BACKGROUND The discovery of coding variants in genes that confer risk of intellectual disability (ID) is an important step towards understanding the pathophysiology of this common developmental disability. METHODS Homozygosity mapping, whole-exome sequencing and co-segregation analyses were employed to identify gene variants responsible for syndromic ID with autistic features in two independent consanguineous families from the Arabian Peninsula. For in-vivo functional studies of the implicated gene’s function in cognition, Drosophila and mice with targeted interference of the orthologous gene were utilized. Behavioural, electrophysiological and structural magnetic resonance imaging analyses were conducted for phenotypic testing. RESULTS Homozygous premature termination codons in PDZD8, encoding an endoplasmic reticulum-anchored lipid transfer protein, showed co-segregation with syndromic ID in both families. Drosophila with knockdown of the PDZD8 ortholog exhibited impaired long-term courtship-based memory. Mice homozygous for a premature termination codon in Pdzd8 exhibited brain structural, hippocampal spatial memory and synaptic plasticity deficits. CONCLUSIONS These data demonstrate the involvement of homozygous loss-of-function mutations in PDZD8 in a neurodevelopmental cognitive disorder. Model organisms with manipulation of the orthologous gene replicate aspects of the human phenotype and suggest plausible pathophysiological mechanisms centered on disrupted brain development and synaptic function. These findings are thus consistent with accruing evidence that synaptic defects are a common denominator of ID and other neurodevelopmental conditions.