POGZ truncating alleles cause syndromic intellectual disability

Janson J White ,Daniel K Arrington,Fan Xia,Melissa Hall,Richard A Gibbs,Apostolos Psychogios,Eric Boerwinkle,Jennifer E Posey,Klaas J Wierenga,Tamar Harel,Christine R Beck,Zhiyv Niu,Sha Tang,Laura Fairbrother,Jing Zhang,Donna M Muzny,Shalini N Jhangiani,Nancy J Mendelsohn,Jill A Rosenfeld,Kelly D Farwell,Magdalena Walkiewicz,James R Lupski,Arthur L Beaudet,Yaping Yang,Kati J Mason,Lynda Pollack,V Reid Sutton,Zӧe Powis ,Janice Baker ,Richard Person ,Christine M Eng

doi:10.1186/s13073-015-0253-0

Abstract

BackgroundLarge-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.MethodsWhole 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.ResultsWe 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.ConclusionsWhile 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.

Highlights

Large-scale cohort-based whole exome sequencing of individuals with neurodevelopmental disorders (NDDs) has identified numerous novel candidate disease genes; detailed phenotypic information is often lacking in such studies
Together with eight pathogenic mutations from the literature, we describe the spectrum of phenotypes in individuals with deleterious mutations in pogo transposable element with zinc finger domain (POGZ)
Variants in POGZ were selected for confirmation and co-segregation with the phenotype because lossof-function mutations in this gene have been found in large cohorts of individuals with neuropsychiatric phenotypes

Summary

Introduction

Large-scale cohort-based whole exome sequencing of individuals with neurodevelopmental disorders (NDDs) has identified numerous novel candidate disease genes; 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. Neurodevelopmental disorders (NDDs) reflect a molecularly and phenotypically heterogeneous classification encompassing intellectual disability (ID), microcephaly, and neurobehavioral traits such as autism spectrum disorder (ASD) [1]. These traits are quite common, with ASD having a prevalence of ~1 % and ID occurring in ~2–3 % of the population. Recent advances in personal genome analysis and the assembly of large cohorts for study have begun to identify potentially pathogenic variants in individuals with ASD; the majority of ASD loci have yet to be identified and may include gene-

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Discussion

Conclusion