Open Access Journal of Biomedical Science and Research Volume 1 Issue 1 Research Article Genetic Skeletal Disorders in Pakistan: A brief Commentary Ahmad Fa, Bilal Mb, Khan Ac and Umair Mb* aDepartment of Biochemistry, Quaid-i-Azam University, Faculty of Biological Sciences, Islamabad, Pakistan bDepartment of Medical Genomics, King Saud bin Abdul-Aziz University for Health Sciences, Saudi Arabia cDepartment of Developmental Medicine, King Saud bin Abdul-Aziz University for Health Sciences, Saudi Arabia

Article Info Abstract

Article History: Genetic skeletal disorders (GSDs) constitute a heterogeneous, rare and a distinctive group Received: 03 January, 2019 Accepted: 27 February, 2019 of rare bone growth disorders, leading to abnormal size and shape of the skeleton. Published: 05 December, 2019 Prevalence, mutation spectrum and geographic distribution of genetic skeletal disorders

(GSDs) in Pakistan are not known. The present study reviewed different GSDs, listed in the * Corresponding author: Umair “Nosology and Classification of Genetic Skeletal Disorders: [1] using to-date literature M, Department of Medical Genomics, King Saud bin Abdul-Aziz published in different data-bases. The most recurrently reported skeletal disorders in University, Ministry of National Pakistan include acromesomelic dysplasia (AMDM, AMDG, AMDH), Polydactyl, Guard-Health Affairs, P.O.Box 3660, Mucopolysaccharidosis, Split hand/Split foot malformation (SHFM), synpolydacyly, Riyadh 11481, Saudi Arabia; Tel: accounting for 56.32% of the total cases. Disorders from nineteen different groups listed in +92-314-5065505; E-mail: [email protected], the “Nosology and Classification of Genetic Skeletal Disorders [1] have not been reported [email protected] from Pakistani population. Most of the publication came from University and research institutes, while very minimal was done by the hospitals. In most of the cases, mutations

were identified using next-generation sequencing technologies. In total, mutations in 45

genes causing nineteen different GSDs were reported from Pakistani population in the literature to-date. The current data will help clinicians and researchers working in the field of rare skeletal disorders in Pakistan, helping diagnosis and proper disease management. The review also highlighted the need to create a multi-level national network (database) that could help to provide proper molecular diagnosis and care to the patients suffering from severe GSDs in Pakistan.

Keywords: Genetic skeletal disorders; Rare genetic diseases; Pakistan

Copyright: © 2019 Ahmad F, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

have been not been performed yet. Most GSDs are reported as Introduction familial cases in the literature having both autosomal dominant Genetic skeletal disorders (GSDs) constitute a diverse, and autosomal recessive inheritance, which is common in heterogeneous, and austere group of rare bone growth disorders, Pakistani population. which arise due to disturbances in the skeletal development processes, growth, pathways, and homeostasis caused by Skeletal dysplasias mutations in different genes involved in the development of the Skeletal dysplasias are clinically and genetically heterogeneous skeletal system. The proper disease diagnosis is a challenge for bone and cartilages growth disorder, which result in abnormal size GSDs as syndromic and non-syndromic forms of GSDs affects and shape of the skeletal system. Skeletal dysplasia’s are also many individuals, thus leading to high health cost and poor quality defined as a generalized abnormality in the skeleton (from the of life [2-13]. Greek word, skeleton meaning “dried up”, mostly associated with The “Nosology and Classification of Genetic skeletal disorders linear skeletal abnormality and having a prevalence of 1/5000 live [1]” listed 436 different GSDs classified into 42 different groups birth [14]. Skeletal disorders in syndromic forms are associated using clinical, radiographic, and molecular diagnostics standards with other organs abnormalities, which result from teratogen and mutations were reported in only 364 different genes [1]. The exposure, somatic mosaicism and imprinting errors. GSDs are Nosology skeletal disorder classification provides an excellent inherited as autosomal dominant/recessive, X-linked guideline for diagnosis and identification of novel skeletal (recessive/dominant), or can be inherited as a denovo entity [15]. disorders for researchers, and also help to better understand the GSDs are mostly classified based on pattering abnormalities, mechanisms underlying these genetic mutations, proteins and linear development, differentiation, and maintenance of the human different pathways involved in skeletal development. Population- skeleton [16]. The last revision of the International Skeletal based studies in Pakistan to determine the prevalence of GSDs Dysplasia Society (ISDS) was performed in 2015 to classify the

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Citation: Ahmad F, Bilal M, Khan A, Umair M (2019). Genetic Skeletal Disorders in Pakistan: A brief Commentary. J Biomed Sci Res 1(1): 101 newly reported genes/disorders, which revealed new molecular Cartilage-hair hypoplasia 4 0 and pathological concepts associated with GSDs. This revision Cenani-Lenz syndactyly syndrome with oro-facial 12 30 cases was reviewed by [1]. Classified total 436 disorders into 42 and skeletal symptoms different groups on the basis of genetic, radiographic, molecular, Chondrodysplasia 24 18 cases (1BP) and biochemical criteria’s. For these 436 disorders mutations in Ellis–van Creveld syndrome 11 1.1BP only 364 genes were identified at that time. The present study Frontonasal dysplasia 8 28 (0.7BP) Infantile GM1 systematically reviewed GSDs reported in Pakistani population 1 330 cases (0.75) gangliosidosis illustrated in different online databases to-date. The review also Infantile malignant 2 0.75BP analyzed and highlighted the challenges involved in proper diagnosis and treatment of these severe GSDs. Joubert Syndrome 6 33 (1.125BP) Marfan syndrome 14 25 Methodology Meckel syndrome 3 3 4.0BP Mucopolysaccharidosis 31 19 cases (15.0BP) Study basis Multiple hereditary 24 0 The present investigation covered all 436 genes reported to cause exostoses Osteoarthropathy, GSDs that has been classified into 42 groups in the “Nosology 4 30 cases and Classification of GSDs [1]. hypertrophic 10 54 (10.0 BP) Bata bases used Osteopetrosis 4 140 (1.0BP) A literature search using different online available database was Polydactyly 64 278 conducted such as PubMed Polydactyly and mesoaxial (https://www.ncbi.nlm.nih.gov/pubmed), Pub plus synostotic syndactyly with 11 6 families phalangeal reduction (http://www.pubplus.org/), Google scholar Pseudoachondroplasia 17 3.3BP (https://scholar.google.com/), OMIM (https://www.omim.org), Roberts syndrome 2 150 cases HGMD (http://www.hgmd.cf.ac.uk/) and research gate SHFM 68 22 (5.4BP) Spondyloepiphyseal (https://www.researchgate.net/). Pakistan Genetic Mutation 13 36 (1BP) dysplasia Database (http://pakmutation.com/) is the only database available Synpolydactyly 79 0 for the mutations reported within Pakistani population Temtamy preaxial 2 18 cases corresponding rare genetic disorders. brachydactyly syndrome Trichorhinophalangeal Search approach 13 200 cases All the genes reported to-date causing skeletal disorders were syndrome type III Total 490 obtained from the “Nosology and Classification of GSDs [1].” The search was made by typing the mesh “gene name Pakistan” using The geographic distribution of GSDs in Pakistan is presented in different search engines such as PubMed, Google scholar, OMIM, Figure 1. GSDs have been reported in all the provinces of HMGD and research gate. Pakistan. However, more patients were reported from the Sindh province of Pakistan (41.42%). Details regarding a number of Results disorders reported from each province have been presented in A total of 490 cases having genetic skeletal disorders in the 19 Table 3. groups of the “Nosology and Classification of GSDs [1]” were reported from Pakistan in the current literature available. All the Discussion cases and mutations reported so far from Pakistan has been Genetic skeletal disorders (GSDs) are a highly heterogeneous documented in Table 1 and Table 2. The five most frequently group of disorders that arise as a result of cartilage or bone growth reported GSDs were Acromesomelic dysplasia (AMDM, AMDG, abnormality. It has been reported in X-linked AMDH), Mucopolysaccharidosis, Polydactyly, SHFM, (dominant/recessive) and autosomal (recessive/dominant) forms Synpolydactyly, accounting for 56.32% of cases (Table 3). and in both syndromic (severe) and non-syndromic forms (mild- severe). Proper diagnosis is very important for the management Table 1: Number of published cases of genetic skeletal diseases in and treatment of these genetic disorders such as family history, Pakistan compared to Orphadata Europe 2018 (www.orphadata.org). complete medical records, photographs/radiographs, MRI Cases Cases reported (additional neurological phenotypes), audiograms etc. Pakistan as Genetic Skeletal Disorders reported and prevalence the world’s 33rd largest country with respect to the area (881913sq- (GSDs) from Europe/100,000 Pakistan km), having five provinces Punjab, Sindh, Khyber Pakhtunkhwa, 3 5 (4.0BP) Gilgit and Baluchistan. Azad Jammu and Kashmir is a disputed Acromesomelic dysplasia 34 60 cases area and comes under the ordinance of Pakistan. GSDs are Brachydactyly 19 153 cases reported in the four provinces of Pakistan (Punjab: 40.81%, Sindh: Camptodactyly- -Coxa-Vara- 9 30 families 41.42%, KPK: 14.89%, Baluchistan: 0.40% and Kashmir: 3.26%). Pericarditis Syndrome No case of GSDs has been reported from the Gilgit region. In a Pubtexto Publishers | www.pubtexto.com 2 J Biomed Sci Res

Citation: Ahmad F, Bilal M, Khan A, Umair M (2019). Genetic Skeletal Disorders in Pakistan: A brief Commentary. J Biomed Sci Res 1(1): 101 developing country like Pakistan, where proper genetic testing is system or any proper database for rare disorders in Pakistan; still an issue, these rare genetic disorders including GSDs have therefore there is very little documented information for the received little attention. Currently, there is no case registration researcher and clinicians.

Table 2: To-date mutations published in genes causing GSDs in Pakistani population.

Gene Disorder OMI No. of Mutation Inherita Mutati Homozygous/Hetero Refere M cases nce on type zygous nce ALX1 Frontonasal 1367 4 c.661-1G>C, p.? AR Splice Homozygous [3] dysplasia 60 site ALX3 Frontonasal 1367 4 c.604C>T, p.Gln202* AR Nonsen Homozygous [2-7] dysplasia 60 se BHLH polydactyly and 6094 2 c.252_270delinsGCA; AR Frames Homozygous [8-12] A9 mesoaxial 32 p.Phe85Glufs*108 hift synostotic syndactyly with phalangeal reduction BHLH Polydactyly and 6094 6 c.211A>G; p.Asn71Asp, AR Missens Homozygous [17] A9 mesoaxial 32 c.218G>C; p.Arg73Pro, e synostotic c.211A>G; p.Asn71Asp syndactyly with phalangeal reduction BHLH Polydactyly and 6094 5 c.311T>C; p.Ile104Thr AR Missens Homozygous [18] A9 mesoaxial 32 e synostotic syndactyly with phalangeal reduction BMPR Chondrodysplasia 2007 2 c.657G>A; p.Trp219* AR Nonsen Homozygous [19] 1B Grebe type 00 se (AMDG ) BMPR acromesomelic 2012 3 c.1190T>G; p.Met397Arg AR Missens Homozygous [8-13, 1B dysplasia Hunter– 50 e 20-22] Thompson (AMDH) Chr 13 PAPA5A 2634 4 13q13.3-q21 AR Loci Homozygous [23] 50 CHST3 Spondyloepiphysea 6037 13 c.802G>T; p.Glu268* AR Nonsen Homozygous [24] l dysplasia 99 se CHSY1 Temtamy preaxial 6052 2 c.1897 G>A; p. Asp633Asn AR Missens Homozygous [25] brachydactyly 82 e syndrome CLCN7 Infantile malignant 6114 2 c.610A>T, c.612C>G; AR Missens Homozygous [26] osteopetrosis 90 p.Ser204Trp e COL10 Chondrodysplasia 1565 17 c.2011T>C; p.Ser671Pro AD Missens Heterozygous [18] A1 00 e COL10 Chondrodysplasia 1565 7 c.133 C>T; p.Pro45Ser AD Missens Heterozygous [27] A1 00 e COMP Pseudoachondropla 1771 17 c.1423G>A; p.Asp475Asn AR Missens Homozygous [26] sia 70 e CTSK osteopetrosis 2658 3 c.136C>T; p.Arg46Trp, AR Frames Homozygous and [28] 00 c.136C>T; p.Arg46Trp hift and compound ,c.266_268del; p.Lys89del, missens heterozygous c.136C>T; p.Arg46Trp e CTSK osteopetrosis 2658 3 c.935C>T; p.Ala277Val AR Missens Homozygous [29] 00 e CTSK osteopetrosis 2658 4 c.728G>A; p.Gly243Glu AR Missens Homozygous [30] 00 e DLX5 SHFM 4 c.482-485dupACCT; AD Frames Heterozygous [31-32] p.Ala163Profs*55 hift DLX6 SHFM 1836 2 c.632T>A; p.Val211Glu AD Missens Heterozygous [31-32] 00 e EPS15 SHFM 2 c.409delA; p.Ser137Alafs*19 AR Frame Homozygous [4-7] L1 shift ESCO2 Roberts syndrome 2683 2 c.879_880delAG; AR Frames Homozygous [33]

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Citation: Ahmad F, Bilal M, Khan A, Umair M (2019). Genetic Skeletal Disorders in Pakistan: A brief Commentary. J Biomed Sci Res 1(1): 101

00 p.Arg293fxX299 hift EVC Ellis–van Creveld 2255 4 c.617G>A; p.Ser206Asn AR Missens Homozygous [34] syndrome 00 e EVC Ellis–van Creveld 2255 2 c.1932_1946dupAGCCCTCCG AR framesh Homozygous [35] syndrome 00 GAGGCT ift EVC2 Ellis–van Creveld 2255 2 c.702 G>A; p.Try234* AR Nonsen Homozygous [35] syndrome 00 se EVC2 Ellis–van Creveld 2255 3 c.30dupC; p.Thr11Hisfs*45 AR framesh Homozygous [5] syndrome 00 ift EXT1 Multiple hereditary 24 IVS1 ds +1G-C AD Splice Heterozygous [36] exostoses site FAM92 PAPA9A 6182 3 c.478C>T; p.Arg160* AR Nonsen Homozygous [37] A 19 se FBN1 Marfan syndrome 1547 14 c.2368T>A; p.Cys790Ser AD Missens Heterozygous [38] 00 e FGFR3 Achondroplasia 1008 3 c.1138 G>A; p.Gly380Arg AD Missens Heterozygous [39,40] 00 e FKBP1 Osteogenesis 6070 8 c.1490G4A; p.Trp497*, AR Nonsen Homozygous [41] 0 imperfecta, type XI 63 c.344G4A; p.Arg115Gln and se, c.831dupC; missens p.Gly278ArgfsX295 e and Frames hift GALN Mucopolysacchari 6122 19 p.Phe216Ser, p.Met38Arg, AR Missens Homozygous [42] S dosis IVA 22 p.Ala291Ser, e and p.Glu121Argfs*37, Frames p.Pro420Arg, p.Arg386Cys hift GDF5 AMDG 2007 6 c.157_158dupC; AR Frames Homozygous [4,7] 00 p.Leu53Profs*41, c.872G>A; hift and p.Trp291* nonsens e GDF5 AMDG 2007 2 c.527T>C; c.1114insGAGT AR Frames Homozygous [10] 00 hift GDF5 AMDG 2007 2 c.527T>C; c.1114insGAGT AR Frames Homozygous [28] 00 hift GDF5 Brachydactyly 1131 3 c.527delT; p.Leu176Argfs*17 AD Frames Heterozygous [8-13] 00 hift GLB1 Infantile GM1 2306 1 c.881-882delAT; p.Tyr294Terfs AR Frames Homozygous [36] gangliosidosis 00 hift GLI1 PAPA8A 6181 4 c.337C>T; p.Arg113* AR Nonsen Homozygous [30] 23 se GLI1 Pre-axial 6181 2 c.1517T>A; p.Leu506Gln AR Missens Homozygous [43] polydactyly 23 e GLI3 Postaxial 1742 19 c.3635delG; AD Frames Heterozygous [19] polydactyly types 00 p.Gly1212Alafs*18 hift A and B with camptodactyly HOXD Synpolydactyly 1860 17 c.742C>T;p.Gln248X AD Nonsen Heterozygous [17] 13 00 se HOXD Synpolydactyly 1860 62 c.184_210dup and AD Frames Heterozygous [23] 13 00 c.187_207dup hift HPGD Osteoarthropathy, 2591 4 c.577T˃C; p.Ser193Pro Missens Homozygous [20,21, hypertrophic 00 e 26] IDUA Mucopolysacchari 6070 12 p.Leu490Pro AR Missens Homozygous [44] dosis 14 e IQCE Post axial 6176 5 c.395-1G4A AR Splice Homozygous [2,7] polydactyly type 42 site 7A (PAPA7A) LRP4 Cenani-Lenz 2127 3 c.316+1G>A AR Splice Homozygous [45] syndactyly 80 site syndrome with oro-facial and skeletal symptoms LRP4 Cenani-Lenz 2127 9 c.2858T>C; p.Leu953Pro AR Missens Homozygous [14] syndactyly 80 e syndrome with oro-facial and Pubtexto Publishers | www.pubtexto.com 4 J Biomed Sci Res

Citation: Ahmad F, Bilal M, Khan A, Umair M (2019). Genetic Skeletal Disorders in Pakistan: A brief Commentary. J Biomed Sci Res 1(1): 101

skeletal symptoms MKS1 Joubert Syndrome 6171 6 c.272_285delACGACCGCCTG AR Frames Homozygous [31] 21 GCA; p.Asn91Ilefs*28 hift NPR2 Acromesomelic 6028 5 c.872A>G; p.Gln291Arg AR Missens Homozygous [46] dysplasia, type 75 e Maroteaux (AMDM) NPR2 AMDM 6028 17 (c.2720 C>T; p.Thr907Met) and AR Missens Homozygous [12,13] 75 c.2986 + 2 T>G e and splice site NPR2 AMDM 6028 9 c.1801C>A; p. Arg601Ser, AR Missens Homozygous [47] 75 c.2245C>T; p.Arg749Trp and e and c.2986+2T>G splice site PRG4 Camptodactyly- 2082 9 c.2816_2817delAA; AR Frames Homozygous [48] Arthropathy-Coxa- 50 p.Lys939fsX38 hift Vara-Pericarditis Syndrome RMRP Cartilage-hair 2502 4 g.70A>G AR Missens Homozygous [6] hypoplasia 50 e ROR2 Brachydactyly type 1130 16 c.2278C >T, p.Gln760* AD Nonsen Heterozygous [5] B 00 se TCIRG Osteopetrosis 2597 1 c.624delC; p.Pro208fsX AR Frames Homozygous [39,40] 1 00 hift TMEM Meckel syndrome 6073 3 c.1575+1G>A and c.870-2A>G AR Splice Homozygous [55] 67 3 61 site (MKS3 ) TRPS1 Trichorhinophalan 1903 8 c.2762G>T; p.Gly921Val AD Missens Heterozygous [56] geal syndrome type 51 e III TRPS1 Trichorhinophalan 1903 5 c.2762G>A;p.Arg921Gln AD Missens Heterozygous [8-12] geal syndrome type 51 e III WNT1 Osteogenesis 6152 9 c.1168G>T; p.Gly324Cys AR Missens Homozygous [57] imperfecta, type 20 e XV WNT1 Osteogenesis 6152 4 c.359-3C4G AR Splice Homozygous [1-7] imperfecta, type 20 site XV WNT1 SHFM 2253 6 c.460C >G; p.Gln154* and AR Nonsen Homozygous [8] 0B 00 c.300_306dupAGGGCGG; se and p.Leu103Argfs*53 framesh ift WNT1 SHFM 2253 11 c.986C>G, p.Thr329Arg AR Missens Homozygous [38,58, 0B 00 e 59] WNT1 SHFM 2253 8 (c.1165_1168delAAGT; AR Frame Homozygous [47] 0B 00 c.300_306dupAGGGCGG shit Xq26.3 SHFM2 3133 36 Locus chromosome Xq26.3 X linked ------[60] loci 50 ZNF14 PAPA6A 6152 4 c.1420C>T; p.Thr474Ile AR Missens Homozygous [61] 1 26 e ZRS Triphalangeal 6055 11 Intronic ZRS287 C>A AD ------Heterozygous [12] Thumb, Pre-axial 22 Polydactyly, Postaxial Polydactyly and Syndactyly ZRS Preaxial 6055 12 Intronic ZRS463T>G AD ------Heterozygous [56] polydactyly/triphal 22 angeal thumb

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Citation: Ahmad F, Bilal M, Khan A, Umair M (2019). Genetic Skeletal Disorders in Pakistan: A brief Commentary. J Biomed Sci Res 1(1): 101

sequencing is mostly performed, which might help researchers to diagnoses easy that is prerequisite for accurate genetic counseling [8-13]. A network representing rare disorders is vital for establishing a proper medical policy, which would significantly reduce the risk of misdiagnosis and improve/develop a treatment for these rare genetic disorders. A strong network and collaborative partnerships of Pakistani research institutes should be established with researchers of different countries to find an ultimate treatment for GSDs. In each hospital, a department associated with genetic counseling for rare genetic disorders should be established in major cities. Conclusion Figure 1: (A) Geographic distribution of the GSDs reported in each In conclusion, the present review has summarized the genetic, province of Pakistan. (B) Percentage of genetic disorders reported from molecular, number, and geographic characteristics of GSDs in the each province. (C) Number of cases reported from each province of Pakistani population. Analyzing the exact skeletal disorders Pakistan. ##BP indicates birth prevalence. reported from this part of the world will help in the proper A systematic bibliographic study of GSDs in Pakistan will help to diagnosis of these rare disorders, and will urge the need of estimate the prevalence of these severe disorders. The present establishing a multi-level network to meet the specific challenge study, to the best of our knowledge is the first systematic review of healthcare for GSDs in Pakistan. Detailed information of of the GSDs from Pakistani population. As the GSDs are also pathophysiologic mechanism(s) and disease-causing genetic representatives of other severe rare genetic disorders, the current defects is mandatory in order to provide proper clinical review also highlighted the fact that the number and type of GSDs intervention for these GSDs. reported in Pakistani literature has progressively increased over the past 10 years (99%). Particularly in the last 5 years, many Competing interests publications reported mutations in different GSDs, which is due to None declared. the robust next generation sequencing technologies and increasing Ethics statement attention to the medical problems. Among the literature published Not required from Pakistan highlighting GSDs, there is a relatively high frequency of novel mutations and also many novel genes. These Acknowledgements mutations in novel genes may also lead to a better understanding We gratefully acknowledge KAIMRC, Riyadh Saudi Arabia for of the novel pathways and mutation spectrum associated with its support. GSDs [62-69]. Author contributions Table 3: GSDs reported from each province. MU, MF drafted the manuscript. MF, MB, AK collected and arranged the data. Conception and design of the work: MU. Number of GSDs case Province reported Percentage (%) Funding: No funding source involved. Sindh 203 41.42 Disclaimer: The authors have no conflict of interest. Punjab 200 40.81 Khyber References Pakhtunkhwa 71 14.89 1. Bonafe L, Cormier-Daire V, Hall C, Lachman R, Mortier G, Kashmir 16 3.26 Mundlos S, et al. Nosology and classification of genetic skeletal Balochistan 2 0.4 disorders. Am J Med Genet A. 2015; 167: 1-24. Gilgit 0 0 2. Ullah A, Hammid A, Umair M, Ahmad W. A novel heterozygous intragenic sequence variant in dlx6 probably underlies first case of Total 326 different genes are involved in causing GSDs, making autosomal dominant split-hand/foot malformation type 1. Mol it a complex heterogeneous group of disorders, thus it makes it Syndromol. 2017; 8: 79-84. very difficult to diagnose the exact disorder. Disorders as a single 3. Ullah A, Kalsoom UE, Umair M, John P, Ansar M, et al. Exome gene mutation (monogenetic) are rare and help us to track down sequencing revealed a novel splice site variant in the ALX1 gene the particular gene function and related pathways. Studying underlying frontonasal dysplasia. Clin Genet. 2017; 91: 494-498. different rare genetic disorders and the pathogenic mutations 4. Umair M, Rafique A, Ullah A, Ahmad F, Ali RH, et al. Novel involved, provide insight into different preventive measures, homozygous sequence variants in the GDF5 gene underlie diagnostic applications, and finally help in therapeutic strategies. acromesomelic dysplasia type-grebe in consanguineous families. As a result, large scale DNA sequencing using next-generation Congenit Anom (Kyoto). 2017; 57: 45-51.

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Citation: Ahmad F, Bilal M, Khan A, Umair M (2019). Genetic Skeletal Disorders in Pakistan: A brief Commentary. J Biomed Sci Res 1(1): 101

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Khan A, Wang R, Han S, Ahmad W, Zhang X. A novel homozygous 34. Umm-E-Kalsoom, Wasif N, Tariq M, Ahmad W. A novel missense missense mutation in BHLHA9 causes mesoaxial synostotic mutation in the EVC gene underlies Ellis-van Creveld syndrome in syndactyly with phalangeal reduction in a Pakistani family. Hum a Pakistani family. Pediatr Int. 2010; 52: 240-246. Genome Var. 2017; 4:17054. 35. Aziz A, Raza SI, Ali S, Ahmad W. Novel homozygous mutations in 19. Graul-Neumann LM, Deichsel A, Wille U, Kakar N, Koll R, et al. the EVC and EVC2 genes in two consanguineous families Homozygous missense and nonsense mutations in BMPR1B cause segregating autosomal recessive Ellis-van Creveld syndrome. Clin acromesomelic chondrodysplasia-type Grebe. Eur J Hum Genet. Dysmorphol. 2016; 25: 1-6. 2014; 22: 726-733. 36. Faiyaz-Ul-Haque M, Ahmad W, Zaidi SH, Hussain S, Haque S, et 20. Khan AK, Muhammad N, Khan SA, Ullah W, Nasir A, et al. A novel al. 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38. Micheal S, Khan MI, Akhtar F, Weiss MM, Islam F, et al. severe recessively inherited Osteogenesis Imperfecta. J Biomed Sci. Identification of a novel FBN1 gene mutation in a large Pakistani 2018; 25: 82. family with Marfan syndrome. Mol Vis. 2012; 18: 1918-26. 53. Khan S, Ali RH, Abbasi S, Nawaz M, Muhammad N, Ahmad W. 39. Ajmal M, Mir A, Shoaib M, Malik SA, Nasir M. Identification and Novel mutations in natriuretic peptide receptor-2 gene underlie in silico characterization of p.G380R substitution in FGFR3, acromesomelic dysplasia, type maroteaux. BMC Med Genet. 2012; associated with achondroplasia in a non-consanguineous Pakistani 13: 44. family. Diagn Pathol. 2017; 12: 47. 54. Khan S, Basit S, Zimri FK, Ali N, Ali G, Ansar M, Ahmad W. A 40. Ajmal M, Mir A, Wahid S, Khor CC, Foo JN, Siddiqi S, et al. novel homozygous missense mutation in WNT10B in familial split- Identification and in silico characterization of a novel p.P208PfsX1 hand/foot malformation. 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Citation: Ahmad F, Bilal M, Khan A, Umair M (2019). Genetic Skeletal Disorders in Pakistan: A brief Commentary. J Biomed Sci Res 1(1): 101

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