ABSTRACT
PURPOSE: To investigate the molecular basis of Bardet-Biedl syndrome (BBS) in five consanguineous families of Pakistani origin. METHODS: Linkage in two families (A and B) was established to BBS7 on chromosome 4q27, in family C to BBS8 on chromosome 14q32.1, and in family D to BBS10 on chromosome 12q21.2. Family E was investigated directly with exome sequence analysis. RESULTS: Sanger sequencing revealed two novel mutations and three previously reported mutations in the BBS genes. These mutations include two deletions (c.580_582delGCA, c.1592_1597delTTCCAG) in the BBS7 gene, a missense mutation (p.Gln449His) in the BBS8 gene, a frameshift mutation (c.271_272insT) in the BBS10 gene, and a nonsense mutation (p.Ser40*) in the MKKS (BBS6) gene. CONCLUSIONS: Two novel mutations and three previously reported variants, identified in the present study, further extend the body of evidence implicating BBS6, BBS7, BBS8, and BBS10 in causing BBS.
Subject(s)
Bardet-Biedl Syndrome/genetics , Consanguinity , Group II Chaperonins/genetics , Mutation , Proteins/genetics , Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/genetics , Adaptor Proteins, Signal Transducing , Adolescent , Adult , Bardet-Biedl Syndrome/diagnosis , Chaperonins , Child , Codon, Nonsense , Cytoskeletal Proteins , DNA Mutational Analysis , Female , Frameshift Mutation , Genetic Linkage , Genetic Testing , Humans , Male , Mutation, Missense , Pedigree , Sequence Analysis, DNA , Sequence Deletion , Young AdultABSTRACT
BackgroundOsteogenesis imperfecta (OI) is a heritable bone fragility disorder usually caused by dominant variants in COL1A1 or COL1A2 genes. Over the last few years, 17 genes including 12 autosomal recessive and five autosomal dominant forms of OI, involved in various aspects of bone formation, have been identified.MethodsWhole-exome sequencing followed by conventional Sanger sequencing was performed in a single affected individual (IV-3) in a family.ResultsHere, we report the clinical and genetic characterization of OI type 3 in a consanguineous family with four affected members. Clinical examinations revealed low bone density, short stature, severe vertebral compression fractures, and multiple long bone fractures in the affected members. Exome sequencing revealed a biallelic pathogenic splice acceptor site variant (c.359-3C>G) in a wingless-type mouse mammary tumor virus integration site family 1 (WNT1) gene located on chromosome 12q13.12.ConclusionWe report a biallelic splice site variant underlying OI type 3 and the first case from the Pakistani population.
Subject(s)
DNA Mutational Analysis/methods , Exome Sequencing , Homozygote , Mutation , Osteogenesis Imperfecta/genetics , RNA Splice Sites , Wnt1 Protein/genetics , Adolescent , Child , Female , Genetic Association Studies , Genetic Predisposition to Disease , Heredity , Humans , Male , Osteogenesis Imperfecta/complications , Osteogenesis Imperfecta/diagnostic imaging , Pakistan , Pedigree , PhenotypeABSTRACT
Ellis-van Creveld syndrome is an autosomal recessive skeletal dysplasia primarily characterized by the features such as disproportionate dwarfism, short ribs, short limbs, dysplastic nails, cardiovascular malformations, post-axial polydactyly (PAP) (bilateral) of hands and feet. EVC/EVC2 located in head-to-head arrangement on chromosome 4p16 are the causative genes for EvC syndrome. In the study, we present two families, A and B, with Pakistani and Republic of Kosovo origin, respectively. They showed features of EvC syndrome and were clinically and genetically characterized. In family A, the affected members showed an additional feature of profound deafness. The whole exome sequencing (WES) in this family revealed two homozygous variants in EVC2 (c.30dupC; p.Thr11Hisfs*45) and TMC1 (c.1696-1G>A) genes. In family B, WES revealed novel compound heterozygous variants (p.Ser307Pro, c.2894+3A>G) in the EVC gene. This study reports first case of variants in the genes causing EvC syndrome and profound deafness in the same family.
Subject(s)
Ellis-Van Creveld Syndrome/genetics , Fingers/abnormalities , Membrane Proteins/genetics , Polydactyly/genetics , Proteins/genetics , Toes/abnormalities , Adolescent , Child , Child, Preschool , Ellis-Van Creveld Syndrome/physiopathology , Female , Fingers/physiopathology , Genetic Association Studies , Genetic Predisposition to Disease , Humans , Intercellular Signaling Peptides and Proteins , Male , Mutation , Pedigree , Phenotype , Polydactyly/physiopathology , Toes/physiopathology , Exome SequencingABSTRACT
Acromesomelic dysplasia Grebe type (AMDG) is characterized by severe knob like non-functional fingers and short acromesomelic limbs, and is inherited in an autosomal recessive manner. Disease causing sequence variants in the GDF5 (Growth Differentiation Factor 5) gene located on chromosome 20q11.22 are responsible for causing AMDG. In the study, presented here, two consanguineous families with AMDG were clinically and genetically characterized. After establishing linkage in the two families (A and B) to GDF5 gene on chromosome 20q11.22, Sanger DNA sequencing was performed in all available affected and unaffected members. Sequence analysis of the GDF5 gene revealed two novel variants including a duplication (c.157_158dupC, p.Leu53Profs*41) in family A, and a nonsense (p.Trp291*) in family B. Our findings extend the body of evidence that supports the importance of GDF5 in the development of limbs.
