title: A recessive form of extreme macrocephaly and mild intellectual disability complements the spectrum of PTEN hamartoma tumour syndrome.
abstract: PTEN hamartoma tumour syndrome (PHTS) is caused by heterozygous variants in PTEN and is characterised by tumour predisposition, macrocephaly, and cognition impairment. Bi-allelic loss of PTEN activity has not been reported so far and animal models suggest that bi-allelic loss of PTEN activity is embryonically lethal. Here, we report the identification of a novel homozygous variant in PTEN, NM_000314.4; c.545T>C; p.Leu182Ser, in two adolescent siblings with severe macrocephaly and mild intellectual disability. The variant is predicted to be damaging and is associated with significantly increased phospho-S6 downstream of PTEN. The absence of tumours in the two homozygous siblings as well as lack of symptoms of PHTS in the heterozygous carriers of the family suggest that this particular variant is functionally hypomorphic rather than deleterious.
authors.affiliation: Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Tobias
authors.initials: T
authors.lastname: Schwerd
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
authors.forename: Andrea V
authors.initials: AV
authors.lastname: Khaled
authors.affiliation: Institut für Humangenetik, Universität zu Lübeck, Lübeck, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Schürmann
authors.affiliation: Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Hannah
authors.initials: H
authors.lastname: Chen
authors.affiliation: University Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany.
authors.forename: Norman
authors.initials: N
authors.lastname: Händel
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Reis
authors.affiliation: Institut für Humangenetik, Universität zu Lübeck, Lübeck, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Gillessen-Kaesbach
authors.affiliation: Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK.|Department of Paediatrics, University of Oxford, Oxford, UK.
authors.forename: Holm H
authors.initials: HH
authors.lastname: Uhlig
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.|Centogene AG, Rostock, Germany.
authors.forename: Rami
authors.identifier: 0000-0002-1542-1399
authors.initials: R
authors.lastname: Abou Jamra
mesh_terms: D000293:Adolescent; D000328:Adult; D045744:Cell Line, Tumor; D005260:Female; D005808:Genes, Recessive; D006223:Hamartoma Syndrome, Multiple / Q000175:diagnosis / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D058627:Megalencephaly / Q000175:diagnosis / Q000235:genetics*; D051059:PTEN Phosphohydrolase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D010641:Phenotype; D035781:Siblings
chemical_list: D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human