CLINICAL REPORT Autosomal Dominant Spondylocostal Dysostosis in Three Generations of a Macedonian Family: Negative Mutation Analysis of DLL3, MESP2, HES7, and LFNG Zoran S. Gucev, 1 * Velibor Tasic, 1 Nada Pop-Jordanova, 1 Duncan B. Sparrow, 2,3 Sally L. Dunwoodie, 2,3 Sian Ellard, 4 Elizabeth Young, 4 and Peter D. Turnpenny 4,5 1 Medical Faculty Skopje, Divizija BB, Skopje, Macedonia 2 Victor Chang Cardiac Research Institute, Sydney, Australia 3 Faculty of Medicine, St. Vincent’s Clinical School, University of New South Wales, Sydney, Australia 4 Institute of Biomedical and Clinical Science, Peninsula Medical School, University of Exeter, Exeter, UK 5 Clinical Genetics Department, Royal Devon & Exeter Hospital, Exeter, UK Received 6 January 2010; Accepted 3 April 2010 The spondylocostal dysostoses (SCDs) are a heterogeneous group of axial skeletal disorders characterized by multiple seg- mentation defects of the vertebrae (SDV) and abnormality of the thoracic cage with mal-aligned ribs and often a reduction in rib number. The four known monogenic forms of SCD follow autosomal recessive inheritance, have generalized SDV, a broad- ly symmetrical thoracic cage, and result from mutations in Notch signaling pathway genes—DLL3, MESP2, LFNG, and HES7. Autosomal dominant (AD) SCD has been reported less often, is very variable, and molecular genetic mechanisms remain elusive. Here, we report a three-generation, non-consanguineous family with four affected individuals demonstrating multiple or generalized SDV. Scoliosis was present and the trunk shortened but the ribs were relatively mildly affected. There were no other significant organ abnormalities, no obvious dysmorphic fea- tures, neurodevelopment was normal, and all investigations, including mutation analysis of DLL3, MESP2, LFNG, and HES7, were normal. A non-pathogenic variant was detected in LFNG but it did not segregate with the phenotype. This Macedonian kindred adds to knowledge of AD SCD and to our knowledge is the first to be tested for the four Notch pathway genes known to be associated with SCD. Ó 2010 Wiley-Liss, Inc. Key words: spondylocostal dysostosis; autosomal dominant; Notch signaling pathway; Macedonia INTRODUCTION The spondylocostal dysostoses (SCDs) are a heterogeneous group of axial skeletal disorders characterized by multiple segmentation defects of the vertebrae (SDV), mal-alignment of the ribs with variable points of intercostal fusion, and sometimes a reduction in rib number. The term ‘‘SCD’’ is best applied to those phenotypes with generalized SDV and a broadly symmetrical thoracic cage [Turnpenny et al., 2007]. The autosomal recessive (AR) forms of SCD manifest this general pattern and have been shown to be due to mutations in genes that are integral to the Notch signaling pathway—DLL3 [Bulman et al., 2000], MESP2 [Whittock et al., 2004a], LFNG [Sparrow et al., 2006], and HES7 [Sparrow et al., 2008]. SCD that clearly follows autosomal dominant (AD) inheri- tance appears to occur less frequently and is very variable within [Van den Sar, 1952; R€ utt and Dagenhardt, 1959; Rimoin et al., 1968; Kubryk and Borde, 1981; Temple et al., 1988; Lorenz and Rupprecht, 1990]. Furthermore, the genetic basis has not been elucidated. In one family reported as a three-generation kindred with AD SCD [Floor et al., 1989], the cause was shown to be Grant sponsor: National Health and Medical Research Council (NHMRC) Project; Grant numbers: 404804, 635500; Grant sponsor: Pfizer Foundation Australia Senior Research Fellowship; Grant sponsor: NHMRC Senior Research Fellowship. *Correspondence to: Zoran S. Gucev, Medical Faculty Skopje, 50 Divizija BB, 1000 Skopje, Macedonia. E-mail: gucevz@gmail.com Published online 11 May 2010 in Wiley InterScience (www.interscience.wiley.com) DOI 10.1002/ajmg.a.33471 How to Cite this Article: Gucev ZS, Tasic V, Pop-Jordanova N, Sparrow DB, Dunwoodie SL, Ellard S, Young E, Turnpenny PD. 2010. Autosomal dominant spondylocostal dysostosis in three generations of a Macedonian family: Negative mutation analysis of DLL3, MESP2, HES7, and LFNG. Am J Med Genet Part A 152A:1378–1382. Ó 2010 Wiley-Liss, Inc. 1378