Intrafamilial variability of ZRS‐associated syndrome: characterization of a mosaic ZRS mutation by pyrosequencing. (6th January 2015)

• Record Type: Journal Article
• Authors: Vanlerberghe, C.; Faivre, L.; Petit, F.; Fruchart, O.; Jourdain, A.‐S.; Clavier, F.; Gay, S.; Manouvrier‐Hanu, S.; Escande, F.
• Is Part Of: Clinical genetics. Volume 88:Number 5(2015:Nov.)
• Page Start: 479
• Page End: 483
• Publication Date: 2015-01-06
• Subjects: Medical genetics -- Periodicals; 616.0420
• DOI: 10.1111/cge.12534
• Languages: English
• ISSNs: 0009-9163

Abstract

<abstract abstract-type="main" id="cge12534-abs-0001"> <title> <x xml:space="preserve">Abstract</x> </title> <p id="cge12534-para-0001">During limb development, the spatio‐temporal expression of <italic>sonic hedgehog</italic> (<italic>SHH</italic>) is driven by the Zone of polarizing activity Regulatory Sequence (ZRS), located 1 megabase upstream from <italic>SHH</italic>. Gain‐of‐function mutations of this enhancer, which cause ectopic expression of <italic>SHH</italic>, are known to be responsible for congenital limb malformations with variable expressivity, ranging from preaxial polydactyly or triphalangeal thumbs to polysyndactyly, which may also be associated with mesomelic deficiency. In this report, we describe a patient affected with mirror‐image polydactyly of the four extremities and bilateral tibial deficiency. The proband's father had isolated preaxial polydactyly type II (PPD2). Using Sanger sequencing, a ZRS point mutation (NC_000007.14, g.156584153A&gt;G, UCSC, Build hg.19) was only identified in the patient. However, pyrosequencing analysis enabled the detection of a 10% somatic mosaic in the blood and saliva from the father. To our knowledge, this is the first description of a ZRS mosaic mutation. This report highlights the complexity of genotype–phenotype correlation in <italic>ZRS</italic>‐associated syndromes and the importance of detecting somatic mosaicism for accurate genetic counselling.</p> </abstract>