Prenatal identification of a pathogenic maternal FGFR1 variant in two consecutive pregnancies with fetal forebrain malformations

Abstract

Objective

Holoprosencephaly (HPE) is the most common aberration of forebrain development, and it leads to a wide spectrum of developmental and craniofacial anomalies. HPE etiology is highly heterogeneous and includes both chromosomal abnormalities and single-gene defects.

Methods

Here, we report an FGFR1 heterozygous variant detected by prenatal exome sequencing and inherited from the asymptomatic mother, in association with recurrent neurological abnormalities in the HPE spectrum in two consecutive pregnancies.

Results

Individuals with germline pathogenic variants in FGFR1 (MIM: 136350) show extensive phenotypic variability, which ranges from asymptomatic carriers to hypogonadotropic hypogonadism, arhinencephaly, Kallmann’s syndrome with associated features such as cleft lip and palate, skeletal anomalies, isolated HPE, and Hartsfield syndrome.

Conclusion

The presented case supports the role of exome sequencing in prenatal diagnosis when fetal midline structural anomalies are suggestive of a genetic etiology, as early as the first trimester of gestation. The profound heterogeneity of FGFR1 allelic disorders needs to be considered when planning prenatal screening even in asymptomatic carriers.

Keywords:

• Prenatal exome sequencing
• holoprosencephaly
• FGFR1
• magnetic resonance imaging
• recurrence risk

Acknowledgements

The authors thank Ilaria Bagni for genetic analysis and Valentina Ferradini for variant classification.

Author contributions

Conceptualization, L.G. and S.N.; methodology, L.G.; software, L.M.; validation, A.N. and G.N.; formal analysis, E.P.; investigation, S.N. and L.B.S.; resources, G.N.; data curation, A.M.N.; writing – original draft preparation, L.G. and M.L.C.; writing – review and editing, I.M. and M.R.D.; visualization, A.M.N.; supervision, A.N. and I.M.; project administration, G.N.

Ethics statement

Ethical approval was not required for the studies involving humans because the submitted report is derived from a hospital case of a patient with evidence of fetal anomalies during her pregnancy, which was addressed to our institution by the attending physician. Therefore, Ethical Committee approval was unnecessary, since no supplementary analysis was performed on the patient, except for the diagnostic genetic test for developmental defects. The internal Ethical Committee approves entire research projects and not reports based on single cases. Ethical approval was not required for this study by local/national guidelines.

Consent form

The study was conducted according to the guidelines of the Declaration of Helsinki. We obtained written consent from the patient beforehand, as required by our regulations. The human samples used in this study were acquired from a by-product of routine care or industry.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The datasets supporting the conclusions of this article are included within the article (and its additional files).

Additional information

Funding

The study was funded by Ministero della Salute FSC 2014-2020, Project ID T3-AN-04 “GENERA”.