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Craniofrontonasal syndrome in a patient with an inv(X)(p22.2q13.1), separating EFNB1 from its enhancer

European Journal of Human Genetics volume 33, pages 546–551 (2025)Cite this article

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Abstract

Craniofrontonasal syndrome (CFNS) is an X-linked developmental disorder caused by loss of function variants (LOFVs) in the ephrin B1 (EFNB1) gene located on Xq13.1. In CFNS, unlike in other X-linked disorders, females with heterozygous EFNB1 pathogenic variants (PVs) have a severe phenotype, whereas males carrying hemizygous EFNB1 PVs have a mild phenotype. Here we report a female CFNS patient who was diagnosed with the typical features of CFNS as a new-born. Chromosomal analysis revealed a de novo pericentric inversion of one X chromosome; inv(X)(p22q13). Molecular testing for EFNB1 mutations and a SNP-array test for genomic imbalances returned negative results. We identified the inversion breakpoints using whole genome sequencing (WGS). One of the breakpoints was about 97 kbp downstream of the 3’ end of the EFNB1 gene, separating a potential EFNB1 enhancer region from the EFNB1 gene. To our knowledge, this is the first case of CFNS caused by a large structural variant, altering the genomic and regulatory context of EFNB1.

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Fig. 1: Analysis of the whole genome sequencing data to identify the breakpoints of the inv(X)(p22q13).
Fig. 2: Confirmation of the breakpoints of the inv(X)(p22.2q13.1).
Fig. 3: Genomic context of the inversion X breakpoints.

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Data availability

The datasets generated and/or analysed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank Evelyn Kornmann for technical support.

Funding

PMK and SKB are supported by the “Family of Marijana Kumerich”.

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Authors and Affiliations

  1. Leukaemia & Blood Cancer Research Unit, Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, 1023, New Zealand

    Purvi M. Kakadia & Stefan K. Bohlander

  2. Zentrum für Humangenetik, Philipps-Universität Marburg, Marburg, 35033, Germany

    Barbara Fritz

Authors
  1. Purvi M. Kakadia
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  2. Barbara Fritz
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  3. Stefan K. Bohlander
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Contributions

PMK designed and performed the experiments, data analysis and wrote the manuscript. SKB designed the project, analysed the data, and reviewed the manuscript. BF performed experiments and reviewed the manuscript.

Corresponding author

Correspondence to Purvi M. Kakadia.

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The authors declare no competing interests.

Ethical approval

The patient gave her written informed consent to the study and publication including her photos in accordance with the declaration of Helsinki. Ethical approval was not sought for as this project was an extended diagnostic genetic testing after genetic counselling to develop a patient-specific test for pre-implantation genetic diagnosis.

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Kakadia, P.M., Fritz, B. & Bohlander, S.K. Craniofrontonasal syndrome in a patient with an inv(X)(p22.2q13.1), separating EFNB1 from its enhancer. Eur J Hum Genet 33, 546–551 (2025). https://doi.org/10.1038/s41431-024-01761-1

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