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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.

Original publication

DOI

10.1038/ejhg.2015.209

Type

Journal article

Journal

Eur J Hum Genet

Publication Date

06/2016

Volume

24

Pages

889 - 894

Keywords

Adolescent, Adult, Cell Line, Tumor, Female, Genes, Recessive, Hamartoma Syndrome, Multiple, Homozygote, Humans, Intellectual Disability, Male, Megalencephaly, PTEN Phosphohydrolase, Pedigree, Phenotype, Siblings