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  • 1
    Language: English
    In: American journal of human genetics, 2012-08-10, Vol.91 (2), p.349-357
    Description: Osteogenesis imperfecta (OI) is a clinically and genetically heterogeneous disorder associated with bone fragility and susceptibility to fractures after minimal trauma. OI type V has an autosomal-dominant pattern of inheritance and is not caused by mutations in the type I collagen genes COL1A1 and COL1A2. The most remarkable and pathognomonic feature, observed in ∼65% of affected individuals, is a predisposition to develop hyperplastic callus after fractures or surgical interventions. To identify the molecular cause of OI type V, we performed whole-exome sequencing in a female with OI type V and her unaffected parents and searched for de novo mutations. We found a heterozygous de novo mutation in the 5′-untranslated region of IFITM5 (the gene encoding Interferon induced transmembrane protein 5), 14 bp upstream of the annotated translation initiation codon (c.−14C〉T). Subsequently, we identified an identical heterozygous de novo mutation in a second individual with OI type V by Sanger sequencing, thereby confirming that this is the causal mutation for the phenotype. IFITM5 is a protein that is highly enriched in osteoblasts and has a putative function in bone formation and osteoblast maturation. The mutation c.−14C〉T introduces an upstream start codon that is in frame with the reference open-reading frame of IFITM5 and is embedded into a stronger Kozak consensus sequence for translation initiation than the annotated start codon. In vitro, eukaryotic cells were able to recognize this start codon, and they used it instead of the reference translation initiation signal. This suggests that five amino acids (Met-Ala-Leu-Glu-Pro) are added to the N terminus and alter IFITM5 function in individuals with the mutation.
    Subject(s): 5' Untranslated Regions - genetics ; Absorptiometry, Photon ; Amino Acid Sequence ; Amino acids ; Base Sequence ; Biological and medical sciences ; Bones ; Causes of ; Cells ; Child ; Codon, Initiator - genetics ; Computational Biology ; Diphosphonates - therapeutic use ; Diseases of the osteoarticular system ; Exome - genetics ; Exome sequencing ; Female ; Fundamental and applied biological sciences. Psychology ; Gene mutations ; Genetic aspects ; Genetic disorders ; Genetic translation ; Genetics of eukaryotes. Biological and molecular evolution ; Genomics ; Genotype & phenotype ; Growth ; Humans ; Infant ; Malformations and congenital and or hereditary diseases involving bones. Joint deformations ; Medical genetics ; Medical sciences ; Membrane Proteins - genetics ; Molecular and cellular biology ; Molecular Sequence Data ; Mutation ; Osteogenesis imperfecta ; Osteogenesis Imperfecta - diagnostic imaging ; Osteogenesis Imperfecta - drug therapy ; Osteogenesis Imperfecta - genetics ; Point Mutation - genetics ; Report ; Research ; Sequence Analysis, DNA ; Usage
    ISSN: 0002-9297
    E-ISSN: 1537-6605
    Source: Cell Press Collection [ECCPC]
    Source: PubMed Central
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  • 2
    Language: English
    In: American journal of human genetics, 2011, Vol.88 (3), p.362-371
    Description: Osteogenesis imperfecta (OI) is a heterogeneous genetic disorder characterized by bone fragility and susceptibility to fractures after minimal trauma. After mutations in all known OI genes had been excluded by Sanger sequencing, we applied next-generation sequencing to analyze the exome of a single individual who has a severe form of the disease and whose parents are second cousins. A total of 26,922 variations from the human reference genome sequence were subjected to several filtering steps. In addition, we extracted the genotypes of all dbSNP130-annotated SNPs from the exome sequencing data and used these 299,494 genotypes as markers for the genome-wide identification of homozygous regions. A single homozygous truncating mutation, affecting SERPINF1 on chromosome 17p13.3, that was embedded into a homozygous stretch of 2.99 Mb remained. The mutation was also homozygous in the affected brother of the index patient. Subsequently, we identified homozygosity for two different truncating SERPINF1 mutations in two unrelated patients with OI and parental consanguinity. All four individuals with SERPINF1 mutations have severe OI. Fractures of long bones and severe vertebral compression fractures with resulting deformities were observed as early as the first year of life in these individuals. Collagen analyses with cultured dermal fibroblasts displayed no evidence for impaired collagen folding, posttranslational modification, or secretion. SERPINF1 encodes pigment epithelium-derived factor (PEDF), a secreted glycoprotein of the serpin superfamily. PEDF is a multifunctional protein and one of the strongest inhibitors of angiogenesis currently known in humans. Our data provide genetic evidence for PEDF involvement in human bone homeostasis.
    Subject(s): Adolescent ; Base Sequence ; Biological and medical sciences ; Care and treatment ; Causes of ; Child ; Child, Preschool ; Chromosomes ; Diseases of the osteoarticular system ; DNA Mutational Analysis ; Exons - genetics ; Eye Proteins - genetics ; Fundamental and applied biological sciences. Psychology ; Gene mutations ; General aspects. Genetic counseling ; Genes ; Genes, Recessive - genetics ; Genetic disorders ; Genetics of eukaryotes. Biological and molecular evolution ; Genotype & phenotype ; Glycoproteins ; Homeostasis ; Homozygosity ; Homozygote ; Humans ; Infant ; Malformations and congenital and or hereditary diseases involving bones. Joint deformations ; Medical genetics ; Medical sciences ; Molecular and cellular biology ; Molecular Sequence Data ; Mutation ; Mutation - genetics ; Nerve Growth Factors - genetics ; Nucleotide sequencing ; Osteogenesis imperfecta ; Osteogenesis Imperfecta - diagnostic imaging ; Osteogenesis Imperfecta - genetics ; Radiography ; Report ; Research ; Serpins - genetics ; Usage
    ISSN: 0002-9297
    E-ISSN: 1537-6605
    Source: Cell Press Collection [ECCPC]
    Source: PubMed Central
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  • 3
    Language: English
    In: Orphanet journal of rare diseases, 2014-09-26, Vol.9 (1), p.145-145
    Description: Osteogenesis imperfecta (OI) is a hereditary disease causing reduced bone mass, increased fracture rate, long bone deformities and vertebral compressions. Additional non skeletal findings are caused by impaired collagen function and include hyperlaxity of joints and blue sclera. Most OI cases are caused by dominant mutations in COL1A1/2 affecting bone formation. During the last years, recessive forms of OI have been identified, mostly affecting posttranslational modification of collagen. In 2011, mutations in SERPINF1 were identified as the molecular cause of OI type VI, and thereby a novel pathophysiology of the disease was elucidated. The subgroup of patients with OI type VI are affected by an increased bone resorption, leading to the same symptoms as observed in patients with an impaired bone formation. Severely affected children are currently treated with intravenous bisphosphonates regardless of the underlying mutation and pathophysiology. Patients with OI type VI are known to have a poor response to such a bisphosphonate treatment. Deciphering the genetic cause of OI type VI in our 4 patients (three children and one adolescent) led to an immediate translational approach in the form of a treatment with the monoclonal RANKL antibody Denosumab (1 mg/kg body weight every 12 weeks). Short-term biochemical response to this treatment was reported previously. We now present the results after 2 years of treatment and demonstrate a long term benefit as well as an increase of bone mineral density, a normalization of vertebral shape, an increase of mobility, and a reduced fracture rate. This report presents the first two-year data of denosumab treatment in patients with Osteogenesis imperfecta type VI and in Osteogenesis imperfecta in general as an effective and apparently safe treatment option.
    Subject(s): Antibodies ; Antibodies, Monoclonal, Humanized - pharmacology ; Antibodies, Monoclonal, Humanized - therapeutic use ; Bone density ; Bone Density - drug effects ; Bone Density - physiology ; Bone mineral density ; Bones ; Child ; Colleges & universities ; Denosumab ; Density ; Female ; Fractures ; Genetic aspects ; Humans ; Laboratories ; Male ; Mutation ; Older people ; Osteogenesis Imperfecta - diagnostic imaging ; Osteogenesis Imperfecta - drug therapy ; Osteogenesis imperfecta VI ; Osteoporosis ; Patients ; Radiography ; RANK Ligand - antagonists & inhibitors ; RANKL Antibody ; Research ; SERPINF1 ; Time Factors ; Viral antibodies ; Vitamin D ; Young Adult
    ISSN: 1750-1172
    E-ISSN: 1750-1172
    Source: BioMedCentral Open Access
    Source: Academic Search Ultimate
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 4
    Language: English
    In: Journal of lipid research, 2018-08, Vol.59 (8), p.1529-1535
    Description: Copy-number variations (CNVs) have been studied in the context of familial hypercholesterolemia but have not yet been evaluated in patients with extreme levels of HDL cholesterol. We evaluated targeted, next-generation sequencing data from patients with very low levels of HDL cholesterol (i.e., hypoalphalipoproteinemia) with the VarSeq-CNV® caller algorithm to screen for CNVs that disrupted the ABCA1, LCAT, or APOA1 genes. In four individuals, we found three unique deletions in ABCA1: a heterozygous deletion of exon 4, a heterozygous deletion that spanned exons 8 to 31, and a heterozygous deletion of the entire ABCA1 gene. Breakpoints were identified with Sanger sequencing, and the full-gene deletion was confirmed by using exome sequencing and the Affymetrix CytoScan HD array. Previously, large-scale deletions in candidate HDL genes had not been associated with hypoalphalipoproteinemia; our findings indicate that CNVs in ABCA1 may be a previously unappreciated genetic determinant of low levels of HDL cholesterol. By coupling bioinformatic analyses with next-generation sequencing data, we can successfully assess the spectrum of genetic determinants of many dyslipidemias, including hypoalphalipoproteinemia.
    Subject(s): ABCA1 protein ; Adult ; ATP Binding Cassette Transporter 1 - deficiency ; ATP Binding Cassette Transporter 1 - genetics ; ATP-binding cassette subfamily A member 1 ; ATP-binding protein ; bioinformatic analysis ; Breakpoints ; Cholesterol ; Computational Biology ; copy-number variation ; diagnostic tools ; Dietary fiber ; DNA Copy Number Variations ; dyslipidemia ; Exons ; Female ; Gene Deletion ; Genes ; genetic testing ; High density lipoprotein ; high density lipoprotein cholesterol ; High-Throughput Nucleotide Sequencing ; Humans ; Hypercholesterolemia ; Hypoalphalipoproteinemia ; Hypoalphalipoproteinemias - genetics ; Male ; Middle Aged ; next-generation sequencing ; Patient-Oriented and Epidemiological Research
    ISSN: 0022-2275
    E-ISSN: 1539-7262
    Source: HighWire Press (Free Journals)
    Source: PubMed Central
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  • 5
    Language: English
    In: American journal of human genetics, 2012-04-06, Vol.90 (4), p.661-674
    Description: Bone morphogenetic protein 1 (BMP1) is an astacin metalloprotease with important cellular functions and diverse substrates, including extracellular-matrix proteins and antagonists of some TGFβ superfamily members. Combining whole-exome sequencing and filtering for homozygous stretches of identified variants, we found a homozygous causative BMP1 mutation, c.34G〉C, in a consanguineous family affected by increased bone mineral density and multiple recurrent fractures. The mutation is located within the BMP1 signal peptide and leads to impaired secretion and an alteration in posttranslational modification. We also characterize a zebrafish bone mutant harboring lesions in bmp1a, demonstrating conservation of BMP1 function in osteogenesis across species. Genetic, biochemical, and histological analyses of this mutant and a comparison to a second, similar locus reveal that Bmp1a is critically required for mature-collagen generation, downstream of osteoblast maturation, in bone. We thus define the molecular and cellular bases of BMP1-dependent osteogenesis and show the importance of this protein for bone formation and stability.
    Subject(s): Analysis ; Animals ; Base Sequence ; Biological and medical sciences ; Bone and Bones - metabolism ; Bone Density Conservation Agents - therapeutic use ; Bone Morphogenetic Protein 1 - genetics ; Bone Morphogenetic Protein 1 - metabolism ; Bone Morphogenetic Protein 1 - physiology ; Bone Morphogenetic Protein 1 - secretion ; Bone morphogenetic proteins ; Bones ; Causes of ; Cell Differentiation ; Cells ; Chemical properties ; Child, Preschool ; Collagen ; Collagen - biosynthesis ; Density ; Diphosphonates - therapeutic use ; DNA sequencing ; Exome ; Female ; Fractures, Bone - drug therapy ; Fractures, Bone - prevention & control ; Fundamental and applied biological sciences. Psychology ; Gene mutations ; General aspects. Genetic counseling ; Genetic Loci ; Genetics ; Genetics of eukaryotes. Biological and molecular evolution ; Heat-Shock Proteins ; Human subjects ; Humans ; Male ; Medical genetics ; Medical sciences ; Molecular and cellular biology ; Molecular Sequence Data ; Mutation ; Nucleotide sequencing ; Osteoblasts - drug effects ; Osteoblasts - physiology ; Osteogenesis - drug effects ; Osteogenesis - genetics ; Osteogenesis - physiology ; Osteoporosis ; Peptide Fragments ; Peptides ; Post-translational modification ; Protein Processing, Post-Translational ; Proteins ; Research ; Signal transduction ; Transforming growth factors ; Zebrafish ; Zebrafish - genetics ; Zebrafish - metabolism
    ISSN: 0002-9297
    E-ISSN: 1537-6605
    Source: Cell Press Collection [ECCPC]
    Source: PubMed Central
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  • 6
    Language: English
    In: American journal of human genetics, 2015-03-05, Vol.96 (3), p.432-439
    Description: As a result of a whole-exome sequencing study, we report three mutant alleles in SEC24D, a gene encoding a component of the COPII complex involved in protein export from the ER: the truncating mutation c.613C〉T (p.Gln205∗) and the missense mutations c.3044C〉T (p.Ser1015Phe, located in a cargo-binding pocket) and c.2933A〉C (p.Gln978Pro, located in the gelsolin-like domain). Three individuals from two families affected by a similar skeletal phenotype were each compound heterozygous for two of these mutant alleles, with c.3044C〉T being embedded in a 14 Mb founder haplotype shared by all three. The affected individuals were a 7-year-old boy with a phenotype most closely resembling Cole-Carpenter syndrome and two fetuses initially suspected to have a severe type of osteogenesis imperfecta. All three displayed a severely disturbed ossification of the skull and multiple fractures with prenatal onset. The 7-year-old boy had short stature and craniofacial malformations including macrocephaly, midface hypoplasia, micrognathia, frontal bossing, and down-slanting palpebral fissures. Electron and immunofluorescence microscopy of skin fibroblasts of this individual revealed that ER export of procollagen was inefficient and that ER tubules were dilated, faithfully reproducing the cellular phenotype of individuals with cranio-lentico-sutural dysplasia (CLSD). CLSD is caused by SEC23A mutations and displays a largely overlapping craniofacial phenotype, but it is not characterized by generalized bone fragility and presented with cataracts in the original family described. The cellular and morphological phenotypes we report are in concordance with the phenotypes described for the Sec24d-deficient fish mutants vbi (medaka) and bulldog (zebrafish).
    Subject(s): Alleles ; Animals ; Bone and Bones - pathology ; Bones ; Causes of ; Child ; Craniosynostoses - genetics ; Endoplasmic Reticulum - metabolism ; Eye Abnormalities - genetics ; Female ; Fractures ; Gene mutations ; Genes ; Genetic aspects ; Genetic research ; Genotype & phenotype ; Heterozygote ; Humans ; Hydrocephalus - genetics ; Male ; Mutation ; Mutation, Missense ; Osteogenesis imperfecta ; Osteogenesis Imperfecta - genetics ; Pedigree ; Phenotype ; Protein Conformation ; Report ; Research ; Sequence Analysis, DNA ; Vesicular Transport Proteins - genetics ; Vesicular Transport Proteins - metabolism ; Zebrafish - genetics
    ISSN: 0002-9297
    E-ISSN: 1537-6605
    Source: PubMed Central
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  • 7
    Language: English
    In: Orphanet journal of rare diseases, 2019-09-18, Vol.14 (1), p.219-219
    Description: Background Osteogenesis imperfecta (OI) is a rare disease leading to hereditary bone fragility. Nearly 90% of cases are caused by mutations in the collagen genes COL1A1/A2 (classical OI) leading to multiple fractures, scoliosis, short stature and nonskeletal findings as blue sclera, hypermobility of joints, bone pain and delayed motor function development. Bisphosphonates are used in most moderate and severely affected patients assuming that an increase of bone mineral density might reduce fractures and bone pain in patients with OI. Denosumab as a RANK ligand antibody inhibiting osteoclast maturation has been approved for osteoporosis treatment in adults. First data from small clinical trials promised a high efficacy of Denosumab in children with OI. Aim of this analysis was a retrospective evaluation of an individualized biomarker-associated treatment regime with Denosumab in 10 children with classical OI which were followed for 1 year after their participation in a pilot trial with Denosumab. Therefore urinary deoxypyridinoline levels were evaluated frequently as an osteoclastic activity marker and depending on that levels Denosumab injections were scheduled individually. Methods Ten patients (age range: 6.16-12.13 years; all participated in the former OI-AK phase 2 trial (NCT01799798)) were included in the follow-up period. Denosumab was administered subcutaneously depending on the individual urinary excretion course of deoxypyridinoline (DPD/Crea) as osteoclastic activity marker with 1 mg/kg body weight. DPD/Crea levels were evaluated before denosumab administration and afterwards. If patients present after an initial decrease after injection with a re-increase up to the DPD/crea level before Denosumab injection next dosage was planned. Changes of areal bone mineral density (aBMD) using dual energy x-ray absorptiometry of the lumbar spine after 12 month was evaluated. Safety was assessed by bone metabolism markers and side effect reporting. Results During follow-up mean relative change of lumbar aBMD was - 6.4%. Lumbar spine aBMD z-Scores decreased from - 1.01 +/- 2.61 (mean +/- SD) to - 1.91 +/- 2.12 (p = 0.015). Mobility changed not significantly (GMFM-88 -6.49 +/- 8.85% (p = 0.08). No severe side effects occurred. Dose intervals could be extended in the mean from 12 weeks previously to 20.3 weeks. Conclusions On average, it was possible to prolong the intervals between drug administrations and to reduce the total dose about by 25% without a decrease of mobility or change of vertebral shape despite a reduction of lumbar aBMD during 1 year of biomarker-directed Denosumab treatment. Further trials are necessary to balance side effects and highest efficacy in children.
    Subject(s): Age ; Biomarkers ; Bisphosphonates ; Body weight ; Bone density ; Bone mineral density ; Bone turnover ; Children ; Clinical trials ; Collagen ; Collagen (type I) ; Denosumab ; Deoxypyridinoline ; Dosage ; Dual energy X-ray absorptiometry ; Excretion ; Fractures ; Genetics & Heredity ; Hypercalciuria ; Immunotherapy ; Injection ; Life Sciences & Biomedicine ; Ligands ; Medicine, Research & Experimental ; Mobility ; Monoclonal antibodies ; Mutation ; Osteoclasts ; Osteogenesis ; Osteogenesis imperfecta ; Osteoporosis ; Pain ; Patients ; Research ; Research & Experimental Medicine ; Science & Technology ; Scoliosis ; Side effects ; TRANCE protein ; Vertebrae
    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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  • 8
    Language: English
    In: American journal of human genetics, 2013-04-04, Vol.92 (4), p.565-574
    Description: We report that hypofunctional alleles of WNT1 cause autosomal-recessive osteogenesis imperfecta, a congenital disorder characterized by reduced bone mass and recurrent fractures. In consanguineous families, we identified five homozygous mutations in WNT1: one frameshift mutation, two missense mutations, one splice-site mutation, and one nonsense mutation. In addition, in a family affected by dominantly inherited early-onset osteoporosis, a heterozygous WNT1 missense mutation was identified in affected individuals. Initial functional analysis revealed that altered WNT1 proteins fail to activate canonical LRP5-mediated WNT-regulated β-catenin signaling. Furthermore, osteoblasts cultured in vitro showed enhanced Wnt1 expression with advancing differentiation, indicating a role of WNT1 in osteoblast function and bone development. Our finding that homozygous and heterozygous variants in WNT1 predispose to low-bone-mass phenotypes might advance the development of more effective therapeutic strategies for congenital forms of bone fragility, as well as for common forms of age-related osteoporosis.
    Subject(s): Analysis ; Animals ; Base Sequence ; Bone and Bones - pathology ; Bone Density - genetics ; Cells, Cultured ; Child ; Child, Preschool ; Congenital diseases ; Female ; Fractures ; Gene expression ; Genetic aspects ; Genetic disorders ; Genotype & phenotype ; Heterozygote ; Humans ; Infant, Newborn ; LDL-Receptor Related Proteins - genetics ; Male ; Medical genetics ; Mice ; Mice, Inbred C57BL ; Molecular Sequence Data ; Mutation ; Mutation - genetics ; Osteoblasts - metabolism ; Osteoblasts - pathology ; Osteogenesis Imperfecta - genetics ; Osteogenesis Imperfecta - pathology ; Osteoporosis ; Osteoporosis - genetics ; Osteoporosis - pathology ; Pedigree ; Phenotype ; Pregnancy ; Proteins ; Signal transduction ; Wnt1 Protein - genetics
    ISSN: 0002-9297
    E-ISSN: 1537-6605
    Source: Cell Press Collection [ECCPC]
    Source: PubMed Central
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  • 9
    Language: English
    In: European journal of human genetics : EJHG, 2018-09, Vol.26 (9), p.1392-1395
    Description: Complete uniparental isodisomy (iUPD)-the presence of two identical chromosomes in an individual that originate from only a single parental homolog-is an underestimated cause of recessive Mendelian disease in humans. Correctly identifying iUPD in an index patient is of enormous consequence to correctly counseling the family/couple, as the recurrence risk for siblings is reduced from 25% to usually 〈1%. In medium/large-scale NGS analyses, we found that complete iUPD can be rapidly and straightforwardly inferred from a singleton dataset (index patient only) through a simple chromosome- and genotype-filtering step in 〈1 min. We discuss the opportunities of iUPD detection in medium/large-scale NGS analyses by example of a case of CHRNG-associated multiple pterygium syndrome due to complete maternal iUPD. Using computer simulations for several detection thresholds, we validate and estimate sensitivity, specificity, positive (PPV), and negative predictive values (NPV) of the proposed screening method for reliable detection of complete iUPD. When screening for complete iUPD, our models suggest that a 〉85% proportion of homozygous calls on a single chromosome with ≥30 sufficiently interspaced called variants results in a sensitivity of 97.9% and specificity of 99.7%. The PPV is 95.1%, the NPV 99.9%. When this threshold is exceeded for a chromosome on which a patient harbors an apparently homozygous disease-associated variant, it should be sufficient cause to discuss iUPD as a plausible or probable mechanism of disease in the genetic analysis report, even when parental segregation has not (yet) been performed.
    Subject(s): Brief Communication ; Chromosomes ; Genetic analysis ; Genotypes ; Mathematical models
    ISSN: 1018-4813
    E-ISSN: 1476-5438
    Source: PubMed Central
    Source: Alma/SFX Local Collection
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  • 10
    Language: English
    In: Human mutation, 2016-09, Vol.37 (9), p.847-864
    Description: ABSTRACT Kabuki syndrome (KS) is a rare but recognizable condition that consists of a characteristic face, short stature, various organ malformations, and a variable degree of intellectual disability. Mutations in KMT2D have been identified as the main cause for KS, whereas mutations in KDM6A are a much less frequent cause. Here, we report a mutation screening in a case series of 347 unpublished patients, in which we identified 12 novel KDM6A mutations (KS type 2) and 208 mutations in KMT2D (KS type 1), 132 of them novel. Two of the KDM6A mutations were maternally inherited and nine were shown to be de novo. We give an up‐to‐date overview of all published mutations for the two KS genes and point out possible mutation hot spots and strategies for molecular genetic testing. We also report the clinical details for 11 patients with KS type 2, summarize the published clinical information, specifically with a focus on the less well‐defined X‐linked KS type 2, and comment on phenotype–genotype correlations as well as sex‐specific phenotypic differences. Finally, we also discuss a possible role of KDM6A in Kabuki‐like Turner syndrome and report a mutation screening of KDM6C (UTY) in male KS patients. Kabuki syndrome is a rare genetic condition that is caused by mutations in the KMT2D gene in approximately 56%–75% of cases and by mutations in KDM6A in 5%–8%. We present a mutation screening of 347 patients with Kabuki syndrome, which identified 208 mutations in KMT2D, as well as twelve novel KDM6A mutations. We discuss the molecular and clinical findings in this large cohort and compare them to the literature with a focus on the rarer X‐linked Kabuki syndrome type 2.
    Subject(s): Abnormalities, Multiple - genetics ; Abnormalities, Multiple - pathology ; DNA-Binding Proteins - genetics ; Face - abnormalities ; Face - pathology ; Female ; Genes ; Genes, X-Linked ; Genetic aspects ; Genetic disorders ; Genetic Predisposition to Disease ; Genotype & phenotype ; Hematologic Diseases - genetics ; Hematologic Diseases - pathology ; Histone Demethylases - genetics ; Humans ; Kabuki syndrome ; KDM6A ; KDM6C ; KMT2D ; Life Sciences ; Male ; Maternal Inheritance ; MLL2 ; Mutation ; Neoplasm Proteins - genetics ; Noonan Syndrome - genetics ; Nuclear Proteins - genetics ; Sequence Analysis, DNA ; UTY ; Vestibular Diseases - genetics ; Vestibular Diseases - pathology
    ISSN: 1059-7794
    E-ISSN: 1098-1004
    Source: Hellenic Academic Libraries Link
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