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Familial hypertelorism, characterized by widely spaced eyes, classically shows autosomal dominant inheritance (Teebi type), but some pedigrees are compatible with X-linkage. No mechanism has been described previously, but clinical similarity has been noted to craniofrontonasal syndrome (CFNS), which is caused by mutations in the X-linked EFNB1 gene. Here we report a family in which females in three generations presented with hypertelorism, but lacked either craniosynostosis or a grooved nasal tip, excluding CFNS. DNA sequencing of EFNB1 was normal, but further analysis revealed a duplication of 937 kb including EFNB1 and two flanking genes: PJA1 and STARD8. We found that the X chromosome bearing the duplication produces ∼1.6-fold more EFNB1 transcript than the normal X chromosome and propose that, in the context of X-inactivation, this difference in expression level of EFNB1 results in abnormal cell sorting leading to hypertelorism. To support this hypothesis, we provide evidence from a mouse model carrying a targeted human EFNB1 cDNA, that abnormal cell sorting occurs in the cranial region. Hence, we propose that X-linked cases resembling Teebi hypertelorism may have a similar mechanism to CFNS, and that cellular mosaicism for different levels of ephrin-B1 (as well as simple presence/absence) leads to craniofacial abnormalities.

Original publication

DOI

10.1002/humu.21521

Type

Journal article

Journal

Hum Mutat

Publication Date

08/2011

Volume

32

Pages

930 - 938

Keywords

Adult, Alleles, Animals, Base Sequence, Child, Chromosomes, Human, X, Ephrin-B1, Female, Gene Duplication, Gene Expression Regulation, Genetic Association Studies, Genotype, Humans, Hypertelorism, Mice, Mice, Inbred C57BL, Mice, Transgenic, Middle Aged, Molecular Sequence Data, Pedigree, Phenotype, Sequence Alignment, Transcription, Genetic, X Chromosome Inactivation