Official websites use. Share sensitive information only on official, secure websites. Address correspondence to Steven J. Clapcote, Ph. The discovery of coding variants in genes that confer risk of intellectual disability ID is an important step toward understanding the pathophysiology of this common developmental disability.
Homozygosity mapping, whole-exome sequencing, and cosegregation analyses were used to identify gene variants responsible for syndromic ID with autistic features in two independent consanguineous families from the Arabian Peninsula. Behavioral, electrophysiological, and structural magnetic resonance imaging analyses were conducted for phenotypic testing.
Homozygous premature termination codons in PDZD8 , encoding an endoplasmic reticulum—anchored lipid transfer protein, showed cosegregation with syndromic ID in both families. Drosophila melanogaster 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. 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.
