title: Autosomal dominant spondylocostal dysostosis in three generations of a Macedonian family: Negative mutation analysis of DLL3, MESP2, HES7, and LFNG.
abstract: The spondylocostal dysostoses (SCDs) are a heterogeneous group of axial skeletal disorders characterized by multiple segmentation 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 broadly 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 features, 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.
authors.affiliation: Medical Faculty Skopje, Divizija BB, Skopje, Macedonia. gucevz@gmail.com
authors.forename: Zoran S
authors.initials: ZS
authors.lastname: Gucev
authors.forename: Velibor
authors.initials: V
authors.lastname: Tasic
authors.forename: Nada
authors.initials: N
authors.lastname: Pop-Jordanova
authors.forename: Duncan B
authors.initials: DB
authors.lastname: Sparrow
authors.forename: Sally L
authors.initials: SL
authors.lastname: Dunwoodie
authors.forename: Sian
authors.initials: S
authors.lastname: Ellard
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Young
authors.forename: Peter D
authors.initials: PD
authors.lastname: Turnpenny
mesh_terms: D000328:Adult; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D002648:Child; D004252:DNA Mutational Analysis; D004413:Dysostoses / Q000000981:diagnostic imaging / Q000235:genetics*; D016695:Glycosyltransferases / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D010375:Pedigree; D011859:Radiography; D018843:Republic of North Macedonia; D013131:Spine / Q000002:abnormalities* / Q000000981:diagnostic imaging
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D016695:Glycosyltransferases; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C496666:DLL3 protein, human; C486601:HES7 protein, human; C498393:LFNG protein, human