AbstractCraniofrontonasal 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.

摘要颅额鼻综合征（CFNS）是一种X连锁发育障碍，由位于Xq13.1的ephrin B1（EFNB1）基因的功能丧失变异（LOFV）引起。在CFNS中，与其他X连锁疾病不同，具有杂合EFNB1致病变异（PVs）的女性具有严重的表型，而携带半合子EFNB1 PVs的男性具有轻度的表型。

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.

。染色体分析显示，一条X染色体从头开始发生周围倒位；发票（X）（p22q13）。EFNB1突变的分子检测和基因组失衡的SNP阵列检测返回阴性结果。

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..

我们使用全基因组测序（WGS）确定了反转断点。其中一个断点位于EFNB1基因3'端下游约97 kbp，将潜在的EFNB1增强子区域与EFNB1基因分开。据我们所知，这是第一例由大型结构变异引起的CFNS，改变了EFNB1的基因组和调控背景。。

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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.

图1：分析全基因组测序数据以确定inv（X）（p22q13）的断点。图2:inv（X）断点的确认（p22.2q13.1）。图3：反转X断点的基因组背景。

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

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Download referencesAcknowledgementsWe thank Evelyn Kornmann for technical support.FundingPMK and SKB are supported by the “Family of Marijana Kumerich”.Author informationAuthors and AffiliationsLeukaemia & Blood Cancer Research Unit, Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, 1023, New ZealandPurvi M.

下载参考文献致谢我们感谢Evelyn Kornmann的技术支持。资助PMK和SKB得到了“Marijana Kumerich家族”的支持。作者信息作者和附属机构奥克兰大学医学与健康科学学院分子医学与病理学系白血病与血癌研究室，奥克兰，1023，新西兰Purvi M。

Kakadia & Stefan K. BohlanderZentrum für Humangenetik, Philipps-Universität Marburg, Marburg, 35033, GermanyBarbara FritzAuthorsPurvi M. KakadiaView author publicationsYou can also search for this author in.

Kakadia和Stefan K.BohlanderZentrum für Humangenetik，德国马尔堡菲利普斯大学，马尔堡，邮编35033。

PubMed Google ScholarBarbara FritzView author publicationsYou can also search for this author in

PubMed Google ScholarBarbara FritzView作者出版物您也可以在

PubMed Google ScholarStefan K. BohlanderView author publicationsYou can also search for this author in

PubMed Google ScholarStefan K.BohlanderView作者出版物您也可以在

PubMed Google ScholarContributionsPMK 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 authorCorrespondence to.

PubMed谷歌学术贡献SPMK设计并进行了实验，数据分析并撰写了手稿。。BF进行了实验并审阅了手稿。对应作者对应。

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

&Bohlander，S.K。inv（X）（p22.2q13.1）患者的颅额鼻综合征，将EFNB1与其增强子分开。。

Eur J Hum Genet (2024). https://doi.org/10.1038/s41431-024-01761-1Download citationReceived: 06 June 2024Revised: 24 October 2024Accepted: 27 November 2024Published: 07 December 2024DOI: https://doi.org/10.1038/s41431-024-01761-1Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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