Homozygosity Mapping and Candidate Prioritization Identify Mutations, Missed by Whole-Exome Sequencing, in SMOC2, Causing Major Dental Developmental Defects

• DOI: 10.1016/j.ajhg.2011.11.002
• Publication Date: 2011-12-11T02:40:20Z
• Authors: Agnès Bloch-Zupan; Xavier Jamet; Christelle Etard; Virginie Laugel; Jean Muller; Véronique Geoffroy; Jean-Pierre Strauss; Valérie Pelletier; Vincent Marion; Olivier Poch; Uwe Strahle; Corinne Stoetzel; Hélène Dollfus
• Keywords: 570; Molecular Sequence Data; Gene Expression; Consanguinity; Mice; 03 medical and health sciences; Genetics; Animals; Humans; Genetics(clinical); Exome; Child; Genetic Association Studies; Adaptor Proteins, Signal Transducing; info:eu-repo/classification/ddc/570; 0303 health sciences; biology; Calcium-Binding Proteins; Homozygote; Chromosome Mapping; Gene Expression Regulation, Developmental; Life sciences; Neoplasm Proteins; Dentin Dysplasia; Child, Preschool; Chromosomes, Human, Pair 6; Female; ddc:570; Carrier Proteins

Inherited dental malformations constitute a clinically and genetically heterogeneous group of disorders. Here, we report on a severe developmental dental defect that results in a dentin dysplasia phenotype with major microdontia, oligodontia, and shape abnormalities in a highly consanguineous family. Homozygosity mapping revealed a unique zone on 6q27-ter. The two affected children were found to carry a homozygous mutation in SMOC2. Knockdown of smoc2 in zebrafish showed pharyngeal teeth that had abnormalities reminiscent of the human phenotype. Moreover, smoc2 depletion in zebrafish affected the expression of three major odontogenesis genes: dlx2, bmp2, and pitx2.