Balanced translocation in a patient with craniosynostosis disrupts the SOX6 gene and an evolutionarily conserved non-transcribed region

• Published in: Journal of medical genetics 2006-06, Vol.43 (6), p.534-540
• Main Authors: Tagariello, A, Heller, R, Greven, A, Kalscheuer, V M, Molter, T, Rauch, A, Kress, W, Winterpacht, A
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Artificial chromosomes; Base Sequence; Biological and medical sciences; Biology; Cardiology. Vascular system; Chickens; Child, Preschool; Chromosome aberrations; Chromosome Mapping; Chromosomes, Human, Pair 11; Cloning; CNG; conserved non-genic sequence; conserved non-genic sequences; Conserved Sequence; Craniosynostoses - diagnosis; Craniosynostoses - genetics; Craniosynostoses - pathology; craniosynostosis; DNA Mutational Analysis; DNA, Intergenic - chemistry; DNA-Binding Proteins - chemistry; DNA-Binding Proteins - genetics; Ears & hearing; FISH; fluorescence in situ hybridisation; General aspects. Genetic counseling; Genes; Genomes; High Mobility Group Proteins - chemistry; High Mobility Group Proteins - genetics; Humans; In Situ Hybridization, Fluorescence; Infant; Laboratories; Letter to JMG; Lymphocytes; Male; Medical genetics; Medical sciences; Mice; Molecular Sequence Data; Mutation; occipitofrontal circumference; OFC; Patients; Sequence Alignment; SOX6; SOXD Transcription Factors; Studies; Tomography, X-Ray Computed; Transcription factors; Transcription Factors - chemistry; Transcription Factors - genetics; translocation; Translocation, Genetic
• ISSN: 0022-2593; 1468-6244; 1468-6244
• DOI: 10.1136/jmg.2005.037820

Craniosynostosis is a congenital developmental disorder involving premature fusion of cranial sutures, which results in an abnormal shape of the skull. Significant progress in understanding the molecular basis of this phenotype has been made for a small number of syndromic craniosynostosis forms. Nevertheless, in the majority of the ∼100 craniosynostosis syndromes and in non-syndromic craniosynostosis the underlying gene defects and pathomechanisms are unknown. Here we report on a male infant presenting at birth with brachycephaly, proptosis, midfacial hypoplasia, and low set ears. Three dimensional cranial computer tomography showed fusion of the lambdoid sutures and distal part of the sagittal suture with a gaping anterior fontanelle. Mutations in the genes for FGFR2 and FGFR3 were excluded. Standard chromosome analysis revealed a de novo balanced translocation t(9;11)(q33;p15). The breakpoint on chromosome 11p15 disrupts the SOX6 gene, known to be involved in skeletal growth and differentiation processes. SOX6 mutation screening of another 104 craniosynostosis patients revealed one missense mutation leading to the exchange of a highly conserved amino acid (p.D68N) in a single patient and his reportedly healthy mother. The breakpoint on chromosome 9 is located in a region without any known or predicted genes but, interestingly, disrupts patches of evolutionarily highly conserved non-genic sequences and may thus led to dysregulation of flanking genes on chromosome 9 or 11 involved in skull vault development. The present case is one of the very rare reports of an apparently balanced translocation in a patient with syndromic craniosynostosis, and reveals novel candidate genes for craniosynostoses and cranial suture formation.