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Objectives: Thanatophoric dysplasia (TD) is the most common form of lethal skeletal dysplasia. It is primarily an autosomal dominant disorder and is characterised by macrocephaly, a narrow thorax, short ribs, brachydactyly, and hypotonia. In addition to these core phenotypic features, TD type I involves micromelia with bowed femurs, while TD type II is characterised by micromelia with straight femurs and a moderate to severe clover-leaf deformity of the skull. Mutations in the FGFR3 gene are responsible for all cases of TD reported to date. The objective of the study here was to delineate further the mutational spectrum responsible for TD., Methods: Conventional polymerase chain reaction (PCR), allele-specific PCR, and sequence analysis were used to identify FGFR3 gene mutations in a fetus with a lethal skeletal dysplasia consistent with TD, which was detected during a routine antenatal ultrasound examination., Results: In this report we describe the identification of two de novo missense mutations in cis in the FGFR3 gene (p.Asn540Lys and p.Val555Met) in a fetus displaying phenotypic features consistent with TD., Conclusion: This is the second description of a case of TD occurring as a result of double missense FGFR3 gene mutations, suggesting that the spectrum of mutations involved in the pathogenesis of TD may be broader than previously recognised.

Objectives: The aim of this study was to develop and validate a comparative genomic hybridisation (CGH) array that would allow simultaneous targeted analysis of a panel of disease genes and low resolution whole genome analysis., Methods: A bespoke Roche NimbleGen 12x135K CGH array (Roche NimbleGen Inc., Madison, Wisconsin, USA) was designed to interrogate the coding regions of 66 genes of interest, with additional widely-spaced backbone probes providing coverage across the whole genome. We analysed genomic deoxyribonucleic acid (DNA) from 20 patients with a range of previously characterised copy number changes and from 8 patients who had not previously undergone any form of dosage analysis., Results: The custom-designed Roche NimbleGen CGH array was able to detect known copy number changes in all 20 patients. A molecular diagnosis was also made for one of the additional 4 patients with a clinical diagnosis that had not been confirmed by sequence analysis, and carrier testing for familial copy number variants was successfully completed for the remaining four patients., Conclusion: The custom-designed CGH array described here is ideally suited for use in a small diagnostic laboratory. The method is robust, accurate, and cost-effective, and offers an ideal alternative to more conventional targeted assays such as multiplex ligation-dependent probe amplification.