Salam A.,Kings College London |
Simpson M.A.,Kings College London |
Stone K.L.,Kings College London |
Takeichi T.,Kings College London |
And 4 more authors.
Matrix Biology | Year: 2014
Finding pathogenic mutations in monogenic diseases represents one of the significant milestones of late 20th century molecular genetics. Mutation data can improve genetic counseling, assist disease modeling and provide a basis for translational research and therapeutics. The logistics of detecting disease mutations, however, has not always been easy or straightforward. Traditional approaches using genetic linkage or candidate gene analysis have often been laborious and expensive, but the advent of next generation sequencing technologies is changing the very nature of modern-day gene discovery and mutation detection. The application of whole-exome and whole-genome sequencing has demonstrated how these new approaches can improve diagnostic sensitivity as well as disclose completely novel and unsuspected disease-gene associations. Use of next generation sequencing in inherited diseases that display genetic heterogeneity is already a cost-effective methodology for mutation detection. Further reductions in sequencing costs and machine run time, as well as improved bioinformatics, are likely to lead to the incorporation of next generation sequencing into routine diagnostics within clinical genetics. In the short term, the impact of next generation sequencing on the genetically diverse and clinically protean heritable connective tissue disorders is likely to mean more comprehensive documentation of individual mutations. Longer term, dissection of bioinformatics data may lead to further insight into individual prognosis and an era of new personal therapeutics. © 2013 International Society of Matrix Biology. Source
Nanda A.,Asad Al Hamad Dermatology Center |
Pasternack S.M.,University of Bonn |
Mahmoudi H.,University of Bonn |
Ishorst N.,University of Bonn |
And 2 more authors.
Pediatric Dermatology | Year: 2014
Woodhouse-Sakati syndrome (WSS) is a rare autosomal recessive disorder characterized by alopecia, hypogonadism, diabetes mellitus, intellectual disability, sensorineural deafness, extrapyramidal signs, and low insulinlike growth factor 1 levels. Inter- and intrafamilial phenotypic variability have been reported. Mutations in the C2orf37 gene cause WSS. The present report describes the clinical signs and symptoms of three affected siblings from a consanguineous Bedouin family from Kuwait. Direct sequencing of the C2orf37 gene revealed that the c.436delC (p.Ala147Hisfs*9) mutation was present in a homozygous state in all affected siblings and in a heterozygous state in the parents and a healthy sister. Nine C2orf37 mutations causing WSS have been identified. This family shared the mutation reported earlier in Saudi families and families of Bedouin tribes from Qatar and Israel. No phenotypic or genotypic correlation has been observed. Despite the great phenotypic variability of WSS, hypotrichosis has been observed in all individuals with WSS reported. This condition has not been reported in the dermatologic literature. WSS should be included in the differential diagnosis of syndromic congenital hypotrichosis. © 2013 Wiley Periodicals, Inc. Source
AlFadhli S.,Kuwait University |
Nanda A.,Asad Al Hamad Dermatology Center
Immunology Letters | Year: 2013
To explore the genetic association of single nucleotide polymorphisms (SNPs) in the coding region of the NOTCH4, exon 3 C+1297T and exon 5 A+3063G, in a case-control analysis of 58 rheumatoid arthritis (RA) and 98 alopecia areata (AA) and 100 ethnically matched healthy subjects. NOTCH4 polymorphisms were genotyped by standard PCR followed by restriction digestion. Analysis of C+1297T SNP revealed a significant association of allele C+1297 (p= 0.03, OR = 1.66, 95%CI 1.04-2.64) and genotype CT (p= 0.002, OR = 2.82, 95%CI 1.42-5.59) with susceptibility to RA. Analysis of A+3063G SNP revealed a significant association of allele A+3063 (p= 0.05, OR = 0.59, 95%CI 0.35-1.008) and genotype AA (p= 0.002, OR = 0.39, 95%CI 0.17-0.87) with RA. Over all analysis between alopecia patients and the studied SNPs failed to show any significant association. Classifying the patients by severity of disease, confined the risk role of CT genotype to the severest form of alopecia universalis (p= 0.006, OR = 3.82, 95%CI 1.39-3.82) and AG genotype to semiuniversalis alopecia (p= 0.004, OR = 4.3, 95%CI 1.5-15.3). Present study is the first to report a statistically significant association between RA and NOTCH4 polymorphisms. © 2013 Elsevier B.V. Source
Almaani N.,Kings College London |
Liu L.,Kings College London |
Dopping-Hepenstal P.J.C.,St Johns Institute Of Dermatology |
Lai-Cheong J.E.,Kings College London |
And 7 more authors.
Acta Dermato-Venereologica | Year: 2011
Autosomal dominant and recessive forms of dystrophic epidermolysis bullosa (DEB) result from mutations in the type VII collagen gene (COL7A1). Although paradigms have emerged for genotype/phenotype correlation in DEB, some pathogenic mutations in COL7A1, notably glycine substitutions within the type VII collagen triple helix, may lead to diagnostic difficulties, since certain glycine substitutions can result in either dominant or recessive mutant alleles. Delineation of glycine substitution mutations into two discrete groups, however, is made difficult by observations that, for some particular glycine substitutions in type VII collagen, the same mutation can result in both dominant and recessive disease. In this report we describe four further glycine missense mutations: p.Gly1483Asp, p.Gly1770Ser, p.Gly2213Arg and p.Gly2369Ser, which can lead to either dominant or recessive DEB, and which result in a spectrum of clinical abnormalities. We also identify a further 30 new glycine substitution mutations that cause either dominant or recessive DEB, but not both. In screening the COL7A1 gene for mutations in individuals with DEB our data highlight that delineation of glycine substitutions in type VII collagen has important implications for genetic counseling. © 2011 Acta Dermato-Venereologica. Source
Nanda A.,Asad Al Hamad Dermatology Center |
El-Kamel M.F.,Asad Al Hamad Dermatology Center |
Al-Oneizi E.M.,Al Sabah Hospital |
Al-Ajmi M.,Paediatric Intensive Care Unit |
And 2 more authors.
Clinical and Experimental Dermatology | Year: 2012
Congenital leukaemia (CL) is a rare malignancy that accounts for < 1% of cases of childhood leukaemias. Leukaemia cutis (LC) refers to cutaneous infiltration with leukaemic cells, and is seen in 30-50% of CL cases. It may precede, follow or occur simultaneously with leukaemia. If left untreated, the prognosis is usually poor, but early diagnosis and treatment may result in a favourable prognosis. We report a case of congenital leukaemia cutis with a progressive, violaceous papulonodular eruption (a 'blueberry muffin' rash), which had been noted at birth, as a presenting sign of acute myeloid leukaemia (AML), which on investigation was classified as AML, FAB M2 type with a t(8; 21)(p11;q22) chromosomal defect. The patient had a favourable response to AML chemotherapy. © The Author(s) CED © 2012 British Association of Dermatologists. Source