title: Mutations in patients with osteogenesis imperfecta from consanguineous Indian families.
abstract: Osteogenesis imperfecta (OI) is a spectrum of genetic disorders with decreased bone density and bone fragility. Most of the cases of OI are inherited in autosomal dominant fashion with mutations in COL1A1 or COL1A2 genes. Over last few years, twelve genes for autosomal recessive OI have been identified. In this study we have evaluated seven patients with OI from consanguineous Indian families. Homozygosity mapping using SNP microarray was done and selected candidate genes were sequenced. Candidate genes were identified in four out of seven patients studied. Four mutations, namely; a homozygous non-sense (p.Q178*) and a deletion (p.F277del) mutations in SERPINF1 gene, a missense mutation (p.M101K) in PPIB gene and a nonsense mutation (p.E45*) in CRTAP gene were identified. In three patients for whom the regions of homozygosity did not reveal any known autosomal recessive OI genes, exome sequencing was performed and we identified a known missense mutation (p.G1012S) in COL1A2 gene in one of the patients. As WNT1 gene was not properly covered in exome sequencing in one patient, the gene was sequenced and a homozygous in-frame deletion of four amino acids (p.Phe176_Leu179del) was identified. In one of the three cases the exome sequencing did not reveal a mutation in any known OI genes, suggesting the possibility of mutations in an unidentified gene. The phenotypes of all the cases are described. This work proves the power of homozygosity mapping followed by candidate gene sequencing approach for clinical application in consanguineous families.
authors.affiliation: Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India.
authors.forename: Joshi
authors.initials: J
authors.lastname: Stephen
authors.affiliation: Department of Medical Genetics, Kasturba Medical College, Manipal University, Manipal, India.
authors.forename: Katta Mohan
authors.initials: KM
authors.lastname: Girisha
authors.affiliation: Diagnostics Division, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, India.
authors.forename: Ashwin
authors.initials: A
authors.lastname: Dalal
authors.affiliation: Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India.
authors.forename: Anju
authors.initials: A
authors.lastname: Shukla
authors.affiliation: Pediatric Orthopaedic Service, Department of Orthopaedics, Kasturba Medical College, Manipal University, Manipal, India.
authors.forename: Hitesh
authors.initials: H
authors.lastname: Shah
authors.affiliation: Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Srivastava
authors.affiliation: Institute of Medical Genetics and Human Genetics, Charité-Universitatsmedizin Berlin, 13353 Berlin, Germany; Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany; Berlin-Brandenburg Center for Regenerative Therapies, Berlin, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Kornak
authors.affiliation: Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India. Electronic address: shubharaophadke@gmail.com.
authors.forename: Shubha R
authors.initials: SR
authors.lastname: Phadke
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D024042:Collagen Type I / Q000235:genetics; D000090602:Collagen Type I, alpha 1 Chain; D003241:Consanguinity; D021983:Cyclophilins / Q000235:genetics; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005136:Eye Proteins / Q000235:genetics; D005260:Female; D006801:Humans; D007194:India; D008297:Male; D018832:Molecular Chaperones; D009154:Mutation; D009414:Nerve Growth Factors / Q000235:genetics; D010013:Osteogenesis Imperfecta / Q000235:genetics*; D010641:Phenotype; D015843:Serpins / Q000235:genetics; D022021:Tacrolimus Binding Proteins / Q000235:genetics; D051155:Wnt1 Protein / Q000235:genetics; D055815:Young Adult; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D021983:Cyclophilins; D016326:Extracellular Matrix Proteins; D005136:Eye Proteins; D018832:Molecular Chaperones; D009414:Nerve Growth Factors; D015843:Serpins; D022021:Tacrolimus Binding Proteins; D051155:Wnt1 Protein; D000099174:Pigment Epithelium-Derived Factor; C108053:CRTAP protein, human; C495247:WNT1 protein, human; C081786:cyclophilin B; C110054:FKBP10 protein, human
keywords: Autosomal recessive; CRTAP; Consanguinity; Exome sequencing; Homozygosity; India; OI; PPIB; SERPINF1; WNT1