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Stefan Mundlos - One of the best experts on this subject based on the ideXlab platform.
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skeletal deterioration in col2a1 related Spondyloepiphyseal Dysplasia occurs prior to osteoarthritis
Osteoarthritis and Cartilage, 2020Co-Authors: Tim Rolvien, Timur A Yorgan, Uwe Kornak, Irm Hermansborgmeyer, Stefan Mundlos, Tobias Schmidt, Andreas Niemeier, Thorsten Schinke, Michael AmlingAbstract:Summary Objective Spondyloepiphyseal Dysplasia, a combination of progressive arthropathy with variable signs of skeletal Dysplasia, can be a result of mutations in the collagen, type II, alpha 1 (COL2A1) gene. However, the bone involvement (e.g., density, microstructure) in this disorder has hitherto not been studied. Design A 50-year-old female patient and her 8-year-old son with flattening of vertebral bodies and early-onset osteoarthritis were genetically tested using a custom designed gene bone panel including 386 genes. Bone microstructure and turnover were assessed using high-resolution peripheral quantitative computed tomography (HR-pQCT) and serum bone turnover markers, respectively. Furthermore, the bone and cartilage phenotype of male mice heterozygous for the loss-of-function mutation of Col2a1 (Col2a1+/d) was analyzed compared to wildtype littermates using μ-CT and histomorphometry. Results We identified a dominant COL2A1 mutation (c.620G>A p.(Gly207Glu)) indicating Spondyloepiphyseal Dysplasia in the female patient and her son, both being severely affected by skeletal deterioration. Although there was no osteoarthritis detectable at first visit, the son was affected by trabecular osteopenia, which progressed over time. In an iliac crest biopsy obtained from the mother, osteoclast indices were remarkably increased. Col2a1+/d mice developed a moderate skeletal phenotype expressed by reduced cortical and trabecular parameters at 4 weeks. Importantly, no articular defects could be observed in the knee joints at 4 weeks, while osteoarthritis was only detectable in 12-week-old mice. Conclusions Our results indicate that collagen type II deficiency in Spondyloepiphyseal Dysplasia leads to skeletal deterioration with early-onset in humans and mice that occurs prior to the development of osteoarthritis.
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omani type Spondyloepiphyseal Dysplasia with cardiac involvement caused by a missense mutation in chst3
Clinical Genetics, 2009Co-Authors: Beyhan Tuysuz, Stefan Mundlos, Shuji Mizumoto, Kazuyuki Sugahara, A Celebi, Seval TurkmenAbstract:We describe a family with progressive skeletal Dysplasia and severe spinal involvement, short stature, premature arthrosis and joint contractures diagnosed as Spondyloepiphyseal Dysplasia Omani type. Mutation analysis in CHST3, the gene encoding for the chondroitin 6-O-sulfotransferase-1 (C6ST-1), revealed a homozygous missense mutation (T141M) in exon 3 in all three affected members of the family. Using recombinant C6ST-1, we showed that the identified missense mutation results in a reduction of C6ST-1 activity to 24-29% of the wild type protein. In addition to the previously noted skeletal features, affected members of this family also had cardiac involvement including mitral, tricuspid and/or aortic regurgitations and type E brachydactyly.
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Spondyloepiphyseal Dysplasia omani type a new recessive type of sed with progressive spinal involvement
American Journal of Medical Genetics, 2004Co-Authors: Anna Rajab, Jurgen Kunze, Stefan MundlosAbstract:We report a large inbred kindred from Oman with a distinct type of Spondyloepiphyseal Dysplasia (SED). We evaluated eight individuals from two consanguineous sibships, one male and seven females between the ages of 2 and 22. The pedigrees strongly suggest autosomal recessive inheritance and both families are likely to be related through distant consanguineous loops. The clinical features include near to normal length at birth, short stature with final height of 110-130 cm, shortening of the upper segment due to severe progressive kyphoscoliosis, severe arthritic changes with joint dislocations, rhizomelic limbs, genu valgum, cubitus valgus, mild brachydactyly, camptodactyly, microdontia, and normal intelligence. Minor radiographic metaphyseal changes were found, but major manifestations were in the spine and the epiphyses. During the first year of life the vertebral bodies are of normal height but the endplates are irregular and intervertebral space is narrow. With age, the vertebral endplates become increasingly irregular, the intervertebral space diminishes further and individual vertebrae start to fuse resulting in a severe short trunk dwarfism with kyphoscoliosis. The epiphysis are small and precocious osteoarthropathy was observed involving small and large joints. The elbow, wrist, and hip joints were affected starting in infancy and showed restricted movement. Osteoarthropathy and spinal involvement resulted in physical handicap in early adulthood. Comparison of these patients with other skeletal Dysplasias suggests that they represent a previously undescribed variant of SED.
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a recurrent rna splicing mutation in the sedl gene causes x linked Spondyloepiphyseal Dysplasia tarda
American Journal of Human Genetics, 2001Co-Authors: George E Tiller, Stefan Mundlos, A K Gedeon, Vickie L Hannig, Damon Dozier, Laura Carrel, Karrie C Trevarthen, William R Wilcox, Jonathan L Haines, Jozef GeczAbstract:Spondyloepiphyseal Dysplasia tarda (SEDL) is a genetically heterogeneous disorder characterized by mild-to-moderate short stature and early-onset osteoarthritis. Both autosomal and X-linked forms have been described. Elsewhere, we have reported the identification of the gene for the X-linked recessive form, which maps to Xp22.2. We now report characterization of an exon-skipping mutation (IVS3+5G→A at the intron 3 splice-donor site) in two unrelated families with SEDL. Using reverse transcriptase (RT)–PCR, we demonstrated that the mutation resulted in elimination of the first 31 codons of the open reading frame. The mutation was not detected in 120 control X chromosomes. Articular cartilage from an adult who had SEDL and carried this mutation contained chondrocytes with abundant Golgi complexes and dilated rough endoplasmic reticulum (ER). RT-PCR experiments using mouse/human cell hybrids revealed that the SEDL gene escapes X inactivation. Homologues of the SEDL gene include a transcribed retropseudogene on chromosome 19, as well as expressed genes in mouse, rat, Drosophila melanogaster Caenorhabditis elegans, and Saccharomyces cerevisiae. The latter homologue, p20, has a putative role in vesicular transport from ER to Golgi complex. These data suggest that SEDL mutations may perturb an intracellular pathway that is important for cartilage homeostasis.
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kniest Dysplasia is caused by dominant collagen ii col2a1 mutations parental somatic mosaicism manifesting as stickler phenotype and mild Spondyloepiphyseal Dysplasia
Pediatric Radiology, 1994Co-Authors: J Spranger, Stefan Mundlos, H Menger, Andreas Winterpacht, Bernhard ZabelAbstract:We describe two unrelated children with Kniest Dysplasia, a severe autosomal dominant form of chondrodysplastic dwarfism associated with cleft palate, progressive arthropathy, myopia and retinal detachment. In the first patient the disorder was caused by a 28 base pair exon 12/intron 12 deletion in the gene coding for type II collagen. Her mother had mild abnormalities of the vertebral bodies and long bones compatible with abnormalities seen in Stickler arthro-ophthalmopathy. The second child had a transition of AG to GG at the 3' splice site of intron 20 of the COL2A1 gene. Her father had premature polvarthrosis interpreted as a sequela of mild Spondyloepiphyseal Dysplasia. Molecular studies revealed that the mother of the first and the father of the second child each had somatic mosaicism of the same mutation as their children. Heterozygous mutations of the gene coding for type II collagen can cause Kniest Dysplasia, and somatic mosaicism for the same mutations can result in the Stickler phenotype or in mild Spondyloepiphyseal Dysplasia leading to premature polyarthrosis.
Rolf E Brenner - One of the best experts on this subject based on the ideXlab platform.
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x linked Spondyloepiphyseal Dysplasia tarda novel and recurrent mutations in 13 european families
Human Mutation, 2004Co-Authors: Jorg Fiedler, Martine Le Merrer, Solange Heuertz, Geert Mortier, Laurence Faivre, Rolf E BrennerAbstract:X-linked Spondyloepiphyseal Dysplasia tarda is a skeletal Dysplasia mainly affecting the vertebrae and epiphyses and commonly associated with the early development of degenerative joint disease. Radiographically the disorder is characterized by a typical hump-shaped deformity of the vertebral bodies. SEDT is caused by mutations in SEDL located on Xp22.12-p22.31. To further elucidate the spectrum of underlying variations we performed a screening of all 6 exons of SEDL within 13 European SEDT families and identified 6 new (c.99delC, c.183_184delGA, c.236-5_236-8delATTA, c.325delT, c.345_346delTG, c.94-?_423+?del) and 9 previously reported mutations (c.1-?_93+?del, c.93+5G>A, c.157_158delAT, c.210G>A, c.236-9_236-12delTTAA, c.267_275delAAGAC, c.324-4_324-10delTCTTTCCinsAA). The recurrent splice site alteration c.93+5G>A (formerly described as IVS3+5G>A) was detected in 3 unrelated families. Two patients were carrying 2 changes in the allele. In one case, a novel variation in exon 4 (c.99delC) was associated with several nucleotide deletions in intron 4 (c.236-5_236-8delATTA), and in the second case we identified a previously reported transition c.210G>A and a novel deletion in exon 6 (c.325delT). All sequence variations identified are either deletions of complete exons or predicted to result in a premature stop codon or to lead into splicing defects and are associated with a loss of considerable parts of the sedlin protein. © 2004 Wiley-Liss, Inc.
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x linked Spondyloepiphyseal Dysplasia tarda molecular cause of a heritable platyspondyly
Spine, 2003Co-Authors: Jorg Fiedler, Annemarie Frances, Martine Le Merrer, Markus Richter, Rolf E BrennerAbstract:STUDY DESIGN Report of a family affected with X-linked Spondyloepiphyseal Dysplasia tarda with special respect to radiologic alterations of the spine from puberty to the forth decade and to molecular analysis of the underlying genetic defect. OBJECTIVES To report the typical radiologic presentation of patients with X-linked Spondyloepiphyseal Dysplasia tarda and the diagnostic tool of mutation screening for that disease in order to avoid confusion with similar occurrences. SUMMARY OF BACKGROUND DATA Spondyloepiphyseal Dysplasia tarda is a genetically heterogeneous disorder that frequently manifests itself with back pain starting around puberty. The X-linked recessive form (X-linked Spondyloepiphyseal Dysplasia tarda) affects males and is clinically characterized by an arm span markedly exceeding total height, a barrel chest deformity, and early development of degenerative joint disease. The disorder is caused by mutations in the SEDL gene located on Xp22.12-p22.31. METHODS Radiologic alterations of the cervical, thoracal, and lumbar spine were assessed in the affected family members and one suspected female carrier in correlation to age. All 6 exon codings for the SEDL gene were analyzed by primer cycle sequencing. RESULTS In 3 male patients from a French family, we identified a 5 base pair deletion in SEDL, exon 5 at position 267-271 (delAAGAC). Carrier status for the mutation could be confirmed in one female member of the family, which is inconspicuous in terms of spine and joint diseases. Radiologic abnormalities of the patients comprised generalized platyspondyly, a hump-shaped deformity of cervical, thoracal, and lumbar vertebral bodies as well as signs of retrospondylophytes, osteochondrosis, and spondylarthrosis. CONCLUSIONS X-linked Spondyloepiphyseal Dysplasia tarda should be kept in mind as a differential diagnosis in men with early onset of back pain and radiologic abnormalities of the vertebral bodies comprising platyspondyly and a central hump.
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x linked Spondyloepiphyseal Dysplasia tarda molecular cause of a heritable disorder associated with early degenerative joint disease
Acta Orthopaedica Scandinavica, 2003Co-Authors: Jorg Fiedler, Carsten Bergmann, Rolf E BrennerAbstract:Spondyloepiphyseal Dysplasia tarda (SEDT) is a genetically heterogeneous disorder often associated with the early onset of osteoarthrosis. The X-linked recessive form (SEDL) affects men and is characterized by reduced height, arm span exceeding total height, and barrel chest deformity. The radiographic phenotype comprises a hump-shaped deformity of vertebral bodies and mild epiphyseal Dysplasia of the femoral head associated with early signs of hip arthrosis. The disorder is caused by mutations in the SEDL (or sedlin) gene on Xp22.12-p22.31. In 4 male patients from a German family, we identified a new nonsense mutation in SEDL exon 4 (C74A). The carrier status for the mutation could be confirmed in 2 women of the family, both of whom show no obvious signs of bone and joint diseases. SEDT should be kept in mind as a differential diagnosis in men with early "primary" bilateral osteoarthrosis
William G Cole - One of the best experts on this subject based on the ideXlab platform.
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characterization of an arginine 789 to cysteine substitution in alpha 1 ii collagen chains of a patient with Spondyloepiphyseal Dysplasia
Journal of Biological Chemistry, 1993Co-Authors: Danny Chan, T K F Taylor, William G ColeAbstract:A child with Spondyloepiphyseal Dysplasia congenita was shown to be heterozygous for a mutation of the COL2A1 gene that encodes the alpha 1 (II) chain of type II collagen. The alpha 1 (II) chains extracted from cartilage contained disulfide-bonded dimeric and trimeric alpha 1 (II) chains. Carboxymethylation confirmed that some of the type II collagen chains contained cysteine residues that are not normally present in alpha 1 (II) chains. Cyanogen bromide peptide mapping showed that the abnormal cysteine residue was located in the alpha 1 (II) CB10.5 peptide. Amplification products of the corresponding region of alpha 1 (II) cDNA prepared from cultured dermal fibroblasts were shown by chemical cleavage and single strand conformation polymorphism analyses to contain a sequence anomaly. DNA sequencing showed a transition of C2913T in exon 41 of one allele of the COL2A1 gene resulting in the substitution of arginine 789 by cysteine in the alpha 1 (II) chain. The mutation resulted in the loss of a MaeII cleavage site that was used to confirm that the proband was heterozygous for the mutation and that neither parent showed evidence of the mutation. The type II collagen extracted from cartilage and from chondrocytes cultured in alginate beads showed similar characteristics. Approximately a third of the type II collagen chains were mutant, and the secretion of molecules containing mutant chains was impaired. The thermal stability of the collagen extracted from cartilage was normal. This study confirmed the importance of dominant negative mutations of the COL2A1 gene in producing the Spondyloepiphyseal Dysplasia congenita phenotype.
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the clinical features of Spondyloepiphyseal Dysplasia congenita resulting from the substitution of glycine 997 by serine in the alpha 1 ii chain of type ii collagen
Journal of Medical Genetics, 1993Co-Authors: William G Cole, R K Hall, J G RogersAbstract:The features of a child with Spondyloepiphyseal Dysplasia congenita resulting from a mutation in one COL2A1 allele were studied. The child was heterozygous for a G to A transition in exon 48 that resulted in the substitution of glycine 997 by serine in the triple helical domain of alpha 1(II) chains of type II collagen. Her longitudinal growth was close to the mean growth curve for children with this chondroDysplasia. Expression of the mutation by chondrocytes would account for the abnormal growth and development of the bones of the limbs and spine. Early expression of the mutation by epithelial cells and later expression by chondrocytes of the developing craniofacial structures would also account for her complex pattern of craniofacial anomalies. The findings in this study confirm that mutations of exon 48 of the COL2A1 gene, that alter the normal Gly-X-Y triplet structure of the corresponding region of alpha 1(II) chains of type II collagen, produce the Spondyloepiphyseal Dysplasia congenita phenotype.
Michael P. Whyte - One of the best experts on this subject based on the ideXlab platform.
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preonset studies of Spondyloepiphyseal Dysplasia tarda caused by a novel 2 base pair deletion in sedl encoding sedlin
Journal of Bone and Mineral Research, 2001Co-Authors: Steven Mumm, Gary S. Gottesman, Michael P. Whyte, Xiafang Zhang, William H McalisterAbstract:Spondyloepiphyseal Dysplasia tarda (SEDT), an X-linked recessive skeletal disorder, presents with disproportionate short stature and "barrel-chest" deformity in affected (hemizygous) adolescent boys. In four reported families to date, mutations in a gene designated SEDL (Spondyloepiphyseal Dysplasia late) cosegregate with SEDT. We diagnosed SEDT in a short-stature, kyphotic 15-year-old boy because of his characteristic vertebral malformations. Clinical manifestations of SEDT were evident in at least four previous generations. A novel 2-base pair (bp) deletion in exon 5 of SEDL was found in the propositus by polymerase chain reaction (PCR) amplification and sequencing of all four coding exons. The mutation ATdel241-242 cosegregated with the kindred's skeletal disease. The deletion is adjacent to a noncanonical splice site for exon 5 but does not alter splicing. Instead, it deletes 2 bp from the coding sequence, causing a frameshift. A maternal aunt and her three young sons were investigated subsequently. Radiographs showed subtle shaping abnormalities of her pelvis and knees, suggesting heterozygosity. X-rays of the spine and pelvis of her 8-year-old son revealed characteristic changes of SEDT, but her younger sons (aged 6 years and 3 years) showed no abnormalities. SEDL analysis confirmed that she and only her eldest boy had the 2-bp deletion. Molecular testing of SEDL enables carrier detection and definitive diagnosis before clinical or radiographic expression of SEDT. Although there is no specific treatment for SEDT, preexpression molecular testing of SEDL could be helpful if avoiding physical activities potentially injurious to the spine and the joints proves beneficial.
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A five-base pair deletion in the sedlin gene causes Spondyloepiphyseal Dysplasia tarda in a six-generation Arkansas kindred.
The Journal of clinical endocrinology and metabolism, 2000Co-Authors: Steven Mumm, Paul T. Christie, Patrick M. Finnegan, Jonathan Jones, Peter H. Dixon, Anna A.j. Pannett, Brian Harding, Gary S. Gottesman, Rajesh V. Thakker, Michael P. WhyteAbstract:A six-generation kindred from Arkansas with X-linked recessive Spondyloepiphyseal Dysplasia tarda (SEDT) was investigated by genetic linkage and mutation analysis. SEDT had been mapped on the X-chromosome (Xp22.2), and the clinical and radiographic evolution of this kindred had been published. Linkage analysis proved informative for all five polymorphic markers tested, and DXS987 and DXS16 co-segregated with the Arkansas kindred (peak logarithm of the odds scores, 3.54 and 3.36, respectively). Subsequently, dinucleotide deletion in a new gene designated “sedlin” was reported to cause SEDT in three families. In an affected man and obligate carrier woman in the Arkansas kindred, we found a 5-bp deletion in exon 5 of sedlin. The defect causes a frameshift, resulting in eight missense amino acids and premature termination. The 5-bp deletion was then demonstrated to segregate with SEDT in the four living generations, including eight affected males and nine obligate carrier females. Furthermore, the deletion wa...
Xinyi Xia - One of the best experts on this subject based on the ideXlab platform.
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a novel insertion mutation in the sedl gene results in x linked Spondyloepiphyseal Dysplasia tarda in a large chinese pedigree
Clinica Chimica Acta, 2009Co-Authors: Xinyi Xia, Yingxia Cui, Yichao Shi, Yufeng Huang, Yuchun Zhou, Xin Zhou, Li Wei, Tingting HuangAbstract:Abstract Background Spondyloepiphyseal Dysplasia tarda (SEDT) is an X-chromosome linked primary skeletal Dysplasia characterized by a disproportionate short-trunked short stature, Dysplasia of the large joints and flattened thoracic and lumber vertebral bodies. The objective of this study is to describe a large Chinese SEDT family with a milder phenotype and describe the molecular and clinical findings. Methods Eight affected males of the family were diagnosed with SEDT according to their clinical and radiological features. Direct DNA sequencing of the SEDL gene was performed. RT-PCR experiments on total RNA from blood lymphocytes were performed to confirm the defect on the SEDL gene. A short summary of all currently known SEDL gene mutations is presented. Results DNA sequencing revealed that all the affected males carried an insertion mutation (c.370-371insA) unreported previously, predicted to result in frameshifts and generate a premature stop codon (p.S124fsX127). The identical mutation was also observed in a 10-year old presymptomatic boy of the family. Eight female carriers had the typical sequencing chromatograms of heterozygotes. Conclusions Identification of the novel insertion mutation (c.370-371insA) in this SEDT family enables carrier detection and presymptomatic/prenatal diagnosis, but also the detailed molecular and clinical features will be useful for extending the evidence for genetic and phenotypic heterogeneity in SEDT.
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rapid molecular prenatal diagnosis of Spondyloepiphyseal Dysplasia congenita by pcr ssp assay
Genetic Testing, 2008Co-Authors: Yingxia Cui, Xinyi Xia, Guohua Zhou, Bin Yang, Yichao Shi, Lianjun Pan, Yufeng HuangAbstract:Heterozygous mutations of COL2A1 gene are responsible for type II collagenopathies. The common skeletal phenotypes include achondrogenesis type II, hypochondrogenesis, Stickler Dysplasia, Kniest Dysplasia, late onset Spondyloepiphyseal Dysplasia, and Spondyloepiphyseal Dysplasia congenita (SEDC). Prevention of SEDC can be achieved by prenatal diagnosis. This study reports the first rapid molecular prenatal diagnosis of SEDC performed in China by polymerase chain reaction sequence-specific primer (PCR-SSP) analysis. The pregnant woman we previously reported with SEDC carried the G to A substitution at nucleotide 1510 in exon 23 of COL2A1 gene, which caused a change from glycine to serine at codon 504 (G504S). By the time the woman got pregnant again, she had terminated two pregnancies and still had no child. In the first pregnancy, the molecular mutation of the family was not yet identified, and therefore prenatal diagnosis was unable to be performed by DNA analysis. In the second pregnancy, G504S mutation was found from fetal DNA. At the time of her third pregnancy, the woman and her husband became extremely worried about the potential SEDC for the fetus. For this reason, a quick and reliable molecular prenatal diagnosis of SEDC was performed by a PCR-SSP on an amniocyte sample collected at the 14th week of pregnancy. No mutation of the fetal DNA was identified. The result was obtained within 24 h after the sample was collected. The technique could be applied in confirmatory diagnosis and prenatal diagnosis for the affected family.
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molecular prenatal diagnosis in 2 pregnancies at risk for Spondyloepiphyseal Dysplasia congenita
Clinica Chimica Acta, 2008Co-Authors: Xinyi Xia, Yingxia Cui, Bin Yang, Yichao Shi, Lianjun Pan, Yufeng Huang, Yao Feng, Peiyuan Zhu, Quan LiangAbstract:Abstract Background Spondyloepiphyseal Dysplasia congenita (SEDC) is an autosomal dominant skeletal Dysplasia characterized by short stature, abnormal epiphyses, and flattened vertebral bodies. Secondary prevention of SEDC can be achieved by prenatal diagnosis. Reports of antenatally-diagnosed SEDC fetuses have been very rare and molecular prenatal diagnosis even rarer. We previously reported a familial G504S mutation in the type II collagen (COL2A1) gene resulting in SEDC. In this study, molecular prenatal diagnosis was performed to 2 couples in this family with pregnancies at risk for SEDC. Methods Amniotic fluid was sampled by amniocentesis under ultrasound guidance at 19 + 3 and 18 + 6 weeks' gestation, respectively. Karyotype and molecular genetic analysis were performed on cultured amniotic fluid cells. Maternal cell contamination was excluded by short tandem repeat (STR) analysis. Direct DNA sequencing and DHPLC were conducted to detect the potential mutation in exon 23 of COL2A1 gene. Both women underwent serial sonograms because they insisted that the molecular diagnosis should be confirmed by another method, although they had been informed that mutation analysis is predictive of the disease. Results Karyotype of both fetuses was normal and molecular genetic analysis revealed that fetus 1 carried a G504S mutation in exon 23, while fetus 2 was normal. In case 1, femur length of the fetus was markedly below the 5th centile at 23 weeks' gestation, which confirms the accuracy of molecular diagnosis. A medical termination was carried out at 27 + 5 weeks' gestation and a male fetus with a relatively large head and short limbs was delivered. The fetal radiograph demonstrated a number of features, including generalised platyspondyly, absent ossification of the vertebral bodies in the cervical region and significant shortening of the long bones. The diagnosis of SEDC was thus confirmed clinically. Ultrasound monitoring of fetus 2 showed that its femur length was normal for gestational age at repeated scans, which was consistent with the molecular diagnosis. Conclusions Molecular analysis allows early and accurate prenatal diagnosis for SEDC once mutation is known in a family. However, considering the poor genotype/phenotype correlation in many cases of SEDC, the combination of ultrasound as well as molecular genetic approach might be needed.