Further characterization of Borjeson-Forssman-Lehmann syndrome in females due to de novo variants in PHF6.

Fecha de publicación: 03/06/2022 Fecha Ahead of Print: 03/06/2022

Autores de IIS La Fe

Francisco Martínez Castellano

Autor

Participantes ajenos a IIS La Fe

Gerber, Celine B.
Fliedner, Anna
Bartsch, Oliver
Berland, Siren
Dewenter, Malin
Haug, Marte
Hayes, Ian
Marin-Reina, Purificacion
Mark, Paul R.
Maystadt, Isabelle
Karadurmus, Deniz
Steindl, Katharina
Wiesener, Antje
Zweier, Markus
Sticht, Heinrich
Zweier, Christiane

Grupos

Investigación Traslacional en Genética

Leader

Francisco Martínez Castellano

Abstract

While inherited hemizygous variants in PHF6 cause X-linked recessive Borjeson-Forssman-Lehmann syndrome (BFLS) in males, de novo heterozygous variants in females are associated with an overlapping but distinct phenotype, including moderate to severe intellectual disability, characteristic facial dysmorphism, dental, finger and toe anomalies, and linear skin pigmentation. By personal communication with colleagues, we assembled 11 additional females with BFLS due to variants in PHF6. We confirm the distinct phenotype to include variable intellectual disability, recognizable facial dysmorphism and other anomalies. We observed skewed X-inactivation in blood and streaky skin pigmentation compatible with functional mosaicism. Variants occurred de novo in 10 individuals, of whom one was only mildly affected and transmitted it to her more severely affected daughter. The mutational spectrum comprises a two-exon deletion, five truncating, one splice-site and three missense variants, the latter all located in the PHD2 domain and predicted to severely destabilize the domain structure. This observation supports the hypothesis of more severe variants in females contributing to gender-specific phenotypes in addition to or in combination with effects of X-inactivation and functional mosaicism. Therefore, our findings further delineate the clinical and mutational spectrum of female BFLS and provide further insights into possible genotype-phenotype correlations between females and males.

Datos de la publicación

ISSN/ISSNe:: 0009-9163, 1399-0004
Tipo:: Article
Páginas:: 182-190
DOI:: 10.1111/cge.14173
Factor de Impacto:: 1,192 SCImago ℠
Cuartil:: Q2 SCImago ℠

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Métricas

Filiaciones

Gerber, Celine B.:: Department of Human Genetics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
Fliedner, Anna:: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
Bartsch, Oliver:: Institute of Human Genetics, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
Berland, Siren:: Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway
Dewenter, Malin:: Institute of Human Genetics, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
Haug, Marte:: Department of Medical Genetics, St. Olav's University Hospital, Trondheim, Norway
Hayes, Ian:: Genetic Health Service New Zealand, Auckland Hospital, Auckland, New Zealand
Marin-Reina, Purificacion:: Genetics Unit/Department of Pediatrics and Medical Genetics, University and Polytechnic Hospital La Fe, Valencia, Spain
Mark, Paul R.:: Spectrum Health, Division of Medical and Molecular Genetics, Grand Rapids, Michigan, USA
Martinez-Castellano, Francisco:: Genetics Unit/Department of Pediatrics and Medical Genetics, University and Polytechnic Hospital La Fe, Valencia, Spain
Maystadt, Isabelle:: Center for Human Genetics, Institute of Pathology and Genetics, Gosselies, Belgium
Karadurmus, Deniz:: Center for Human Genetics, Institute of Pathology and Genetics, Gosselies, Belgium
Steindl, Katharina:: Institute of Medical Genetics, University of Zurich, Schlieren-Zurich, Switzerland
Wiesener, Antje:: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
Zweier, Markus:: Institute of Medical Genetics, University of Zurich, Schlieren-Zurich, Switzerland
Sticht, Heinrich:: Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
Zweier, Christiane:: Department of Human Genetics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland

Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany