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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




Journal article


Eur J Hum Genet

Publication Date





889 - 894


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