PDZD8 – PDZD8-related Intellectual Developmental Disorder with Autism and Dysmorphic Facies

Biallelic loss of function variants in PDZD8 cause a rare autosomal recessive syndrome characterized by global developmental delay, intellectual disability (ID), autism spectrum disorder (ASD), and facial dysmorphism, termed Intellectual Developmental Disorder with Autism and Dysmorphic Facies (IDDADF) (PMID:40016860). All six reported individuals from three consanguineous families present with ID, autistic behavior (ASD diagnosed in five), and dysmorphic facies, consistent with a core clinical phenotype of developmental delay, cognitive impairment, autism, and facial anomalies.

Genetic evidence supports a strong autosomal recessive inheritance pattern with homozygous PDZD8 variants segregating with disease in each family. Six affected individuals across three families demonstrate cosegregation of biallelic PDZD8 disruption, confirmed by homozygosity mapping and whole-exome sequencing (PMID:40016860). The variant spectrum includes loss-of-function alleles such as c.2197_2200del (p.Val732_Ser733insTer), consistent with gene inactivation. Additional affected relatives co-segregate in each pedigree, reinforcing pathogenicity.

Functional studies in Pdzd8tm1b knockout mice recapitulate key human phenotypes. Mutant mice exhibit ASD-relevant stereotyped motor behaviors, increased locomotor activity in the dark phase, impaired social recognition, elevated ER stress– and mitochondrial fusion–related transcripts in brain tissue, increased dendritic spine density, and altered neuroanatomical volumes by MRI (PMID:40016860). Metabolic profiling reveals increased basal metabolic rate and reduced plasma triglycerides in male mutants, further supporting systemic effects of PDZD8 deficiency.

No conflicting reports have challenged this association. Limitations include the small number of families and unbalanced sex distribution in some mouse cohorts, and mRNA-level markers without protein validation. Nonetheless, the concordance of human genetic data and mouse phenotypes provides a robust mechanistic link.

Integration of genetic and experimental evidence yields a strong clinical validity classification. Defining c.2197_2200del (p.Val732_Ser733insTer) as representative, PDZD8 deficiency disrupts ER function and neural development, leading to IDDADF. These findings inform molecular diagnosis, genetic counseling for autosomal recessive PDZD8-related IDDADF, and provide a preclinical model for therapeutic exploration.

Key Take-home: Biallelic PDZD8 LoF variants cause a distinctive syndromic ID with autism and facial dysmorphism, supported by human segregation and a concordant mouse model, offering clear diagnostic utility.

References

• Molecular autism • 2025 • Autistic behavior is a common outcome of biallelic disruption of PDZD8 in humans and mice. PMID:40016860

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