Publications by authors named "Ok Hwa Kim"

83 Publications

Novel RPL13 Variants and Variable Clinical Expressivity in a Human Ribosomopathy With Spondyloepimetaphyseal Dysplasia.

J Bone Miner Res 2021 Feb 13;36(2):283-297. Epub 2020 Oct 13.

Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.

Spondyloepimetaphyseal dysplasias (SEMDs) are a heterogeneous group of disorders with variable growth failure and skeletal impairments affecting the spine and long bone epiphyses and metaphyses. Here we report on four unrelated families with SEMD in which we identified two monoallelic missense variants and one monoallelic splice site variant in RPL13, encoding the ribosomal protein eL13. In two out of four families, we observed autosomal dominant inheritance with incomplete penetrance and variable clinical expressivity; the phenotypes of the mutation-positive subjects ranged from normal height with or without hip dysplasia to severe SEMD with severe short stature and marked skeletal dysplasia. In vitro studies on patient-derived dermal fibroblasts harboring RPL13 missense mutations demonstrated normal eL13 expression, with proper subcellular localization but reduced colocalization with eL28 (p < 0.001). Cellular functional defects in fibroblasts from mutation-positive subjects indicated a significant increase in the ratio of 60S subunits to 80S ribosomes (p = 0.007) and attenuated global translation (p = 0.017). In line with the human phenotype, our rpl13 mutant zebrafish model, generated by CRISPR-Cas9 editing, showed cartilage deformities at embryonic and juvenile stages. These findings extend the genetic spectrum of RPL13 mutations causing this novel human ribosomopathy with variable skeletal features. Our study underscores for the first time incomplete penetrance and broad phenotypic variability in SEMD-RPL13 type and confirms impaired ribosomal function. Furthermore, the newly generated rpl13 mutant zebrafish model corroborates the role of eL13 in skeletogenesis. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)..
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http://dx.doi.org/10.1002/jbmr.4177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988564PMC
February 2021

Biallelic variants p.Arg1133Cys and p.Arg1379Cys in COL2A1: Further delineation of phenotypic spectrum of recessive Type 2 collagenopathies.

Am J Med Genet A 2020 02 22;182(2):338-347. Epub 2019 Nov 22.

Center for Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.

The phenotypic spectrum of Type 2 collagenopathies ranges from lethal achondrogenesis Type 2 to milder osteoarthritis with mild chondrodysplasia. All of them are monoallelic except for the two recent reports showing that biallelic variants in COL2A1 can cause spondyloepiphyseal dysplasia congenita in two children. Here we report two additional families with homozygous variants, c.4135C>T (p.Arg1379Cys) and c.3190C>T (p.Arg1133Cys) in COL2A1 resulting in two distinct skeletal dysplasia phenotypes of intermediate severity. Though all six patients from four families exhibit a spondylo-epimetaphyseal dysplasia, they demonstrate a wide variation in severity of short stature and involvement of epiphyses, metaphyses, and vertebrae. We hypothesize that the variants are likely to be hypomorphic, given the underlying mechanisms of disease causation for known heterozygous variants in COL2A1. With this report, we provide further evidence to the existence of autosomal recessive Type 2 collagenopathy.
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http://dx.doi.org/10.1002/ajmg.a.61414DOI Listing
February 2020

Genetic abnormalities in a large cohort of Coffin-Siris syndrome patients.

J Hum Genet 2019 Dec 17;64(12):1173-1186. Epub 2019 Sep 17.

Asahikawa-Kosei General Hospital, Hokkaido, Japan.

Coffin-Siris syndrome (CSS, MIM#135900) is a congenital disorder characterized by coarse facial features, intellectual disability, and hypoplasia of the fifth digit and nails. Pathogenic variants for CSS have been found in genes encoding proteins in the BAF (BRG1-associated factor) chromatin-remodeling complex. To date, more than 150 CSS patients with pathogenic variants in nine BAF-related genes have been reported. We previously reported 71 patients of whom 39 had pathogenic variants. Since then, we have recruited an additional 182 CSS-suspected patients. We performed comprehensive genetic analysis on these 182 patients and on the previously unresolved 32 patients, targeting pathogenic single nucleotide variants, short insertions/deletions and copy number variations (CNVs). We confirmed 78 pathogenic variations in 78 patients. Pathogenic variations in ARID1B, SMARCB1, SMARCA4, ARID1A, SOX11, SMARCE1, and PHF6 were identified in 48, 8, 7, 6, 4, 1, and 1 patients, respectively. In addition, we found three CNVs including SMARCA2. Of particular note, we found a partial deletion of SMARCB1 in one CSS patient and we thoroughly investigated the resulting abnormal transcripts.
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http://dx.doi.org/10.1038/s10038-019-0667-4DOI Listing
December 2019

A Case of Familial Spondyloenchondrodysplasia with Immune Dysregulation Masquerading as Moyamoya Syndrome.

J Clin Neurol 2019 Jul;15(3):407-409

Department of Pediatrics, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Korea.

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http://dx.doi.org/10.3988/jcn.2019.15.3.407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6620444PMC
July 2019

Novel loss-of-function variants of TRAPPC2 manifesting X-linked spondyloepiphyseal dysplasia tarda: report of two cases.

BMC Med Genet 2019 05 3;20(1):70. Epub 2019 May 3.

Division of Pediatric Orthopaedics, Seoul National University Children's Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.

Background: X-linked spondyloepiphyseal dysplasia tarda (SEDT-XL) is a skeletal disorder characterized by defective structures of vertebral bodies and/or of epiphyses of the long bones, resulting in moderately short stature and early joint degeneration. TRAPPC2 gene, which is important for collagen secretion, has been reported as causative for SEDT-XL.

Case Presentation: Here, we report two variants of TRAPPC2 gene of SEDT-XL patients, a missense variant of start codon, c.1A > T, and a deletion variant, c.40delG. To understand molecular consequence of the variants, we establish an in vitro gene expression assay system and demonstrate that both mutated genes are transcribed, but are not properly translated, indicative of the pathogenic nature of those TRAPPC2 variants.

Conclusions: In the current study, we provide additional experimental data showing that loss-of-function TRAPPC2 variants are probably causative for SEDT-XL phenotype. These findings further contribute to the understanding the clinical picture related to TRAPPC2 gene.
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http://dx.doi.org/10.1186/s12881-019-0802-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6500034PMC
May 2019

Hypomorphic Mutations in TONSL Cause SPONASTRIME Dysplasia.

Am J Hum Genet 2019 03 14;104(3):439-453. Epub 2019 Feb 14.

Department of Bio and Brain Engineering, Korean Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea.

SPONASTRIME dysplasia is a rare, recessive skeletal dysplasia characterized by short stature, facial dysmorphism, and aberrant radiographic findings of the spine and long bone metaphysis. No causative genetic alterations for SPONASTRIME dysplasia have yet been determined. Using whole-exome sequencing (WES), we identified bi-allelic TONSL mutations in 10 of 13 individuals with SPONASTRIME dysplasia. TONSL is a multi-domain scaffold protein that interacts with DNA replication and repair factors and which plays critical roles in resistance to replication stress and the maintenance of genome integrity. We show here that cellular defects in dermal fibroblasts from affected individuals are complemented by the expression of wild-type TONSL. In addition, in vitro cell-based assays and in silico analyses of TONSL structure support the pathogenicity of those TONSL variants. Intriguingly, a knock-in (KI) Tonsl mouse model leads to embryonic lethality, implying the physiological importance of TONSL. Overall, these findings indicate that genetic variants resulting in reduced function of TONSL cause SPONASTRIME dysplasia and highlight the importance of TONSL in embryonic development and postnatal growth.
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http://dx.doi.org/10.1016/j.ajhg.2019.01.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407524PMC
March 2019

Severe hypotonia and postnatal growth impairment in a girl with a missense mutation in COL1A1: Implication of expanded phenotypic spectrum of type I collagenopathy.

Brain Dev 2017 Oct 28;39(9):799-803. Epub 2017 Jun 28.

Department of Pediatrics, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea. Electronic address:

Background: It is known that type I collagenopathy has a broad-spectrum phenotypic variability. Here, we report a case of a Korean girl with a heterozygous COL1A1 mutation who had an atypical presentation.

Case Presentation: A 26-month-old girl presented with delayed motor development and failure to thrive. She had severe growth retardation. She exhibited right-sided plagiocephaly, blue sclerae, and facial dysmorphism, including a small pointed chin, frontal bossing, and a triangular face, but had microcephaly. Whole-exome sequencing revealed a novel de novo heterozygous sequence variant in COL1A1 (p.Gly1127Asp), which was validated by Sanger sequencing. Radiological finding showed generalized osteoporosis with progressive scoliosis of the spine without evidence of platyspondyly related to fractures and bowing of the long bones, and markedly delayed carpal bone age. Muscle pathology showed a marked size variation of myofibers and selective type 1 atrophy.

Conclusions: This study expanded the clinical and genetic spectrum of type I collagenopathy with a COL1A1 variant. Therefore, we suggest that type I collagenopathy should be considered in the patients who have some features of osteogenesis imperfecta simultaneously with atypical features such as facial dysmorphism.
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http://dx.doi.org/10.1016/j.braindev.2017.04.020DOI Listing
October 2017

Autosomal dominant brachyolmia: transient metaphyseal striations.

Skeletal Radiol 2017 Sep 10;46(9):1297-1300. Epub 2017 Jun 10.

Department of Orthopaedic Surgery, Yonsei University College of Medicine, Severance Children's Hospital, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, South Korea.

We report transient proximal and distal femoral metaphyseal striations that have not previously been described in autosomal dominant brachyolmia. The pelvis/hip radiograph of a 13-year-old boy demonstrated bilaterally symmetrical proximal femoral metaphyseal vertical striations. Additional vertical striations were also observed at the distal femur and proximal tibia metaphysis. Radiography of the thoracolumbar spine demonstrated platyspondyly with irregular endplates and overfaced pedicles. TRPV4 mutations were confirmed in this patient. Similar proximal femoral metaphyseal vertical striations were noted in the patient's sibling. Those streaks disappeared on the follow-up radiographs, and we considered it a unique radiologic finding transiently observed in autosomal dominant brachyolmia.
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http://dx.doi.org/10.1007/s00256-017-2684-8DOI Listing
September 2017

Confirmation of CAGSSS syndrome as a distinct entity in a Danish patient with a novel homozygous mutation in IARS2.

Am J Med Genet A 2017 Apr;173(4):1102-1108

Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark.

Since the original description of the IARS2-related cataracts, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, skeletal dysplasia syndrome (CAGSSS; OMIM 616007) in an extended consanguineous family of French-Canadian descent, no further patients have been reported. IARS2 (OMIM 612801) encodes the mitochondrial isoleucine-tRNA synthetase which belongs to the class-I aminoacyl-tRNA synthetase family, and has been implicated in CAGSSS and a form of Leigh syndrome. Here, we report on a female Danish patient with a novel homozygous IARS2 mutation, p.Gly874Arg, who presented at birth with bilateral hip dislocation and short stature. At 3 months, additional dysmorphic features were noted and at 18 months her radiographic skeletal abnormalities were suggestive of an underlying spondyloepimetaphyseal dysplasia (SEMD). Retrospective analysis of the neonatal radiographs confirmed that the skeletal changes were present at birth. It was only with time that several of the other manifestations of the CAGSSS emerged, namely, cataracts, peripheral neuropathy, and hearing loss. Growth hormone deficiency has not (yet) manifested. We present her clinical features and particularly highlight her skeletal findings, which confirm the presence of a primary SEMD skeletal dysplasia in a growing list of mitochondrial-related disorders including CAGSSS, CODAS, EVEN-PLUS, and X-linked SEMD-MR syndromes.
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http://dx.doi.org/10.1002/ajmg.a.38116DOI Listing
April 2017

Orthopedic Manifestations of Type I Camurati-Engelmann Disease.

Clin Orthop Surg 2017 Mar 13;9(1):109-115. Epub 2017 Feb 13.

Division of Pediatric Orthopedics, Seoul National University Children's Hospital, Seoul, Korea.

Background: Camurati-Engelmann disease (CED) is a rare genetic skeletal disorder characterized by limb pain, muscle emaciation and weakness, and cortical thickening of the diaphysis of long bones. It is caused by mutations in the transforming growth factor beta 1 (TGFB1) (type I) or other unknown gene(s) (type II). We present 8 consecutive patients with type I CED.

Methods: We retrospectively reviewed medical records and radiographs of type I CED patients with special reference to the mode of presentation, process of diagnostic work-up, and disease course. They were 4 sporadic patients, and two pairs of mother and son.

Results: We categorized the mode of presentation into three groups. Group I had 4 patients who mainly presented with motor disturbances in young age. They drew medical attention for waddling gait, awkward ambulation or running, difficulty in going upstairs, or a positive Gower's sign at age 4 to 6 years. Subsequent development of limb pain and radiographic abnormality led to the diagnosis of CED at age 6 to 29 years. Group II had 3 patients who mainly presented with limb pain at age 15, 20, and 54 years, respectively. Radiographic evaluation and molecular genetic test led to the diagnosis of CED. The remaining 1 patient (group III) was asymptomatic until age 9 years when bony lesions at the tibiae were found incidentally. For the last 10 years, he intermittently complained of leg pain in the morning or after sports activities, which did not interfere with daily life. All the patients in group I showed a body mass index in the underweight range (< 18.4 kg/m). At the latest follow-up, 4 patients in groups I and II required medication for the limb pain.

Conclusions: CED presents with a wide range of severity. Awareness of this rare disease entity may be the key to timely correct diagnosis. This disease entity should be considered in the differential diagnosis of limb pain or motor disturbance in children to avoid unnecessary diagnostic work-up.
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http://dx.doi.org/10.4055/cios.2017.9.1.109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5334020PMC
March 2017

Additional three patients with Smith-McCort dysplasia due to novel RAB33B mutations.

Am J Med Genet A 2017 Mar 27;173(3):588-595. Epub 2017 Jan 27.

Department of Medical Genetics, Kasturba Medical College, Manipal University, Manipal, India.

Smith-McCort dysplasia (SMC OMIM 615222) and Dyggve-Melchior-Clausen dysplasia (DMC OMIM 223800) are allelic skeletal dysplasias caused by homozygous or compound heterozygous mutations in DYM (OMIM 607461). Both disorders share the same skeletal phenotypes characterized by spondylo-epi-metaphyseal dysplasia with distinctive lacy ilia. The difference rests on the presence or absence of intellectual disability, that is, intellectual disability in DMC and normal cognition in SMC. However, genetic heterogeneity was suspected in SMC. Recently, RAB33B (OMIM 605950) has been identified as the second gene for SMC. Nevertheless, only two affected families have been reported so far. Here we present three SMC patients with four novel pathogenic variants in RAB33B, including homozygosity for c.211C>T (p.R71*), homozygosity for c.365T>C (p.F122S), and compound heterozygosity for c.48delCGGGGCAG (p.G17Vfs*58) and c.490C>T (p.Q164*). We also summarize the clinical, radiological, and mutation profile of RAB33B after literature mining. This report ascertains the pathogenic relationship between RAB33B and SMC. © 2017 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajmg.a.38064DOI Listing
March 2017

First Korean Case of Infantile Hypophosphatasia with Novel Mutation in ALPL and Literature Review.

Ann Clin Lab Sci 2016 May;46(3):302-7

Departments of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

Hypophosphatasia is a rare hereditary disorder characterized by defective bone and tooth mineralization and deficiency of tissue non-specific alkaline phosphatase activity. The prognosis for the infantile form is poor, with approximately 50% of patients dying within the first year of life from respiratory failure. We describe the clinical and biochemical findings as well as the molecular analysis of a Korean boy with infantile hypophosphatasia and present a literature review. A 1-month-old boy visited the clinic because of poor feeding, frequent vomiting, hypotonia, and failure to thrive from birth. Laboratory tests revealed high total calcium, low phosphorous, low alkaline phosphatase, low parathyroid hormone, and normal 25-hydroxyvitamin D. Intravenous hydration with normal saline was started, and dietary calcium intake was restricted. Skeletal X-rays showed a markedly increased distance of the anterior fontanelle, impaired mineralization, and rachitic changes in the metaphyses. By Sanger sequencing of the ALPL gene, we identified two heterozygous variants, including a missense (c.334G>A; p.Gly112Ser) and a nonsense (c.1039C>T; p.Gln347*) variant. The c.334G>A (p.Gly112Ser) variant had previously been reported in a patient with lethal type hypophosphatasia, while the nonsense c.1039C>T (p.Gln347*) variant was novel. In the current case, the accurate diagnosis and prompt intervention-including dietary calcium intake restriction, tracheostomy to prevent progression to respiratory failure, and fundoplication with gastrostomy to ensure the administration of adequate calories-seemed to play an important role for avoiding preventable morbidity and premature mortality.
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May 2016

BGN Mutations in X-Linked Spondyloepimetaphyseal Dysplasia.

Am J Hum Genet 2016 06 26;98(6):1243-1248. Epub 2016 May 26.

Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea. Electronic address:

Spondyloepimetaphyseal dysplasias (SEMDs) comprise a heterogeneous group of autosomal-dominant and autosomal-recessive disorders. An apparent X-linked recessive (XLR) form of SEMD in a single Italian family was previously reported. We have been able to restudy this family together with a second family from Korea by segregating a severe SEMD in an X-linked pattern. Exome sequencing showed missense mutations in BGN c.439A>G (p.Lys147Glu) in the Korean family and c.776G>T (p.Gly259Val) in the Italian family; the c.439A>G (p.Lys147Glu) mutation was also identified in a further simplex SEMD case from India. Biglycan is an extracellular matrix proteoglycan that can bind transforming growth factor beta (TGF-β) and thus regulate its free concentration. In 3-dimensional simulation, both altered residues localized to the concave arc of leucine-rich repeat domains of biglycan that interact with TGF-β. The observation of recurrent BGN mutations in XLR SEMD individuals from different ethnic backgrounds allows us to define "XLR SEMD, BGN type" as a nosologic entity.
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http://dx.doi.org/10.1016/j.ajhg.2016.04.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4908150PMC
June 2016

Enhancing patterns of breast cancer on preoperative dynamic contrast-enhanced magnetic resonance imaging and resection margin in breast conserving therapy.

Breast Dis 2016 Feb;36(1):27-35

Department of Surgery, Haeundae Paik Hospital, College of Medicine, Inje University, Busan, Korea.

Background: The association between enhancing patterns of preoperative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and resection margins after BCS has not been studied in detail before.

Objective: We investigated the association between surgical outcomes and enhancing patterns observed on DCE-MRI.

Methods: 269 enhancing patterns on DCE-MRI scans were selected, and subdivided into the following groups: (1) a single mass-like enhancement, (2) a single non-mass-like enhancement (NME), (3) mass-like enhancing breast cancer with other mass-like enhancing lesions, and (4) mass-like enhancing breast cancer with additional NMEs. Associations between enhancing patterns on DCE-MRI and re-excision rate, size of specimen, and ratio of tumor/specimen were evaluated retrospectively.

Results: The conversion rate from breast conserving therapy (BCT) to mastectomy as a result of MRI findings was 13.4%, re-excision rate during BCT was 8.2% and excision rate of another suspicious lesion was 7.4%. The single NME group had the highest re-excision rate after BCT (22.2%) (p = 0.02). The ratio of tumor/specimen (p = 0.61) and mean specimen size (p = 0.38) were not influenced by enhancement patterns. The false positive rate and positive predictive values of using DCE-MRI for defining the extension of breast cancer was 22.2% and 71.4%, respectively.

Conclusion: Enhancement patterns on DCE- MRI, especially NME, could increase re-excision rates.
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http://dx.doi.org/10.3233/BD-150195DOI Listing
February 2016

Identification of the Mutations in the Prostaglandin Transporter Gene, SLCO2A1 and Clinical Characterization in Korean Patients with Pachydermoperiostosis.

J Korean Med Sci 2016 May 22;31(5):735-42. Epub 2016 Mar 22.

Department of Internal Medicine, Endocrine Research Institute, Yonsei University College of Medicine, Seoul, Korea .

Pachydermoperiostosis (PDP), or primary hypertrophic osteoarthropathy, is a rare genetic disease affecting both skin and bones. Both autosomal dominant with incomplete penetrance and recessive inheritance of PDP have been previously confirmed. Recently, hydroxyprostaglandin dehydrogenase (HPGD) and solute carrier organic anion transporter family member 2A1 (SLCO2A1) were reported as pathogenic genes responsible for PDP. Both genes are involved in prostaglandin E2 (PGE2) degradation. We aimed to identify responsible genes for PDP and the clinical features in Korean patients with PDP. Six affected individuals and their available healthy family members from three unrelated Korean families with PDP were studied. All of the patients displayed complete phenotypes of PDP with finger clubbing, pachydermia, and periostosis. Mutation analysis revealed a novel heterozygous mutation in the SLCO2A1 gene at nucleotide 302 causing a substitution of the amino acid isoleucine to serine at codon 101 (p.IIe101Ser) in affected individuals. We also identified known SLCO2A1 mutations, one homozygous for c.940+1G>A, and another compound heterozygous for c.940+1G>A and c.1807C>T (p.Arg603*) from two PDP families. Genetic analyses of the PDP patients showed no abnormality in the HPGD gene. Our study further supports the role of mutations in the SLCO2A1 gene in the pathogenesis of PDP and could provide additional clues to the genotype-phenotype relations of PDP.
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http://dx.doi.org/10.3346/jkms.2016.31.5.735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4835599PMC
May 2016

Axial Spondylometaphyseal Dysplasia Is Caused by C21orf2 Mutations.

PLoS One 2016 14;11(3):e0150555. Epub 2016 Mar 14.

Laboratory of Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, 108-8639, Japan.

Axial spondylometaphyseal dysplasia (axial SMD) is an autosomal recessive disease characterized by dysplasia of axial skeleton and retinal dystrophy. We conducted whole exome sequencing and identified C21orf2 (chromosome 21 open reading frame 2) as a disease gene for axial SMD. C21orf2 mutations have been recently found to cause isolated retinal degeneration and Jeune syndrome. We found a total of five biallelic C21orf2 mutations in six families out of nine: three missense and two splicing mutations in patients with various ethnic backgrounds. The pathogenic effects of the splicing (splice-site and branch-point) mutations were confirmed on RNA level, which showed complex patterns of abnormal splicing. C21orf2 mutations presented with a wide range of skeletal phenotypes, including cupped and flared anterior ends of ribs, lacy ilia and metaphyseal dysplasia of proximal femora. Analysis of patients without C21orf2 mutation indicated genetic heterogeneity of axial SMD. Functional data in chondrocyte suggest C21orf2 is implicated in cartilage differentiation. C21orf2 protein was localized to the connecting cilium of the cone and rod photoreceptors, confirming its significance in retinal function. Our study indicates that axial SMD is a member of a unique group of ciliopathy affecting skeleton and retina.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0150555PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4790905PMC
August 2016

SOFT syndrome caused by compound heterozygous mutations of POC1A and its skeletal manifestation.

J Hum Genet 2016 Jun 21;61(6):561-4. Epub 2016 Jan 21.

Department of Orthopaedic Surgery, Seoul National University College of Medicine, Seoul, Korea.

SOFT syndrome (MIM614813) is an extremely rare primordial dwarfism characterized by short stature, onychodysplasia, facial dysmorphism and hypotrichosis, which is caused by biallelic mutations in the POC1A gene. Only 19 patients with mutation-confirmed SOFT syndrome have been reported to date, all of whom carried homozygous variants that were strongly associated with consanguineous marriages. We report an 8.5-year-old boy with SOFT syndrome showing primordial dwarfism, no effect of growth-hormone therapy and skeletal dysplasia. This is the first report of compound heterozygous variants in POC1A, one previously reported and the other novel. A characteristic skeletal manifestation is reported.
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http://dx.doi.org/10.1038/jhg.2015.174DOI Listing
June 2016

Extending the phenotype of BMPER-related skeletal dysplasias to ischiospinal dysostosis.

Orphanet J Rare Dis 2016 Jan 4;11. Epub 2016 Jan 4.

Department of Paediatrics and Department of Clinical and Experimental Medicine, Linköping University, Norrköping, Sweden.

Ischiospinal dysostosis (ISD) is a polytopic dysostosis characterized by ischial hypoplasia, multiple segmental anomalies of the cervicothoracic spine, hypoplasia of the lumbrosacral spine and occasionally associated with nephroblastomatosis. ISD is similar to, but milder than the lethal/semilethal condition termed diaphanospondylodysostosis (DSD), which is associated with homozygous or compound heterozygous mutations of bone morphogenetic protein-binding endothelial regulator protein (BMPER) gene. Here we report for the first time biallelic BMPER mutations in two patients with ISD, neither of whom had renal abnormalities. Our data supports and further extends the phenotypic variability of BMPER-related skeletal disorders.
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http://dx.doi.org/10.1186/s13023-015-0380-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4700746PMC
January 2016

Mutations in the heat-shock protein A9 (HSPA9) gene cause the EVEN-PLUS syndrome of congenital malformations and skeletal dysplasia.

Sci Rep 2015 Nov 24;5:17154. Epub 2015 Nov 24.

Centre for Molecular Diseases, Department of Pediatrics, Lausanne University Hospital (CHUV), Lausanne, Switzerland.

We and others have reported mutations in LONP1, a gene coding for a mitochondrial chaperone and protease, as the cause of the human CODAS (cerebral, ocular, dental, auricular and skeletal) syndrome (MIM 600373). Here, we delineate a similar but distinct condition that shares the epiphyseal, vertebral and ocular changes of CODAS but also included severe microtia, nasal hypoplasia, and other malformations, and for which we propose the name of EVEN-PLUS syndrome for epiphyseal, vertebral, ear, nose, plus associated findings. In three individuals from two families, no mutation in LONP1 was found; instead, we found biallelic mutations in HSPA9, the gene that codes for mHSP70/mortalin, another highly conserved mitochondrial chaperone protein essential in mitochondrial protein import, folding, and degradation. The functional relationship between LONP1 and HSPA9 in mitochondrial protein chaperoning and the overlapping phenotypes of CODAS and EVEN-PLUS delineate a family of "mitochondrial chaperonopathies" and point to an unexplored role of mitochondrial chaperones in human embryonic morphogenesis.
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http://dx.doi.org/10.1038/srep17154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4657157PMC
November 2015

Acromesomelic dysplasia, type maroteaux caused by novel loss-of-function mutations of the NPR2 gene: Three case reports.

Am J Med Genet A 2016 Feb 14;170A(2):426-434. Epub 2015 Nov 14.

Division of Pediatric Orthopaedics, Seoul National University Children's Hospital, Seoul, Republic of Korea.

The C-type natriuretic peptide (CNP)-natriuretic peptide receptor 2 (NPR2) signaling pathway plays an important role in chondrocyte development. Homozygous loss-of-function mutations of the NPR2 gene cause acromesomelic dysplasia, type Maroteaux (AMDM). The aim of this study was to identify and characterize NPR2 loss-of-function mutations in patients with AMDM. The NPR2 gene was sequenced in three Korean patients with AMDM and functional analysis of the mutated proteins was performed in vitro. Five novel NPR2 mutations were found in the three patients: two compound heterozygous mutations [c.1231T>C (Tyr411His) and c.2761C>T (Arg921X) in Patient 1 and c.1663A>T (Lys555X) and c.1711-1G>C (M571VfsX12) in Patient 3] and a homozygous mutation [c.2762G>A (Arg921Gln) in Patient 2]. Serum NT-proCNP concentration was significantly increased in each patient compared to control subjects. Cells transfected with the expression vector of each mutant except those found in Patient 3 showed a negligible or a markedly low cGMP response after treatment with CNP. HA-tagged wild-type (wt) and HA-mutant NPR2 were expressed at comparable levels: there were two bands of ∼130 and ∼120 kDa in wt and Arg921Gln, a single ∼120 kDa band in Tyr411His, and a single ∼110 kDa in the nonsense mutant. With respect to subcellular localization, Arg921Gln as well as wt-NPR2 reached the cell surface, whereas Tyr411His and Arg921X mutants did not. The Tyr411His and Arg921X NPR2 proteins were co-localized with an endoplasmic reticulum (ER) marker and failed to traffic from the ER to the Golgi apparatus. These results are consistent with deglycosylation experiments. Tyr411His and Arg921X NPR2 are complete loss-of-function mutations, whereas Arg921Gln behaves as a receptor for CNP with limited function.
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http://dx.doi.org/10.1002/ajmg.a.37463DOI Listing
February 2016

Subcutaneous intravascular papillary endothelial hyperplasia: ultrasound features and pathological correlation.

Skeletal Radiol 2016 Feb 12;45(2):227-33. Epub 2015 Nov 12.

Department of Radiology, Daegu Catholic University Medical Center, Daegu, Republic of Korea.

Background: To describe grayscale and color Doppler ultrasound features of subcutaneous intravascular papillary endothelial hyperplasia (IPEH).

Materials And Methods: The ultrasound appearances of ten histologically proven subcutaneous IPEH in ten patients (age range, 15-69 years; mean age, 38.2 years; six females, four males) were reviewed retrospectively by two musculoskeletal radiologists. Color Doppler examination and surgical excision were performed in all cases. The correlations between the ultrasound and pathological features of the lesions were done.

Results: All ten cases were pathologically diagnosed as pure forms of IPEH. The mean size of the lesions was 1.3 cm. The margins of the lesions were circumscribed in seven of ten patients. Three had lobular margins. The distinct internal septum-like structures were seen in seven of ten cases (70 %). The vascularity was rich in three (30 %), moderate in four (40 %), and little in three (30 %) of the ten cases. The most common vascular pattern was one or more vessels peripherally or both peripherally and centrally located in the lesion. The detectable origin vessel was noted in four of ten cases (40 %).

Conclusions: Although sonographic features of subcutaneous IPEH are non-specific, they should be included in the differential diagnosis of a small, well-defined, oval or elliptical, heterogeneous, hypoechoic soft tissue mass, showing a vascular pattern of one or more vessels in the lesion and variable vascularity. The presence of the internal septum-like structures and detectable origin vessel may be help to distinguish the lesion from the other soft tissue masses.
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http://dx.doi.org/10.1007/s00256-015-2281-7DOI Listing
February 2016

Ultrasonographic findings of the various diseases presenting as calf pain.

Clin Imaging 2016 Jan-Feb;40(1):1-12. Epub 2015 Sep 24.

Department of Radiology, University of Michigan Medical Center, MI, US.

There are various causes of calf pain. The differential diagnoses affecting the lower leg include cystic lesions, trauma-related lesions, infection or inflammation, vascular lesions, neoplasms, and miscellaneous entities. Ultrasound (US) provide detailed anatomical information of the calf structures, and it offers the ability to confirm, other calf abnormalities, particularly when deep vein thrombosis (DVT) is ruled out. The purpose of this article is to review the causes of a painful calf presenting as DVT and incidental findings found as part of the work-up of DVT, and to provide a broad overview of US findings and clinical features of these pathologies.
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http://dx.doi.org/10.1016/j.clinimag.2015.09.015DOI Listing
August 2016

Comprehensive genetic exploration of skeletal dysplasia using targeted exome sequencing.

Genet Med 2016 06 24;18(6):563-9. Epub 2015 Sep 24.

Division of Pediatric Orthopaedics, Seoul National University Children's Hospital, Seoul, Korea.

Purpose: The purpose of this study was to evaluate the clinical utility of targeted exome sequencing (TES) as a molecular diagnostic tool for patients with skeletal dysplasia.

Methods: A total of 185 patients either diagnosed with or suspected to have skeletal dysplasia were recruited over a period of 3 years. TES was performed for 255 genes associated with the pathogenesis of skeletal dysplasia, and candidate variants were selected using a bioinformatics analysis. All candidate variants were confirmed by Sanger sequencing, correlation with the phenotype, and a cosegregation study in the family.

Results: TES detected "confirmed" or "highly likely" pathogenic sequence variants in 74% (71 of 96) of cases in the assured clinical diagnosis category and 20.3% (13 of 64 cases) of cases in the uncertain clinical diagnosis category. TES successfully detected pathogenic variants in all 25 cases of previously known genotypes. The data also suggested a copy-number variation that led to a molecular diagnosis.

Conclusion: This study demonstrates the feasibility of TES for the molecular diagnosis of skeletal dysplasia. However, further confirmation is needed for a final molecular diagnosis, including Sanger sequencing of candidate variants with suspected, poorly captured exons.Genet Med 18 6, 563-569.
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http://dx.doi.org/10.1038/gim.2015.129DOI Listing
June 2016

Novel COL2A1 variant (c.619G>A, p.Gly207Arg) manifesting as a phenotype similar to progressive pseudorheumatoid dysplasia and spondyloepiphyseal dysplasia, Stanescu type.

Hum Mutat 2015 Oct 6;36(10):1004-8. Epub 2015 Aug 6.

Department of Pediatrics, University of Wisconsin-Madison, Madison, Wisconsin, 53705.

Progressive pseudorheumatoid dysplasia (PPRD) is a rare, autosomal-recessive condition characterized by mild spondyloepiphyseal dysplasia (SED) and severe, progressive, early-onset arthritis due to WISP3 mutations. SED, Stanescu type, is a vaguely delineated autosomal-dominant dysplasia of unknown genetic etiology. Here, we report three individuals from two unrelated families with radiological features similar to PPRD and SED, Stanescu type who share the same novel COL2A1 variant and were matched following discussion at an academic conference. In the first family, we performed whole-exome sequencing on three family members, two of whom have a PPRD-like phenotype, and identified a heterozygous variant (c.619G>A, p.Gly207Arg) in both affected individuals. Independently, targeted sequencing of the COL2A1 gene in an unrelated proband with a similar phenotype identified the same heterozygous variant. We suggest that the p.Gly207Arg variant causes a distinct type II collagenopathy with features of PPRD and SED, Stanescu type.
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http://dx.doi.org/10.1002/humu.22839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4575260PMC
October 2015

Identification of p.Glu131Lys Mutation in the IHH Gene in a Korean Patient With Brachydactyly Type A1.

Ann Lab Med 2015 May 1;35(3):387-9. Epub 2015 Apr 1.

Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

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http://dx.doi.org/10.3343/alm.2015.35.3.387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4390715PMC
May 2015

Identifying the need for a multidisciplinary approach for early recognition of mucopolysaccharidosis VI (MPS VI).

Mol Genet Metab 2015 May 26;115(1):41-7. Epub 2015 Mar 26.

Department of Metabolic Medicine, Lady Cilento Children's Hospital, 501 Stanley Street, South Brisbane, QLD 4101, Australia.

Mucopolysaccharidosis VI (MPS VI, Maroteaux-Lamy syndrome) is caused by deficient activity of the enzyme, N-acetylgalactosamine-4-sulfatase, resulting in impaired degradation of the glycosaminoglycan dermatan sulfate. Patients experience a range of manifestations including joint contractures, short stature, dysostosis multiplex, coarse facial features, decreased pulmonary function, cardiac abnormalities, corneal clouding and shortened life span. Recently, clinicians from institutions in the Asia-Pacific region met to discuss the occurrence and implications of delayed diagnosis and misdiagnosis of MPS VI in the patients they have managed. Eighteen patients (44% female) were diagnosed. The most common sign presented by the patients was bone deformities in 11 patients (65%). Delays to diagnosis occurred due to the lack of or distance to diagnostic facilities for four patients (31%), alternative diagnoses for two patients (15%), and misleading symptoms experienced by two patients (15%). Several patients experienced manifestations that were subtler than would be expected and were subsequently overlooked. Several cases highlighted the unique challenges associated with diagnosing MPS VI from the perspective of different specialties and provide insights into how these patients initially present, which may help to elucidate strategies to improve the diagnosis of MPS VI.
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http://dx.doi.org/10.1016/j.ymgme.2015.03.005DOI Listing
May 2015

Mutations in LONP1, a mitochondrial matrix protease, cause CODAS syndrome.

Am J Med Genet A 2015 Jul 21;167(7):1501-9. Epub 2015 Mar 21.

Medical Genetics Service, CHUV, University of Lausanne, Switzerland.

Cerebral, ocular, dental, auricular, skeletal anomalies (CODAS) syndrome (MIM 600373) was first described and named by Shehib et al, in 1991 in a single patient. The anomalies referred to in the acronym are as follows: cerebral-developmental delay, ocular-cataracts, dental-aberrant cusp morphology and delayed eruption, auricular-malformations of the external ear, and skeletal-spondyloepiphyseal dysplasia. This distinctive constellation of anatomical findings should allow easy recognition but despite this only four apparently sporadic patients have been reported in the last 20 years indicating that the full phenotype is indeed very rare with perhaps milder or a typical presentations that are allelic but without sufficient phenotypic resemblance to permit clinical diagnosis. We performed exome sequencing in three patients (an isolated case and a brother and sister sib pair) with classical features of CODAS. Sanger sequencing was used to confirm results as well as for mutation discovery in a further four unrelated patients ascertained via their skeletal features. Compound heterozygous or homozygous mutations in LONP1 were found in all (8 separate mutations; 6 missense, 1 nonsense, 1 small in-frame deletion) thus establishing the genetic basis of CODAS and the pattern of inheritance (autosomal recessive). LONP1 encodes an enzyme of bacterial ancestry that participates in protein turnover within the mitochondrial matrix. The mutations cluster at the ATP-binding and proteolytic domains of the enzyme. Biallelic inheritance and clustering of mutations confirm dysfunction of LONP1 activity as the molecular basis of CODAS but the pathogenesis remains to be explored.
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http://dx.doi.org/10.1002/ajmg.a.37029DOI Listing
July 2015

Skeletal overgrowth syndrome caused by overexpression of C-type natriuretic peptide in a girl with balanced chromosomal translocation, t(1;2)(q41;q37.1).

Am J Med Genet A 2015 May 27;167A(5):1033-8. Epub 2015 Feb 27.

Department of Pediatrics, Seoul National University College of Medicine, Seoul, Republic of Korea.

Chromosomal translocation of 2q37.1 just distal to the NPPC gene coding for C-type natriuretic peptide (CNP) and subsequent overproduction of CNP have been reported to cause a skeletal overgrowth syndrome. Loeys-Dietz syndrome (LDS) is one of marfanoid overgrowth syndromes, of which subtype IV is caused by haploinsufficiency of transforming growth factor beta 2 (TGFB2). We report on a girl with clinical phenotypes of overgrowth syndrome, including long and slim body habitus, macrodactyly of the big toe, scoliosis, ankle valgus deformity, coxa valga, slipped capital femoral epiphysis, and aortic root dilatation. Karyotyping revealed a balanced chromosomal translocation between 1q41 and 2q37.1, and the breakpoints could be mapped by targeted resequencing analysis. On chromosome 2q37.1, the translocation took place 200,365 bp downstream of NPPC, and serum level of the amino terminal of CNP was elevated. The contralateral site of translocation on chromosome 1q41 disrupted TGFB2 gene, presumed to cause its haploinsufficiency. This case supports the concept that NPPC is overexpressed because of the loss of a specific negative regulatory control in the normal chromosomal location, and demonstrates the effectiveness of targeted resequencing in the mapping of breakpoints.
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http://dx.doi.org/10.1002/ajmg.a.36884DOI Listing
May 2015