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An example of the utility of genomic analysis for fast and accurate clinical diagnosis of complex rare phenotypes

Le Quesne Stabej, Polona, James, Chela, Ocaka, Louise, Tekman, Mehmet, Grunewald, Stephanie, Clement, Emma, Stanescu, Horia C., Kleta, Robert, Morrogh, Deborah, Calder, Alistair, Williams, Hywel J. and Bitner-Glindzicz, Maria 2017. An example of the utility of genomic analysis for fast and accurate clinical diagnosis of complex rare phenotypes. Orphanet Journal of Rare Diseases 12 , 24. 10.1186/s13023-017-0582-8

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Background We describe molecular diagnosis in a complex consanguineous family: four offspring presented with combinations of three distinctive phenotypes; non-syndromic hearing loss (NSHL), an unusual skeletal phenotype comprising multiple fractures, cranial abnormalities and diaphyseal expansion, and significant developmental delay with microcephaly. We performed Chromosomal Microarray Analysis on the offspring with either the skeletal or developmental delay phenotypes, and linkage analysis and whole exome sequencing (WES) on all four children, parents and maternal aunt. Results Chromosomal microarray and FISH analysis identified a de novo unbalanced translocation as a cause of the microcephaly and severe developmental delay. WES identified a NSHL-causing splice variant in an autosomal recessive deafness gene PDZD7 which resided in a linkage region and affected three of the children. In the two children diagnosed with an unusual skeletal phenotype, WES eventually disclosed a heterozygous COL1A1 variant which affects C-propetide cleavage site of COL1. The variant was inherited from an apparently unaffected mosaic father in an autosomal dominant fashion. After the discovery of the COL1A1 variant, the skeletal phenotype was diagnosed as a high bone mass form of osteogenesis imperfecta. Conclusions Next generation sequencing offers an unbiased approach to molecular genetic diagnosis in highly heterogeneous and poorly characterised disorders and enables early diagnosis as well as detection of mosaicism.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Medicine
Publisher: BMC
ISSN: 1750-1172
Date of First Compliant Deposit: 15 January 2020
Date of Acceptance: 31 January 2017
Last Modified: 17 Jan 2020 08:57

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