Identification of biallelic loss-of-function PREP variants in three individuals with syndromic intellectual disability

Biallelic loss-of-function *PREP* (prolyl endopeptidase) variants with confirmed protein absence

Three individuals from two unrelated families presented with intellectual disability, behavioral abnormalities, strabismus, generalized muscular hypotonia, dysmorphic features, and epilepsy. Trio exome and genome sequencing identified two rare homozygous PREP variants: c.1570_1573dup, p.(Asn525Thrfs5) and c.1839-2A>G. RNA-seq confirmed that the intronic variant generated two aberrant mRNA isoforms, and immunoblot showed absence of PREP protein in patient cells. These data confirm PREP* deficiency, previously an unvalidated candidate, as a cause of a recessive syndromic neurodevelopmental disorder.

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This paper moves PREP from candidate to validated gene through the combination of segregation, RNA-seq, and protein absence — an approach consistent with current gene-disease validity standards. The cohort remains small (three patients), justifying moderate novelty, but the functional contribution is solid. RNA-seq again demonstrates its value for qualifying splice variants, accessible to exome/genome analysis.