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

Jain, Vani, Foo, Seow Hoong, Chooi, Stephen, Moss, Celia, Goodwin, Richard, Berland, Siren, Clarke, Angus J. ORCID: https://orcid.org/0000-0002-1200-9286, Davies, Sally J., Corrin, Sian, Murch, Oliver, Doyle, Samantha, Graham, Gail E., Greenhalgh, Lynn, Holder, Susan E., Johnson, Diana, Kumar, Ajith, Ladda, Roger L., Sell, Susan, Begtrup, Amber, Lynch, Sally A., McCann, Emma, Østern, Rune, Pottinger, Caroline, Splitt, Miranda and Fry, Andrew E. ORCID: https://orcid.org/0000-0001-9778-6924 2023. Börjeson–Forssman–Lehmann syndrome: Delineating the clinical and allelic spectrum in 14 new families. European Journal of Human Genetics 31 , pp. 1421-1429. 10.1038/s41431-023-01447-0

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Abstract

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	Springer Nature
ISSN:	1018-4813
Date of First Compliant Deposit:	16 October 2023
Date of Acceptance:	3 August 2023
Last Modified:	29 Nov 2023 15:29
URI:	https://orca.cardiff.ac.uk/id/eprint/163203

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