Genome medicine · 2016
POGZ truncating alleles cause syndromic intellectual disability.
СтатьяПоддержка NIH: внешняя программаНазвание и аннотация: Перевод в очереди
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White Janson, Beck Christine R, Harel Tamar, Posey Jennifer E, Jhangiani Shalini N, Tang Sha, Farwell Kelly D, Powis Zöe, Mendelsohn Nancy J, Baker Janice A, Pollack Lynda, Mason Kati J, Wierenga Klaas J, Arrington Daniel K, Hall Melissa, Psychogios Apostolos, Fairbrother Laura, Walkiewicz Magdalena, Person Richard E, Niu Zhiyv, Zhang Jing, Rosenfeld Jill A, Muzny Donna M, Eng Christine, Beaudet Arthur L, Lupski James R, Boerwinkle Eric, Gibbs Richard A, Yang Yaping, Xia Fan, Sutton V Reid
Аннотация
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.
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.