Toggle Main Menu Toggle Search

Open Access padlockePrints

Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families

Lookup NU author(s): Dr Miranda Splitt



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2023, The Author(s). Börjeson-Forssman-Lehmann syndrome (BFLS) is an X-linked intellectual disability syndrome caused by variants in the PHF6 gene. We ascertained 19 individuals from 15 families with likely pathogenic or pathogenic PHF6 variants (11 males and 8 females). One family had previously been reported. Six variants were novel. We analysed the clinical and genetic findings in our series and compared them with reported BFLS patients. Affected males had classic features of BFLS including intellectual disability, distinctive facies, large ears, gynaecomastia, hypogonadism and truncal obesity. Carrier female relatives of affected males were unaffected or had only mild symptoms. The phenotype of affected females with de novo variants overlapped with the males but included linear skin hyperpigmentation and a higher frequency of dental, retinal and cortical brain anomalies. Complications observed in our series included keloid scarring, digital fibromas, absent vaginal orifice, neuropathy, umbilical hernias, and talipes. Our analysis highlighted sex-specific differences in PHF6 variant types and locations. Affected males often have missense variants or small in-frame deletions while affected females tend to have truncating variants or large deletions/duplications. Missense variants were found in a minority of affected females and clustered in the highly constrained PHD2 domain of PHF6. We propose recommendations for the evaluation and management of BFLS patients. These results further delineate and extend the genetic and phenotypic spectrum of BFLS.

Publication metadata

Author(s): Jain V, Foo SH, Chooi S, Moss C, Goodwin R, Berland S, Clarke AJ, Davies SJ, Corrin S, Murch O, Doyle S, Graham GE, Greenhalgh L, Holder SE, Johnson D, Kumar A, Ladda RL, Sell S, Begtrup A, Lynch SA, McCann E, Ostern R, Pottinger C, Splitt M, Fry AE

Publication type: Article

Publication status: Published

Journal: European Journal of Human Genetics

Year: 2023

Pages: Epub ahead of print

Online publication date: 14/09/2023

Acceptance date: 03/08/2023

Date deposited: 27/09/2023

ISSN (print): 1018-4813

ISSN (electronic): 1476-5438

Publisher: Nature Publishing Group


DOI: 10.1038/s41431-023-01447-0

PubMed id: 37704779


Altmetrics provided by Altmetric


Funder referenceFunder name
Baily Thomas Charitable Fund
Epilepsy Research UK grant P1205
Wales Gene Park