POGZ truncating alleles cause syndromic intellectual disability.

TitlePOGZ truncating alleles cause syndromic intellectual disability.
Publication TypeJournal Article
Year of Publication2016
AuthorsWhite, J, Beck, CR, Harel, T, Posey, JE, Jhangiani, SN, Tang, S, Farwell, KD, Powis, Z, Mendelsohn, NJ, Baker, JA, Pollack, L, Mason, KJ, Wierenga, KJ, Arrington, DK, Hall, M, Psychogios, A, Fairbrother, L, Walkiewicz, M, Person, RE, Niu, Z, Zhang, J, Rosenfeld, JA, Muzny, DM, Eng, CM, Beaudet, AL, Lupski, JR, Boerwinkle, E, Gibbs, RA, Yang, Y, Xia, F, V Sutton, R
JournalGenome Med
Volume8
Issue1
Pagination3
Date Published2016 Jan 06
ISSN1756-994X
KeywordsAdolescent, Adult, Alleles, Child, Preschool, Exome, Female, Heterozygote, Humans, Infant, Intellectual Disability, Male, Mutation, Sequence Analysis, DNA, Transposases
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.

DOI10.1186/s13073-015-0253-0
Alternate JournalGenome Med
PubMed ID26739615
PubMed Central IDPMC4702300
Grant ListHHSN268201100012C / HL / NHLBI NIH HHS / United States
HHSN268201100010C / HL / NHLBI NIH HHS / United States
HHSN268201100008C / HL / NHLBI NIH HHS / United States
U54 HG006542 / HG / NHGRI NIH HHS / United States
T32 GM007526 / GM / NIGMS NIH HHS / United States
HHSN268201100005C / / PHS HHS / United States
HHSN268201100007C / HL / NHLBI NIH HHS / United States
HHSN268201100008 / HL / NHLBI NIH HHS / United States
HHSN268201100009C / / PHS HHS / United States
HHSN268201100011C / HL / NHLBI NIH HHS / United States
HHSN268201100005 / HL / NHLBI NIH HHS / United States
HD024064 / HD / NICHD NIH HHS / United States
U54 HD083092 / HD / NICHD NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States
T32GM008307 / GM / NIGMS NIH HHS / United States
HHSN268201100010C / / PHS HHS / United States
HG006542 / HG / NHGRI NIH HHS / United States
P30 HD024064 / HD / NICHD NIH HHS / United States
HHSN268201100006C / HL / NHLBI NIH HHS / United States
HHSN268201100008C / / PHS HHS / United States
HHSN268201100012C / / PHS HHS / United States
T32 GM07526 / GM / NIGMS NIH HHS / United States
HHSN268201100011 / HL / NHLBI NIH HHS / United States
HHSN268201100007C / / PHS HHS / United States
HHSN268201100009C / HL / NHLBI NIH HHS / United States
HHSN268201100011C / / PHS HHS / United States
HHSN268201100005C / HL / NHLBI NIH HHS / United States
R01 NS058529 / NS / NINDS NIH HHS / United States
HHSN268201100009 / HL / NHLBI NIH HHS / United States
T32 GM008307 / GM / NIGMS NIH HHS / United States
HHSN268201100006C / / PHS HHS / United States
NS058529 / NS / NINDS NIH HHS / United States