The Origin of EFNB1 Mutations in Craniofrontonasal Syndrome: Frequent Somatic Mosaicism and Explanation of the Paucity of Carrier Males
Open accessAbstract
Craniofrontonasal syndrome (CFNS) is an X-linked disorder that exhibits a paradoxical sex reversal in phenotypic severity: females characteristically have frontonasal dysplasia, craniosynostosis, and additional minor malformations, but males are usually mildly affected with hypertelorism only. Despite this, males appear underrepresented in CFNS pedigrees, with carrier males encountered infrequently compared with affected females. To investigate these unusual genetic features of CFNS, we exploited the recent discovery of causative mutations in the EFNB1 gene, which encodes ephrin-B1, to survey the molecular alterations in 59 families (39 newly investigated and 20 published elsewhere). We identified the first complete deletions of EFNB1, catalogued 27 novel intragenic mutations, and used Pyrosequencing and analysis of nearby polymorphic alleles to quantify mosaic cases and to determine the parental origin of verified germline mutations. Somatic mosaicism was demonstrated in 6 of 53 informative families, and, of 17 germline mutations in individuals for whom the parental origin of mutation could be demonstrated, 15 arose from the father. We conclude that the major factor accounting for the relative scarcity of carrier males is the bias toward mutations in the paternal germline (which present as affected female offspring) combined with reduced reproductive fitness in affected females. Postzygotic mutations also contribute to the female preponderance, whereas true nonpenetrance in males who are hemizygous for an EFNB1 mutation appears unusual. These results highlight the importance of considering possible origins of mutation in the counseling of families with CFNS and provide a generally applicable approach to the combined analysis of mosaic and germline mutations.
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Causative mutations in EFNB1 confer loss of function and are diverse (whole gene deletions, intragenic nonsense and frameshifting and splice site mutations, and missense substitutions), providing an explanation for the paradoxical inheritance pattern.
“The identification of causative mutations in EFNB1, which confer loss of function and are correspondingly diverse (whole gene deletions, intragenic nonsense and frameshifting and splice site mutations, and missense substitutions; Figure 2d) (refs.31,32), has provided an explanation for the paradoxical inheritance pattern.”
From Craniosynostosis (2011) · cites this paper as [32]
In EFNB1 mutation pedigrees, 19% of first affected individuals had mosaicism.
“At the opposite end of the spectrum, mosaicism was present in 19% of first affected individuals in pedigrees with EFNB1 mutations, so the mutation must be looked for very carefully in the parents (for example, by heteroduplex analysis in addition to DNA sequencing).32”
From Craniosynostosis (2011) · cites this paper as [32]
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- Authors
- Twigg, S. R. F., Matsumoto, K., Kidd, A. M. J., Goriely, A., Taylor, I. B., Fisher, R. B., Hoogeboom, A. J. M., Mathijssen, I. M. J., Lourenço, M. T., Morton, J. E. V., Sweeney, E., Wilson, L. C., Brunner, H. G., Mulliken, J. B., Wall, S. A., & Wilkie, A. O. M.
- Affiliations
- University of Oxford (GB)
- Wellington Hospital (NZ)
- St James's University Hospital (GB)
- Erasmus MC (NL)
- Hospital de Dona Estefânia (PT)
- Birmingham Women's Hospital (GB)
- Liverpool Women's Hospital (GB)
- Boston Children's Hospital (US)
- Corresponding author
- Wilkie, Andrew O.M.
- ORCID
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2006-06
- Volume
- 78
- Issue
- 6
- Pages
- 999-1010
- ISSN
- 0002-9297 (ISSN-L)
- OpenAlex
- W2160030814
- Cited by
- 103
- References
- 46
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 1 · 2023: 3 · 2022: 5 · 2021: 9 · 2020: 8 · 2019: 2 · 2018: 4 · 2017: 2 · 2015: 5 · 2014: 3 · 2013: 9 · 2012: 4
- FWCI
- 3.98
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Funders
- Wellcome Trust
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Craniofacial Disorders and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and rare skin diseases.
- Keywords
- craniofrontonasal syndrome, ephrin-B1, somatic mosaicism, X-linked disorders, postzygotic mutation, frontonasal dysplasia, craniosynostosis, hypertelorism, reproductive fitness, genetic counseling
- MeSH terms
- Female, Heterozygote, Humans, Male, Mosaicism, Mutation, Pedigree, Germ-Line Mutation, Craniofacial Abnormalities, Ephrin-B1
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