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A systematic review of genetic skeletal disorders reported in Chinese biomedical journals between 1978 and 2012.
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PMID:  22913777     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Little information is available on the prevalence, geographic distribution and mutation spectrum of genetic skeletal disorders (GSDs) in China. This study systematically reviewed GSDs as defined in "Nosology and Classification of genetic skeletal disorders (2010 version)" using Chinese biomedical literature published over the past 34 years from 1978 to 2012. In total, 16,099 GSDs have been reported. The most frequently reported disorders were Marfan syndrome, osteogenesis imperfecta, fibrous dysplasia, mucopolysaccharidosis, multiple cartilaginous exostoses, neurofibromatosis type 1 (NF1), osteopetrosis, achondroplasia, enchondromatosis (Ollier), and osteopoikilosis, accounting for 76.5% (12,312 cases) of the total cases. Five groups (group 8, 12, 14, 18, 21) defined by "Nosology and Classification of genetic skeletal disorders" have not been reported in the Chinese biomedical literature. Gene mutation testing was performed in only a minor portion of the 16,099 cases of GSDs (187 cases, 1.16%). In total, 37 genes for 41 different GSDs were reported in Chinese biomedical literature, including 43 novel mutations. This review revealed a significant imbalance in rare disease identification in terms of geographic regions and hospital levels, suggesting the need to create a national multi-level network to meet the specific challenge of care for rare diseases in China.
Authors:
Yazhou Cui; Heng Zhao; Zhenxing Liu; Chao Liu; Jing Luan; Xiaoyan Zhou; Jinxiang Han
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Publication Detail:
Type:  Journal Article; Review     Date:  2012-08-22
Journal Detail:
Title:  Orphanet journal of rare diseases     Volume:  7     ISSN:  1750-1172     ISO Abbreviation:  Orphanet J Rare Dis     Publication Date:  2012  
Date Detail:
Created Date:  2012-11-08     Completed Date:  2013-04-10     Revised Date:  2013-07-12    
Medline Journal Info:
Nlm Unique ID:  101266602     Medline TA:  Orphanet J Rare Dis     Country:  England    
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Languages:  eng     Pagination:  55     Citation Subset:  IM    
Affiliation:
Shandong Academy of Medical Sciences, Shandong Medical Biotechnological Center, Jinan, 250062, China.
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MeSH Terms
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Bone Diseases / epidemiology*
China
Genetic Diseases, Inborn / epidemiology*
Humans
Publishing*
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Journal ID (nlm-ta): Orphanet J Rare Dis
Journal ID (iso-abbrev): Orphanet J Rare Dis
ISSN: 1750-1172
Publisher: BioMed Central
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open-access:
Received Day: 27 Month: 3 Year: 2012
Accepted Day: 20 Month: 8 Year: 2012
collection publication date: Year: 2012
Electronic publication date: Day: 22 Month: 8 Year: 2012
Volume: 7First Page: 55 Last Page: 55
PubMed Id: 22913777
ID: 3492206
Publisher Id: 1750-1172-7-55
DOI: 10.1186/1750-1172-7-55

A systematic review of genetic skeletal disorders reported in Chinese biomedical journals between 1978 and 2012
Yazhou Cui12 Email: cuiyazhou@yahoo.com.cn
Heng Zhao12 Email: zhaoheng1224@163.com
Zhenxing Liu12 Email: zijian2311@163.com
Chao Liu12 Email: 15266570735@126.com
Jing Luan12 Email: yimu1140@126.com
Xiaoyan Zhou12 Email: yan19850923@126.com
Jinxiang Han12 Email: samshjx@sina.com
1Shandong Academy of Medical Sciences, Shandong Medical Biotechnological Center, Jinan, 250062, China
2Key Laboratory for Biotech Drugs of the Ministry of Health, Key Laboratory for Rare Disease Research of Shandong Province, Jinan, 250062, China

Introduction

Genetic skeletal disorders (GSDs) arise from disturbances of the complex processes of skeletal development, growth, and homeostasis caused by gene mutations. These disorders represent a challenge in terms of diagnosis and treatment due to their rarity and variety [1,2]. The recently published “Nosology and Classification of Genetic skeletal disorders (2010 version)” listed 456 GSDs that were classified into 40 groups by clinical, radiographic, and molecular criteria; of these, 316 conditions were associated with mutations in 226 different genes [3]. The Nosology not only provides a guideline for the diagnosis of the patients and the recognition of the novel disorders for clinicians, but also is helpful for better understanding the mechanisms of genes, proteins and pathways involved in skeletal biology.

Until now, population-based studies to determine the prevalence of GSDs have been not been performed in China. Most GSDs have been reported in “case reports” in Chinese biomedical literature, but these sources are usually not available to international readers. Therefore, an introduction to the published literature on GSDs in China would enrich our knowledge on the prevalence and molecular characteristics of these rare diseases.

This study systematically reviewed GSDs reported in Chinese biomedical literature published over the past 34 years from January 1978 to January 2012. This study also analyzed the current state and specific challenges in diagnosing and treating rare diseases in China.


Methods
Rare diseases covered

This bibliographic study covered a total of 456 GSDs in 40 groups defined in “Nosology and Classification of GSDs (2010 version).” This study has been performed with the approval of the ethics committee of Shandong Academy of Medical Science.

Selection of database sources

A literature search was conducted using China Biomedical Database (CBM) ( http://sinomed.imicams.ac.cn) and covered sources from January 1978 to January 2012. The CBM is the largest Chinese biomedical bibliographic database [4], and includes a total of 6,840,907 articles from more than 1,600 biomedical journals published in Chinese prior to January 12, 2012.

Search strategy

The CBM database and public web search engines were first used to search for alternative Chinese terms for the English terms describing each disorder, and then all the terms for the disorder (both in English and Chinese) were used to search for publications in the CBM database. English terms for disorders were included since most Chinese biomedical articles contain an English abstract. The following search algorithm was used: “English disorder terms OR Chinese disorder terms [fulltext]”. For diseases with different subtypes (for example, Osteogenesis Imperfecta, types I–V), only the main term (“Osteogenesis Imperfecta”) was used in the search, and information on the type was gleaned from the text.

Inclusion and exclusion criteria

Clinical data and diagnostic information were gleaned from the abstract or full text of the articles searched for in the CBM database. Cases of GSDs with a confirmed diagnosis were included. Detailed clinical, imaging, and laboratory data needed to be described for case reports. Exact diagnostic criteria had to be included for research reports involving multiple cases or families. For each study included, informed consent to publication was obtained from the patient. Patient medical information was carefully compared for series of reports on the same disorders by the same authors or institutions, and redundant cases were excluded.


Results

According to our criteria 3,208 Chinese reports were qualified for inclusion. A total of 16,099 cases of GSDs in 35 groups of the “Nosology and Classification of Genetic Skeletal Disorders (2010 version)” was reported in the literature. The number of published cases is listed in Table 1. The 10 most frequently reported GSDs were Marfan syndrome, osteogenesis imperfecta, fibrous dysplasia, mucopolysaccharidosis, multiple cartilaginous exostoses, neurofibromatosis type 1 (NF1), osteopetrosis, achondroplasia, enchondromatosis (Ollier), and osteopoikilosis, accounting for 76.5% of cases (12,312 cases). Five groups (group 8 TRPV4 group, group 12 spondylometaphyseal dysplasias, group 14 severe spondylodysplastic dysplasias, group 18 bent bones dysplasias, and group 21 chondrodysplasia punctata) described in the Nosology have not been reported yet by Chinese biomedical literature.

The geographic distribution of cases is shown in Figure 1. GSDs have been reported in all of China’s provinces and province-level municipalities. However, the number of cases varied geographically. More patients were reported in the East and South of China, which have a higher population density and better medical services than other areas. Beijing, Guangdong, Shandong, Shanghai and Jiangsu ranked among the top 5 provinces or province-level municipalities where disorders were reported.

As shown in Figure 2, the number of patients with GSDs reported each year in the CBM database increased gradually since 1978 and rapidly increased starting in 1994. Most GSD cases were reported by pediatricians, radiologists, and orthopedists. 49.0% of the cases were diagnosed at a university hospital,10.8% were diagnosed at a provincial hospital, 32.7% were diagnosed at a municipal hospital, and the remainder (7.5%) was diagnosed at hospitals on country level or even from smaller communities. (Figure 3).

Gene mutations were evaluated in 187 cases or families out of 16,099 total reported cases, accounting for only a minor portion (1.16%). As shown in Table 2, a total of 37 genes for 41 different GSDs were reported, including 43 novel mutations that have not been reported before. The EXT1 and EXT2 genes (30 cases) for multiple cartilaginous exostoses, the FBN1 gene for Marfan syndrome (24 cases), and the FGFR3 gene for achondroplasia (22 cases) were most frequently reported in Chinese biomedical literature from the CBM database. Compared to the reported geographic distribution of GSDs (Figure 2), genetic testing was only performed at university hospitals in a few areas (Figure 4). Affiliated hospitals of Shanghai Jiaotong University, Chinese Academy Of Medical Science & Peking Union Medical College, Zhongshan University, Central South University, and Peking University rank the top 5 University hospitals which performed most gene testing of GSDs.


Discussion

As the world’s most densely populated nation, China has the world’s largest number of rare disease groups [5]. In 1984, the concept of rare diseases was introduced in China. Until recently, however, the problem presented by rare diseases has received little attention [6]. Currently, there is no case registration system for most rare diseases, so there is very little documented information on the epidemiology of those diseases in China [7]. China still lacks an official definition and spectrum of rare diseases.

A bibliographic study will help to estimate the prevalence of rare diseases [8]. Most rare diseases have been reported in Chinese biomedical publications. Presently, only 86 Chinese biomedical journals have abstracts in English included in Pubmed [9]. Therefore, most reports on rare diseases in China are unavailable to international readers. To our knowledge, the current study is the first systematic review of the Chinese biomedical literature on rare disease groups.

GSDs are representative for many other groups of rare diseases. The current systematic review found that the number and type of GSDs reported in Chinese biomedical literature increased gradually over the past 30 years. In the last 5 years in particular, there were 1,057 cases reported annually, which is due to the rapid improvement of general healthcare and increasing attention to the medical problems caused by rare diseases in China. Although most genetic skeletal disease groups have been reported in Chinese biomedical literature, but only a small portion of patients were exactly molecularly characterized. For example, 1,314 cases of osteogenesis imperfecta were reported in the CBM database but in only 5% the exact type has been determined. This situation might be mainly due to the fact that most of these patients were diagnosed based on clinical and radiographic criteria and because gene mutation testing has been unavailable at most hospitals until now. In only 1% of all cases with GSDs a causative gene mutation was identified. Among these reported mutations, there is a relatively high frequency of novel mutations. These novel variations may also lead to a better understanding of the mutation spectrum and impact of genes associated with GSDs. For example, 5 cases of novel mutations in COL1A1 have been reported in Chinese biomedical literature. Among them, 4 cases belong to glycine single base substitution mutations in the triple-helical region (p.G632x, p.G1157D) and splicing sites (IVS27 + 1 G > A, IVS8-2A > G), which are the most and second common mutation types in COL1A1 gene. Mutations in the C-propeptide coding region have been identified less frequent than other forms of mutation. D1441 is one of a few residues absolutely conserved in this region, a previous study reported a defect in this site (D1441Y) resulting in a lethal variant of osteogenesis imperfecta with features of dense bone diseases [10], however, a novel mutation in this site described in a Chinese family (D1441H) led to only mild osteogenesis imperfecta (type 1), which suggesting mutations in this region show great heterogeneity in clinical outcome.

This systematic review of genetic skeletal diseases also revealed that reporting of rare diseases varies significantly in different regions and medical resources available in China. Cases of rare diseases were more frequently reported in large municipalities such as Beijing and Shanghai instead of areas with a larger population but a relatively lower level of development such as Sichuan and Henan Provinces. Country level hospitals and below are mainly responsible for treating rural residents and represent more than 70% of the medical resources in China [11]. In this review, we found that only 7.5% of the cases of rare diseases were diagnosed by these hospitals, which is significantly lower than that diagnosed by urban hospitals. In actuality, there are also significant disparities in health care between university hospitals and provincial and municipal hospitals. Currently, gene mutation testing for genetic rare diseases in China is done only by university hospitals in several key municipalities.

We further compared the number of GSD cases reported in Chinese biomedical literature with those of published cases or estimated prevalence of these diseases in Europe from bibliographic data issued by Orphanet [8] (Table 1). Generally, the number of GSDs reported in Chinese biomedical literatures is lower than in Europe, but, with some exceptions, the proportions between the different entities are similar. One of these exceptions are the multiple epiphyseal dysplasias, whose frequency in Europe is 5/100,000, while only a total of 122 cases were reported in Chinese biomedical literature in the past 34 years. Although publication bias and genetic differences between Caucasian and Asian people may exist, we think this discrepancy is mainly due to the fact that China is still lagging behind Europe in terms of the medical resources for these rare diseases, especially in the widespread underdeveloped regions and hospitals on basic levels, therefore, many patients with genetic skeletal disorders could not acquire proper and timely diagnosis in China.

Creating a network for rare diseases is an important medical policy that should significantly reduce misdiagnosis and improve the level of treatment. A network for collaboration with national medical resources has been set up in countries and regions such as Europe, North America, and Japan [12,13]. A number of centers offering counseling on rare diseases have been established in major Chinese cities and several provinces, but a national network has yet to be created. Given the fact that there is a huge gap in terms of medical services in different areas and hospital levels of China, a stronger network of diagnosis and treatment including all levels of hospitals across the country should be created to improve healthcare for rare diseases in the future.


Conclusion

In conclusion, this systematic review summarized the number, geographic and genetic characteristics of GSDs in Chinese biomedical publications. Analyzing number of the diseases revealed an imbalance in the distribution of areas and hospitals diagnosing rare diseases, which suggests that a multi-level network should be created to meet the specific challenge of healthcare for rare diseases in China.


Competing interests

The authors declare that they have no competing interests.


Authors’ contributions

JH and YC put forward the idea and designed the key points. YC was responsible for the article writing and data analysis. HZ, ZL and CL were responsible for the data collection. HZ, JL and XZ participated in data analysis. All authors read and approved the final manuscript.


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Figures

[Figure ID: F1]
Figure 1 

Geographic distribution of reported cases of genetic skeletal disorders (GSDs) in Chinese biomedical literature. The number of cases reported varied geographically, and focused in the East and South of China. Beijing, Guangdong, Shandong, Shanghai and Jiangsu ranked among the top 5 provinces or province-level municipalities where GSDs were reported.



[Figure ID: F2]
Figure 2 

Case number of genetic skeletal disorders reported in Chinese biomedical literatures from 1978 to 2011. The number of GSDs reported each year in the CBM database increased gradually since 1978 and rapidly increased starting in 1994. 1,057 cases were reported annually in recent 5 years.



[Figure ID: F3]
Figure 3 

Hospital distribution of reported cases of genetic skeletal disorders in Chinese biomedical literatures. Most of the GSDs were diagnosed in hospitals in cities including university hospitals (49.0%), provincial hospitals (10.8%), and municipal hospital (32.7%). Only 7.5% of GSD cases were reported by hospitals on country level and below, which account for about 70% of the medical resources in China.



[Figure ID: F4]
Figure 4 

Geographic distribution of reported genetic skeletal disorders with gene mutation testing in Chinese biomedical literature. Genetic testing for GSDs was only performed at university hospitals in a few areas, far less than the regions where GSDs were reported.



Tables
[TableWrap ID: T1] Table 1 

Number of published cases of genetic skeletal diseases in Chinese and Europe biomedical literature listed in alphabetical order of diseases*


Diseases or group of diseases Number of Cases reported in Chinese biomedical literature Number of published cases in Europe[8] Estimated prevalence in Europe (/100,000)[8]
Achondroplasia
685
 
4.5
Acrofacial dysostosis, Nager type
3
90
 
alpha-Mannosidosis
1
 
0.1
Apert syndrome
16
 
1.25
Asphyxiating thoracic dysplasia
45
150
 
Brachydactyly
88
80
 
Caffey disease
280
N.A.
 
Calcium pyrophosphate deposition disease (familial chondrocalcinosis) type 2
1
N.A.
 
Cartilage-hair hypoplasia (CHH; metaphyseal dysplasia,McKusick type)
3
N.A.
 
Cherubism
105
N.A.
 
Chondrodysplasia punctata
7
 
0.5
Chondroectodermal dysplasia (Ellis–van Creveld)
11
150
 
Cleidocranial dysplasia
260
N.A
 
Congenital contractural arachnodactyly
7
N.A.
 
Craniofrontonasal syndrome
1
3
 
Craniometaphyseal dysplasia
4
70
 
Craniostenosis (Craniosynostosis)
302
72
 
Crouzon syndrome
161
 
2
Currarino triad
31
 
1
de Lange syndrome
7
 
1.9
Diaphyseal dysplasia Camurati-Engelmann
14
200
 
Dysplasia epiphysealis hemimelica (Trevor)
53
N.A.
 
Ectrodactyly-ectodermal dysplasia cleft-palate syndrome
5
N.A.
 
Ehlers–Danlos syndrome
57
 
0.2
Enchondromatosis (Ollier)
369
600
 
Enchondromatosis with hemangiomata (Maffucci)
80
250
 
Endosteal hyperostosis, van Buchem type
8
N.A.
 
Familial expansile osteolysis
1
N.A.
 
Familial hip dysplasia (Beukes)
45
N.A.
 
Familial osteochondritis dissecans
1
N.A.
 
Fanconi anemia
107
 
0.3
Fibrous dysplasia, polyostotic form
982
 
<50
Frontometaphyseal dysplasia
1
<30
 
Frontonasal dysplasia
4
N.A.
 
Fucosidosis
1
100
 
Fuhrmann syndrome
1
11
 
GM1 Gangliosidosis, several forms
7
N.A.
 
Grebe dysplasia
2
N.A.
 
Greig cephalopolysyndactyly syndrome
2
100
 
Hajdu–Cheney syndrome
7
N.A.
 
Hallermann–Streiff syndrome
32
<100
 
Hanhart syndrome(hypoglossia-hypodactylia)
1
<50
 
Holt-Oram syndrome
218
 
1
Hypertrophic osteoarthropathy
36
N.A.
 
Hypochondroplasia
3
 
3.3
Hypophosphatasia, perinatal lethal and infantile forms
19
N.A.
 
Hypophosphatemic rickets
43
<100
 
Idiopathic juvenile osteoporosis
1
5
 
Immuno-osseous dysplasia (Schimke)
3
50
 
Infantile systemic hyalinosis/Juvenile hyaline fibromatosis (ISH/JHF)
3
N.A.
 
Klippel-Feil anomaly with laryngeal malformation
318
 
2
Kniest dysplasia
1
2
 
Langer type (Homozygous dyschondrosteosis)
2
N.A.
 
Larsen syndrome
9
100
 
Lipomembraneous osteodystrophy with leukoencephalopathy (presenile dementia with bone cysts; Nasu–Hakola)
2
 
0.15
Mandibulo-facial dysostosis(Treacher-Collins, Franceschetti-Klein)
198
 
6
Marfan syndrome
5064
 
20
Marshall syndrome
2
63
 
Meckel syndrome
35
 
2.5
Melorheostosis
153
300
 
Melorheostosis with osteopoikilosis
6
N.A.
 
Mesomelic dysplasia
4
2
 
Metaphyseal dysplasia, Jansen type
3
16
 
Metaphyseal dysplasia, Schmid type (MCS)
53
N.A.
 
Mucolipidosis II (I-cell disease),alpha/beta type
2
 
0.15
Mucopolysaccharidosis
958
 
3.56
Multicentric carpal-tarsal osteolysis with and without nephropathy
2
<10
 
Multiple cartilaginous exostoses
911
 
2
Multiple epiphyseal dysplasia
122
 
5
Multiple sulfatase deficiency
1
50
 
Multiple synostoses syndrome
1
20
 
Nail-patella syndrome
61
 
2
Neonatal hyperparathyroidism, severe form
4
N.A.
 
Neurofibromatosis type 1 (NF1)
881
 
25
Oculodentoosseous dysplasia
8
243
 
Omodysplasia
1
30
 
Oral-facial-digital syndrome
15
 
1.2
Osteoectasia with hyperphosphatasia (juvenile Paget disease)
4
50
 
Osteogenesis imperfecta
1314
 
6.5
Osteopetrosis
810
 
1.75
Osteopoikilosis
338
300
 
Pachydermoperiostosis (hypertrophic osteoarthropathy,primary, autosomal dominant)
25
204
 
Pallister-Hall syndrome
1
100
 
Parietal foramina
11
 
5
Pfeiffer syndrome
4
 
1
Poland anomaly
27
3
 
Preaxial polydactyly
16
 
25
Progeria, Hutchinson–Gilford type
20
 
0.005
Progressive osseous heteroplasia
20
N.A.
 
Progressive pseudorheumatoid dysplasia (PPRD; SED with progressive arthropathy)
6
N.A.
 
Proteus syndrome
22
200
 
Proximal symphalangism
15
N.A.
 
Pseudoachondroplasia (PSACH)
51
 
1.6
Pyknodysostosis
14
 
0.13
Pyle disease
2
<30
 
Radio-ulnar synostosis
55
<20
 
Saethre–Chotzen syndrome
1
 
3
Schwartz–Jampel syndrome (myotonic chondrodystrophy)
4
100
 
SED tarda, X-linked (SED-XL)
156
 
0.55
SED, Wolcott–Rallison type
1
<60
 
Short rib-polydactyly syndrome
57
N.A.
 
Shprintzen-Goldberg syndrome
1
<50
 
Sotos syndrome
38
 
7
Split hand-foot malformation
25
 
1.1
Spondylocostal dysostosis
1
4
 
Spondyloepiphyseal dysplasia congenita (SEDC)
50
 
0.34
Spondylometaphyseal dysplasia
6
 
1
Spondylometaphyseal dysplasia, Kozlowski type
2
 
0.1
Sterile multifocal osteomyelitis,periostitis, and pustulosis (CINCA/NOMID-like)
1
N.A.
 
Stickler syndrome
7
 
13.5
Syndactyly type 5 (HOXD13)
7
N.A.
 
Thanatophoric dysplasia
28
 
3.5
Thrombocytopenia-absent radius
1
N.A.
 
Tibial hemimelia
2
 
0.1
Trichorhinophalangeal dysplasia 15 >100  

*: Different types belong to one diseases have been combined as one item when the typing information was not provided in literature.


[TableWrap ID: T2] Table 2 

Gene mutation of genetic skeletal disorders published in Chinese biomedical literature from 1978 to 2012*


Gene Name of disorder MIM No. No. of case reported* Mutation Location Type Novel
ACVR1
Fibrodysplasia ossificans progressiva (FOP)
135100
2
c.617 G > A (p.R206H)
exon 4
missense
 
 
 
 
1
c.1067 G > A (p.G356D)
exon 7
missense
 
ALPL
Hypophosphatasia, infantile forms
241500
1
c.18delA and c.G407C (p.V7Yfs18X and p.R136P)
exon 2 and 5
nonsense and missense
yes
ALPL
Hypophosphatasia, adult form
146300
1
c.1366 G > A (p.G456R)
exon 12
missense
 
 
 
 
1
c.1581C > G (p.P446G)
exon 12
missense
yes
 
 
 
1
c.583 G > A (p.R136H)
exon 5
missense
 
CLCN5
Dent’s disease
300554
1
p.L594fsX595
exon 10
nonsense
yes
 
 
 
1
p.R637X
exon 10
nonsense
 
 
 
 
1
p.R467X
exon 9
nonsense
 
 
 
 
1
p.IVS4-2A > G
exon 4
splicing
yes
 
 
 
1
c.1022C > T (p.S244L)
exon 7
missense
 
 
 
 
1
c.1805 T > G (p.V505G)
exon 9
missense
yes
CLCN7
Osteopetrosis, late-onset form type 2 (OPTA2)
166600
1
c.C856T (p.R286W)
exon 10
missense
 
COL1A2
Osteogenesis imperfecta
 
1
c.A3350G (p.Y1117C)
exon 49
missense
 
 
 
 
1
c.G3305C (p.G1102A)
exon 49
missense
 
COL1A1
Osteogenesis imperfecta
166220
1
c.1678 G > A (p.G560S)
exon 25
missense
 
 
 
166200
1
p.Gly632x
exon 28
nonsense
yes
 
 
166200
1
p.D1441H
exon 52
missense
yes
 
 
166200
1
c.1875 + 1 G > A (IVS 27 + 1 G > A)
intron 27
splicing
yes
 
 
166200
1
IVS8-2A > G
intron 8
splicing
yes
 
 
 
1
c.2461 G > A (p.G821S)
exon 36
missense
 
 
 
 
1
c.3470 G > A (p.G1157D)
 
missense
yes
COL2A1
Spondyloepiphyseal dysplasia congenita (SEDC)
183900
1
c.1510 G > A (p.G504S)
 
missense
 
 
 
 
1
c.2401 G > A (p.G801S)
 
missense
 
EFNB1
Craniofrontonasal Syndrome
304110
1
c.161C > G (p.P54R)
exon 2
missense
yes
COMP
Pseudoachondroplasia
177170
1
c.815 T > C (p.L272P)
exon 8
missense
 
EIF2AK3
SED, Wolcott–Rallison type
226980
1
c.1408-1409insT and c.1596 T > A (p.S470FfsX7 and p.C532X)
exon 8 and 9
nonsense
 
EXT1
Multiple cartilaginous exostoses 1
133700
1
c.1564-7delC
exon 7
frameshift
yes
 
 
 
1
I8 + 2 T > G
intron 8
splicing
yes
 
 
 
1
c.651_664delinsTTT (p.K218fsX220)
exon 1
nonsense
 
 
 
 
1
c.680delG (p.R227fs)
exon 1
frameshift
 
 
 
 
1
c.1182delG (p.Arg394SerfsX9)
exon 4
nonsense
yes
 
 
 
1
c.1108 G > T (p.E370X)
exon 3
nonsense
yes
 
 
 
1
c.335delA (p.Asn112ThrfsX24)
exon 1
nonsense
yes
 
 
 
1
c.361C > T (p.Q121X)
exon 1
nonsense
yes
 
 
 
1
c.1879_1881delCAC (p.His627del)
exon 9
In frame deletion
yes
 
 
 
1
c.651_664delinsTTT (p.K218fsX220)
exon 1
frameshift
 
 
 
 
1
1633-26(C > A)
intron 7
splicing
 
 
 
 
1
c.2120delT
exon 6
frameshift
 
 
 
 
1
c.811 T > C (p.Y271H)
exon 1
missense
yes
EXT2
Multiple cartilaginous exostoses 2
133701
1
c.668 G > C (p.Arg223Pro)
exon 2
missense
 
 
 
 
1
c.950delT (p.Phe317SerfsX15)
exon 6
nonsense
yes
 
 
 
3
c.1016 G > A (p.Cys339Tyr)
exon 6
missense
 
 
 
 
1
c.398 T > G (p.L133R)
exon 2
missense
 
 
 
 
1
c.751C > T (p.Q251X)
exon 5
missense
 
 
 
 
1
c.544C > T (p.R182X)
exon 3
missense
 
 
 
 
1
c.536 G > A (p.Arg179Lys)
exon 2
missense
 
 
 
 
1
c.1006C > T (p.G1n336X)
exon 6
nonsense
yes
 
 
 
1
IVS2 + 1 G > A
intron 2
splicing
 
 
 
 
1
IVS7 + 1 G > T
intron 7
splicing
 
 
 
 
1
c.789-796delTGTT
exon 5
frameshift
yes
 
 
 
1
c.637 G > A
exon 4
nonsense
 
 
 
 
1
c.313A > T (p.Lys105X)
exon 2
nonsense
 
 
 
 
1
319insGT
exon 2
frameshift
 
 
 
 
1
536 + 1 G > A (IVS2 + 1 G > A)
intron 2
splicing
 
FBN1
Marfan syndrome
154700
1
c.3463 G > A (p.Asp1155Asn)
exon 27
missense
yes
 
 
 
1
c.5015 G > C (p.C1672S)
exon 40
missense
 
 
 
 
3
c.5309 G > A (p.C1770Y)
exon 43
missense
 
 
 
 
2
c.7241 G > A (p.R2414Q)
exon 58
missense
 
 
 
 
2
c.7769 G > A (p.C2590Y)
exon 62
missense
 
 
 
 
2
c.2261A > G (p.Y754C)
exon 18
missense
 
 
 
 
1
c.[6862_6871delGGCTGTGTAG;6871 + 1_6871 + 11delGTAAGAGGATC] (p.Gly2288MetfsX109)
exon 55
nonsense
yes
 
 
 
1
c.2462 G > A (p.Cys821Tyr)
exon 20
missense
yes
 
 
 
1
c.5015 G > C (p.C1672S)
exon 40
missense
 
 
 
 
1
c.3295 G > T (p.E1099X)
exon 26
nonsense
 
 
 
 
2
c.4307insTCGT (p.G1441X)
exon 34
nonsense
yes
 
 
 
1
c.4621C > T (p.R1541X)
exon 37
nonsense
 
 
 
 
1
c.8080C > T (p.A2694X)
exon 64
nonsense
 
 
 
 
2
IVS29 + 4A > T
intron 29
splicing
 
 
 
 
1
IVS50 + 1 G > A
intron 50
splicing
 
 
 
 
1
c.3069 G > T (p.Lys1023Asn)
exon 24
missense
yes
 
 
 
1
c.3243-3256delGCCTCTGCACCCA
exon 25
frameshift
 
FGFR1
Pfeiffer syndrome
101600
1
c.755C > G (p.Pro252Arg)
exon 5
missense
 
FGFR2
Pfeiffer syndrome
101600
1
IVS8 A > G
exon 8
splicing
 
 
 
 
1
p.Asp321Ala
exon 9
missense
 
 
Apert syndrome
101200
1
c.934C > G (p.S252W)
exon 7
missense
 
 
Crouzon syndrome
123500
1
c.833 G > T (p.C278F)
exon 8
missense
 
 
 
 
1
p.Tyr340His
exon 9
missense
 
 
 
 
1
p.Cys342Trp
exon 9
missense
yes
 
 
 
1
p.Cys342Tyr
exon 9
missense
 
 
 
 
1
p.Ala344Ala
exon 9
missense
 
 
 
 
1
p.Gly338Arg
exon 9
missense
 
 
 
 
1
p.Ala344Gly
exon 9
missense
 
 
 
 
1
p.Gln289Pro
exon 7
missense
 
FGFR3
Achondroplasia
100800
21
c.1138 G > A (p.G380R)
exon 10
missense
 
 
 
 
1
p.Ser217Cys
exon 5
missense
 
FGFR3
Thanatophoric dysplasia
187600
1
c.742C > T (p.R248C)
exon 7
missense
 
GALNS
Mucopolysaccharidosis type 4A
253000
1
c.1567 T > G and c.374C > T
exon 14 and 4
nonsense and missense
yes
GDF5
Multiple synostoses syndrome type 2
186500
2
c.1471 G > A (p.E491K)
exon 2
missense
 
GNAS1
Albright hereditary osteodystrophy
103580
1
1-bp (C) deletion at codon 291
exon 11
frameshift
 
HLXB9
Currarino triad
176450
2
c.552C > G (p.Tyr184X)
 
nonsense
 
TP63
Split hand-foot malformation, isolated form, type 4 (SHFM4)
605289
1
c.956 G > A (p.R280H)
exon 7
missense
 
HOXD13
Synpolydactyly
186000
1
c.32 G > C (p.G11A)
exon 1
missense
 
 
 
 
1
c.64 G > T (p.A22S)
exon 1
missense
yes
 
 
 
3
9-residue polyalanine expansion
exon 1
 
 
 
yes
 
 
 
 
 
 
 
 
 
1
8-residue polyalanine expansion
exon 1
 
 
 
 
 
1
7-residue polyalanine expansion
exon 1
 
 
IDS
Mucopolysaccharidosis type 2
309900
1
c.892C > T (p.Q298X)
exon 7
nonsense
 
 
 
 
1
c.1468delA
exon 9
frameshift
 
 
 
 
1
c.263 G > A (p.Arg88His)
exon 3
missense
 
 
 
 
1
1103_1123del19
exon 8
frameshift
 
IHH
Brachydactyly type A1
112500
1
c.G298A (p.D100N)
exon 1
missense
 
NF1
Neurofibromatosis type 1
162200
1
c.1009 G > T
exon 7
nonsense
yes
 
 
 
1
c.3443-3444delCA
exon 20
frameshift
yes
 
 
 
1
c.4339C > T (p.G1336X)
 
nonsense
 
 
 
 
1
c.5839C > T (p.R1947X)
exon 31
nonsense
 
 
 
 
1
p.Leu1141Arg
exon 20
missense
 
TP63
Ankyloblepharon-ectodermal dysplasia-cleft lip/palate
106260
1
c.838C > T (p.R280C)
exon 7
missense
 
 
Limb-mammary syndrome (including ADULT syndrome)
603273
1
c.893 G > A (p.R298Q)
exon 8
missense
 
PHEX
Hypophosphatemic rickets, X-linked dominant
307800
1
IVS20-1 G > T
intron 20
splicing
 
 
 
 
1
c.1861C > T (p.GIn621X)
exon 18
missense
yes
PTPN11
Baller–Gerold syndrome
218600
1
IVS11-1 G > A and c.3401A > T
intro 11 and exon 10
splicing and nonsense
 
ROR2
Brachydactyly type B
113000
1
c.2265C > A (p.Y755X)
exon 9
nonsense
 
 
 
 
1
c.1398-1399insA
exon 9
nonsense
 
RUNX2
Cleidocranial dysplasia
119600
1
c.346 T > A (p.W116R)
exon 1
missense
 
 
 
 
1
c.610A > T (p.K204X)
exon 3
nonsense
 
 
 
 
1
c.346 T > A (p.W116R)
exon 1
missense
 
 
 
 
1
c.475 G > C (p.G159R)
exon 2
missense
yes
 
 
 
1
c.673C > T (p.R225W)
exon 3
missense
 
 
 
 
1
c.1171C > G (p.R391X)
exon 7
nonsense
 
 
 
 
1
c.674 G > A (p.R225Q)
exon 3
missense
 
SALL1
Townes–Brocks syndrome (Renal-Ear-Anal-Radial syndrome)
107480
4
c.1792 G > C
exon 2
missense
 
SEDL
SED tarda, X-linked (SED-XL)
313400
1
c.218C > T (p.S73L)
exon 4
missense
 
 
 
 
1
c.370-371insA (p.S124fsX127)
exon 6
nonsense
yes
 
 
 
1
c.218C > T (p.S73L)
exon 4
missense
 
 
 
 
1
c.239A > G (p.H80R)
exon 4
missense
 
 
 
 
1
c.G209A
exon 4
nonsense
 
 
 
 
1
c.262-266delGACAT
exon 5
frameshift
 
 
 
 
1
D109-S123del (p.S124fsX126)
intron 5-exon 6
nonsense
 
 
 
 
1
IVS5-2-1delAG322-332delTTTTCAATGAA
intron 5-exon 6
splicing
yes
 
 
 
1
IVS2-2A > C
intron 2
 
 
SH3BP2
Cherubism
118400
5
c.1505 G > C (p.Arg415Pro)
exon 9
missense
 
 
 
 
2
c.G1520A (p.Gly420Glu)
exon 9
missense
 
SHOX
Dyschondrosteosis
127300
1
c.115 T > G
exon 2
 
 
 
 
 
1
c.1171-1172insA
exon 3
frameshift
 
 
 
 
1
c.996A > T (p.E102V)
exon 3
missense
 
SOX9
Campomelic dysplasia (CD)
114290
1
p.R178L
exon 2
missense
yes
TBX5
Holt-Oram syndrome
142900
1
c.416delC
exon 4
frameshift
 
 
 
 
1
c.145C > A
exon 2
missense
 
 
 
 
1
c.161 T > C
exon 2
missense
 
TGFbeta1
Diaphyseal dysplasia Camurati-Engelmann
131300
1
p.R218H
exon 4
missense
 
WISP3
Progressive pseudorheumatoid dysplasia
208230
1
c.624-625insA and c.729-735delGAGAAAA
exon 4 and exon 4
frameshift and frameshift
yes
 
 
 
1
c.624-625insA and c.866-867insA
exon 4 and exon 5
frameshift and frameshift
yes
 
 
 
1
c.866_867insA and c.866-867insA
exon 5 and exon 5
frameshift and frameshift
yes
      1 c.589 + 2 T > C and c.624dupA intro 3 and exon 4 splicing and nonsense yes

*: “Pedigree mutation”, that is an identical mutation has been reported in more than one affected siblings in a family, was counted as one case. Mutation information was extracted from the full text, as its original description, all the novel mutations were claimed in the papers by the authors, and then were confirmed by searching the previous literature and the Human Gene Mutation Database.



Article Categories:
  • Review

Keywords: Rare diseases, Genetic skeletal diseases, China, Bibliographic study.

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