POGZ truncating alleles cause syndromic intellectual disability

Abstract

Background: Large-scale cohort-based whole exome sequencing of individuals with neurodevelopmental disorders (NDDs) has identified numerous novel candidate disease genes; however, detailed phenotypic information is often lacking in such studies. De novo mutations in pogo transposable element with zinc finger domain (POGZ) have been identified in six independent and diverse cohorts of individuals with NDDs ranging from autism spectrum disorder to developmental delay.

Methods: Whole exome sequencing was performed on five unrelated individuals. Sanger sequencing was used to validate variants and segregate mutations with the phenotype in available family members.

Results: We identified heterozygous truncating mutations in POGZ in five unrelated individuals, which were confirmed to be de novo or not present in available parental samples. Careful review of the phenotypes revealed shared features that included developmental delay, intellectual disability, hypotonia, behavioral abnormalities, and similar facial characteristics. Variable features included short stature, microcephaly, strabismus and hearing loss.

Conclusions: While POGZ has been associated with neurodevelopmental disorders in large cohort studies, our data suggest that loss of function variants in POGZ lead to an identifiable syndrome of NDD with specific phenotypic traits. This study exemplifies the era of human reverse clinical genomics ushered in by large disease-directed cohort studies; first defining a new syndrome molecularly and, only subsequently, phenotypically.

Fig. 1

Photographs of patients displaying common facial features. Shared facial dysmorphology among affected individuals includes brachycephaly, long and flat malar region, broad and depressed nasal tip, short philtrum, thin vermillion border, downturned corners of the mouth and pointed chin

Fig. 2

Locations and chromatograms of variants identified. a The functional protein domains of POGZ. Functional protein domains include zinc-finger domains (orange and yellow), a predicted proline-rich domain (red), CENP-B like DNA binding domain (green), DDE transposase domain (blue) and a coiled-coil domain (purple). The seven truncating mutations and one deleterious missense previously reported are indicated by stars above the predicted domains. b Truncating mutations identified in the current study are indicated at their respective locations on the protein with arrows, and the chromatograms displaying each mutation are presented below the details of the individual nucleotide and amino acid changes