormalities - etiology ; Tooth Abnormalities - genetics ; Young Adult
    ISSN: 0009-9163
    E-ISSN: 1399-0004
    Source: Hellenic Academic Libraries Link
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  • 8
    Language: English
    In: Orphanet journal of rare diseases, 2019-07-16, Vol.14 (1), p.179-179
    Description: BackgroundThe protein O-mannosyltransferase 1, encoded by the POMT1 gene, is a key enzyme in the glycosylation of alpha-dystroglycan. POMT1-related disorders belong to the group of dystroglycanopathies characterized by a proximally pronounced muscular dystrophy with structural or functional involvement of the brain and/or the eyes. The phenotypic spectrum ranges from the severe Walker-Warburg syndrome (WWS) to milder forms of limb girdle muscular dystrophy (LGMD). The phenotypic severity of POMT1-related dystroglycanopathies depends on the residual enzyme activity. A genotype-phenotype correlation can be assumed.ResultsThe clinical, neuroradiological, and genetic findings of 35 patients with biallelic POMT1 mutations (15 WWS, 1 MEB (muscle-eye-brain disease), 19 LGMD) from 27 independent families are reported. The representative clinical course of an infant with WWS and the long-term course of a 32years old patient with LGMD are described in more detail. Specific features of 15 patients with the homozygous founder mutation p.Ala200Pro are defined as a distinct and mildly affected LGMD subgroup. Ten previously reported and 8 novel POMT1 mutations were identified. Type and location of each of the POMT1 mutations are evaluated in detail and a list of all POMT1 mutations reported by now is provided. Patients with two mutations leading to premature protein termination had a WWS phenotype, while the presence of at least one missense mutation was associated with milder phenotypes. In the patient with MEB-like phenotype two missense mutations were observed within the catalytic active domain of the enzyme.ConclusionsOur large cohort confirms the importance of type and location of each POMT1 mutation for the individual clinical manifestation and thereby expands the knowledge on the genotype-phenotype correlation in POMT1-related dystroglycanopathies. This genotype-phenotype correlation is further supported by the observation of an intrafamiliar analogous clinical manifestation observed in all affected 13 siblings from 5 independent families. Our data confirm the progressive nature of the disease also in milder LGMD phenotypes, ultimately resulting in loss of ambulation at a variable age. Our data define two major clinical POMT1 phenotypes, which should prompt genetic testing including the POMT1 gene: patients with a severe WWS manifestation predominantly present with profound neonatal muscular hypotonia and a severe and progressive hydrocephalus with involvement of brainstem and/or cerebellum. The presence of an occipital encephalocele in a WWS patient might point to POMT1 as causative gene within the different genes associated with WWS. The milder LGMD phenotypes constantly show markedly elevated creatine kinase values in combination with microcephaly and cognitive impairment.
    Subject(s): Analysis ; Dystroglycan ; Female ; Gene mutations ; Genetic aspects ; Genetic Association Studies ; Genetics & Heredity ; Glycosylation ; Humans ; Hydrocephalus ; Infant ; Infant, Newborn ; Life Sciences & Biomedicine ; Limb girdle muscular dystrophy ; Lissencephaly ; Male ; Mannosyltransferases - genetics ; Medicine, Research & Experimental ; Muscle-eye-brain disease ; Muscular Dystrophies, Limb-Girdle - genetics ; Muscular dystrophy ; Mutation - genetics ; Occipital encephalocele ; POMT1 ; Research ; Research & Experimental Medicine ; Science & Technology ; Walker-Warburg syndrome ; Walker-Warburg Syndrome - genetics
    ISSN: 1750-1172
    E-ISSN: 1750-1172
    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
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 9
    Language: English
    In: American journal of medical genetics. Part A, 2017-03, Vol.173 (3), p.727-732
    Description: Constitutional ring chromosomes can be found for all human chromosomes and are very rare chromosomal abnormalities. A complete ring chromosome without loss of genetic material results from fusion of subtelomeric regions or telomere–telomere fusion. In cases of complete ring chromosome, an increased incidence of severe growth failure with no or only minor anomalies has been observed and attributed to ring syndrome. Ring syndrome is thought to be caused by “dynamic mosaicism” due to ring instability. We report a 6‐year‐old boy with de novo ring chromosome 4 and typical characteristics of the ring syndrome, namely, proportionate severe growth failure, microcephaly, and minor anomalies. Cytogenetic studies showed complete ring chromosome 4 with mitotic instability. Microarray gave normal results, thus excluding the loss of detectable genetic material. The literature of complete ring chromosome 4 is reviewed. Our case report supports the theory of ring syndrome. No studies about the effects and possible side effects of growth hormone therapy on patients with ring chromosomes have yet been published. We suggest that cytogenetic monitoring of the rate of secondary aberrations in patients with ring chromosome undergoing growth hormone therapy might be feasible. Since the diagnosis would have been missed by molecular karyotyping, our case report underlines the continuing role of classical cytogenetics for the evaluation of structural chromosomal abnormalities in patients with mental and/or physical anomalies. Standard karyotyping is still indispensable and should have an ongoing role as first‐tier analysis together with molecular karyotyping. © 2017 Wiley Periodicals, Inc.
    Subject(s): Analysis ; Child ; Chromosome Aberrations ; Chromosome Disorders - diagnosis ; Chromosome Disorders - genetics ; Chromosomes, Human, Pair 4 - genetics ; Comparative Genomic Hybridization ; complete ring chromosome 4 ; Cytogenetic Analysis - methods ; Cytogenetics ; Facies ; Genetic Association Studies ; Genetic research ; Humans ; In Situ Hybridization, Fluorescence ; Karyotyping ; Male ; Phenotype ; Ring Chromosomes ; ring syndrome ; Somatotropin ; Telomeres
    ISSN: 1552-4825
    E-ISSN: 1552-4833
    Source: Hellenic Academic Libraries Link
    Source: Alma/SFX Local Collection
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  • 10
    Language: English
    In: BMJ Open, 2013, Vol.3 (3), p.e001917
    Description: Objectives Till date, mutations in the genes PAX3 and MITF have been described in Waardenburg syndrome (WS), which is clinically characterised by congenital hearing loss and pigmentation anomalies. Our study intended to determine the frequency of mutations and deletions in these genes, to assess the clinical phenotype in detail and to identify rational priorities for molecular genetic diagnostics procedures. Design Prospective analysis. Patients 19 Caucasian patients with typical features of WS underwent stepwise investigation of PAX3 and MITF. When point mutations and small insertions/deletions were excluded by direct sequencing, copy number analysis by multiplex ligation-dependent probe amplification was performed to detect larger deletions and duplications. Clinical data and photographs were collected to facilitate genotype–phenotype analyses. Setting All analyses were performed in a large German laboratory specialised in genetic diagnostics. Results 15 novel and 4 previously published heterozygous mutations in PAX3 and MITF were identified. Of these, six were large deletions or duplications that were only detectable by copy number analysis. All patients with PAX3 mutations had typical phenotype of WS with dystopia canthorum (WS1), whereas patients with MITF gene mutations presented without dystopia canthorum (WS2). In addition, one patient with bilateral hearing loss and blue eyes with iris stroma dysplasia had a de novo missense mutation (p.Arg217Ile) in MITF. MITF 3-bp deletions at amino acid position 217 have previously been described in patients with Tietz syndrome (TS), a clinical entity with hearing loss and generalised hypopigmentation. Conclusions On the basis of these findings, we conclude that sequencing and copy number analysis of both PAX3 and MITF have to be recommended in the routine molecular diagnostic setting for patients, WS1 and WS2. Furthermore, our genotype–phenotype analyses indicate that WS2 and TS correspond to a clinical spectrum that is influenced by MITF mutation type and position.
    Subject(s): Amino acids ; Deoxyribonucleic acid--DNA ; Genes ; Genotype & phenotype ; Hearing impairment ; Mutation ; Patients ; Transcription factors
    ISSN: 2044-6055
    E-ISSN: 2044-6055
    Source: HighWire Press (Free Journals)
    Source: PubMed Central
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