POGZ truncating alleles cause syndromic intellectual disability

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.

Identification of a RAI1-associated disease network through integration of exome sequencing, transcriptomics, and 3D genomics

“…Individual BAB2330 and four other carriers of heterozygous truncating variants in POGZ allowed the recent description of a new syndromic form of intellectual disability [57, 58]. We compared the phenotype of the remaining individuals (Additional file 1: Supplementary Text, Table 1, Additional file 2: Table S1) with those associated with the identified molecular diagnoses, including 47,XYY, Mowat-Wilson syndrome (MOWS; OMIM#235730), mental retardation and microcephaly with pontine and cerebellar hypoplasia (MICPCH; OMIM#300749), Kabuki syndrome-1 (KABUK1; OMIM#147920), glycine encephalopathy (GCE; OMIM#605899), X-linked syndromic mental retardation 13 (MRXS13; OMIM#300055), cardiofaciocutaneous syndrome (CFC4; OMIM #615280), and X-linked syndromic mental retardation Claes-Jensen type (MRXSC; OMIM#300534) (Additional file 2: Table S4).…”

“…Likewise individual BA2492 has a constellation of symptoms (sleep disturbance, DD, cognitive impairment, brachydactyly) compatible with only the most severe 47,XYY sex chromosome aneuploidy cases [76]. Consistent with the hypothesis of expanded phenotypes, the phenotypic variability of White-Sutton syndrome associated with variants in POGZ keeps extending with clinical features including ASD, DD, ID, schizophrenia, and microcephaly [57, 71, 77–83]. We can also not formally rule out that we have not yet determined the true genetic cause(s) of the phenotypic spectrum of these individuals or they occur in presence of more complex, blended phenotypes as exemplified by BAB4947 above.…”

“…We identified potentially causal genetic alterations in ten individuals. They comprise variants in the JAKMIP1 , ZEB2 , CASK , KMT2D , GLDC , MECP2 , MAP2K2 , KDM5C , and POGZ genes, which are associated with ASD, MOWS, MICPCH, KABUK1, GCE, MRXS13, CFC4, MRXSC, and a new ID syndrome [57], respectively, as well as a 47,XYY karyotype. Interestingly, although 8/15 individuals in this study were male, two of the three mutations on the X chromosome were seen in female patients as opposed to the male patients.…”

Genome-wide enrichment of damaging de novo variants in patients with isolated and complex congenital diaphragmatic hernia

“…The Pogo Transposable Element With Znf Domain (POGZ [OMIM:*614787]) has been identified as the causative gene for White-Sutton syndrome (OMIM:#616364) in a large-scale WES study of individuals with neurodevelopmental disorders (White et al 2016). Proband T57 in our cohort is a male who presented with a right-sided Morgagni hernia, microcephaly, seizures, abnormal ears, micropenis, facial dysmorphism, and optic nerve hypoplasia.…”

“…A patient with a p.T922H fs mutation in POGZ was previously reported with microcephaly, short stature, global developmental delay, non-ocular visual impairment, failure to thrive, and multiple congenital abnormalities, including diaphragmatic hernia and a duplicated renal collecting system (White et al 2016). All the frameshift mutations in POGZ , in addition to the mutation identified in patient T57, are predicted to disrupt three C-terminal-domains (CENP-B like DNA, DDE, and coiled-coil) (White et al 2016).…”