Alternative titles; symbols
SNOMEDCT: 772127009; ORPHA: 468678; DO: 0070067;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1q21.3 | White-Sutton syndrome | 616364 | Autosomal dominant | 3 | POGZ | 614787 |
A number sign (#) is used with this entry because of evidence that White-Sutton syndrome (WHSUS) is caused by heterozygous mutation in the POGZ gene (614787) on chromosome 1q21.
White-Sutton syndrome (WHSUS) is a neurodevelopmental disorder characterized by delayed psychomotor development apparent in infancy and a characteristic constellation of dysmorphic facial features. Additional features may include hypotonia, sensorineural hearing impairment, visual defects, joint laxity, and gastrointestinal difficulties, such as poor feeding (summary by White et al., 2016). A significant number of patients have autism or autistic features (summary by Stessman et al., 2016).
The Deciphering Developmental Disorders Study (2015) identified 2 unrelated patients with intellectual disability who carried heterozygous de novo mutations in the POGZ gene. One patient had global developmental delay, iris coloboma, behavioral and psychiatric problems, hypoglycemic seizures, and abnormality of the outer ear. The other patient had bilateral sensorineural hearing impairment, generalized hypotonia, abnormalities on electroretinogram (ERG) and visually evoked potentials (VEPs), global developmental delay, cerebral atrophy, and a thin corpus callosum.
Stessman et al. (2016) reported 25 unrelated individuals with disruptive mutations in the POGZ gene, including 19 with a primary diagnosis of intellectual disability and 6 with had a primary diagnosis of autism, although most had features of both disorders. All individuals had some degree of developmental delay and intellectual disability varying from borderline to severe; most had mild intellectual disability. Speech and language were generally more affected than motor development. Most patients also had autistic features, although many had a seemingly contrary overly social or friendly demeanor. Hyperactivity, sleeping problems, and visual problems, mainly hypermetropia, were commonly observed as well. Many had mild dysmorphic features, such as brachycephaly, microcephaly, hypertelorism, midface hypoplasia, and small mouth with thin upper lip, but there was no overall common pattern or gestalt. Twelve (48%) of the 25 patients were clinically obese, even though many also had severe feeding problems earlier in life. The patients were ascertained from several large cohorts of patients who underwent whole-exome, whole-genome, or targeted sequencing.
White et al. (2016) reported 5 unrelated children with a syndromic form of intellectual disability. All had delayed psychomotor development apparent in infancy or early childhood, and most had hypotonia and behavioral abnormalities ranging from self-injurious behavior to autistic features. Common clinical features included short stature, brachycephaly, and gastrointestinal manifestations, such as feeding difficulties, gastroesophageal reflux disease, or constipation. Visual abnormalities were variable, and included myopia, astigmatism, rod-cone dystrophy, hyperopia, optic atrophy, and cortical blindness. Less common features included sensorineural hearing loss (3 patients), microcephaly (3 patients), midface hypoplasia (3 patients), abnormal ears (3 patients), joint laxity (2 patients), short neck (2 patients), and sleep difficulties (2 patients). Only 1 patient had complex partial seizures. Another patient had multiple congenital anomalies, including diaphragmatic hernia, duplicated renal system, mild congenital cardiac malformations, and delayed myelination on brain imaging. Three patients had no structural abnormalities on brain imaging.
Assia Batzir et al. (2020) reported clinical information on 22 patients from 21 families with White-Sutton syndrome collected through review of medical records and patient photos and questionnaires completed by families; 2 of the patients were previously reported by the Deciphering Developmental Disorders Study (2015). Median age at diagnosis was 8 years. Clinical features included a broad range of impaired intellectual development and/or developmental delay with or without autism; speech delay was seen in all patients. Hypotonia was noted in all 17 patients for whom neurologic examination findings were available. Seizures were reported in 30% of patients, and abnormal head imaging was seen in 67% of those who had imaging performed. Common facial features included a high and broad forehead, tented or triangular mouth with downturned corners, midface hypoplasia or retrusion, broad nasal root, and flat nasal bridge. Ophthalmologic problems and hearing loss were reported in 74% and 37.5%, respectively. The majority of patients for whom information was available had gastrointestinal involvement, including dysphagia/swallowing problems in 53%, gastroesophageal reflux in 50%, constipation in 47%, history of feeding difficulties in 65%, and cyclic vomiting in 37.5%; severe gastrointestinal involvement (e.g., intestinal malrotation, pancreatitis, rectal prolapse, and congenital diaphragmatic hernia) was seen in 3 patients. Disordered sleep was reported in 6 patients, and on the basis of a standardized questionnaire to assess sleep in childhood, 4 patients had results consistent with a clinical diagnosis of obstructive sleep apnea.
The heterozygous mutations in patients with WHSUS reported by Tan et al. (2016) and Stessman et al. (2016) occurred de novo.
The Deciphering Developmental Disorders Study (2015) examined 1,133 children with severe, undiagnosed developmental disorders, and their parents, using a combination of exome sequencing and array-based detection of chromosomal rearrangements. The authors discovered 12 novel genes associated with developmental disorders. The POGZ gene was implicated in a gene-specific analysis (p = 4.31 x 10(-10)). The Deciphering Developmental Disorders Study (2015) identified 2 patients with intellectual disability who carried heterozygous mutations in the POGZ gene: one mutation was a frameshift (614787.0001) and the other was predicted to result in loss of function (614787.0002). No functional studies were performed. A metaanalysis of previously published developmental disorder studies identified 3 additional de novo loss-of-function mutations in POGZ, 2 from autism studies (Iossifov et al., 2012; Neale et al., 2012) and 1 from a schizophrenia study (Fromer et al., 2014).
In a 5-year-old Chinese girl with White-Sutton syndrome, Tan et al. (2016) identified a de novo heterozygous truncating mutation in the POGZ gene (614787.0006). The mutation, which was found by next-generation sequencing of the POGZ gene in 765 patients with neurodevelopmental disorders, was confirmed by Sanger sequencing. Western blot analysis of patient blood cells showed the presence of a truncated protein and decreased levels of the wildtype protein.
In 25 unrelated patients with WHSUS, Stessman et al. (2016) identified de novo heterozygous truncating mutations in the POGZ gene (see, e.g., 614787.0007-614787.0010). Functional studies of the mutations and studies of patient cells were not performed, but all of the mutations were predicted to disrupt the POGZ gene and result in a loss of function. Three additional patients with autism spectrum disorder were found to have de novo heterozygous missense variants in the POGZ gene; however, functional studies of these variants were not performed. The patients were ascertained from several large cohorts comprising over 17,000 patients with neurodevelopmental disorders who underwent whole-exome, whole-genome, or targeted sequencing. Stessman et al. (2016) estimated that POGZ mutations may be responsible for up to 0.14% of individuals with autism and/or intellectual disability.
In 5 unrelated children with WHSUS, White et al. (2016) identified 5 different heterozygous truncating mutations in the POGZ gene (see, e.g., 614787.0003-614787.0005). The mutations were shown to occur de novo in 4 patients; the mutation in the fifth patient was not present in the mother, but paternal DNA was not available. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were all predicted to result in truncated proteins lacking the DNA-binding domain, the DDE domain, and the coiled-coil domain. Functional studies were not performed, but all of the mutations were predicted to result in a loss of function. Two patients carried variants of unknown significance in additional genes (RAI1, 607642 and STIL, 181590, respectively), which may have contributed to the phenotype.
Assia Batzir et al. (2020) reported 22 individuals, including 2 who were previously reported by the Deciphering Developmental Disorders Study (2015), with 21 different heterozygous loss-of-function mutations in the POGZ gene, 15 of which had not previously been reported (see, e.g., 614787.0011); all patients had features consistent with White-Sutton syndrome. Eighteen mutations occurred de novo, 1 was inherited from a mildly affected mother, and parents were not tested in 2 other patients. Of the 21 mutations in this cohort, 19 were truncating (including a large deletion encompassing exons 4-19, 10 nonsense, and 8 insertion/deletions leading to frameshifts) and 2 were splice site mutations. Most of the mutations (57%) occurred within the last exon (exon 19), emphasizing the importance of this exon in POGZ function. Six of the truncating mutations were predicted to undergo nonsense-mediated RNA decay by computational analysis, whereas 13 were predicted to escape nonsense-mediated RNA decay. Review of a large clinical laboratory database showed that 13 out of 9,206 patients (0.14%) who underwent exome sequencing for neurodevelopmental disorders with or without other system involvement had pathogenic POGZ variants.
Stessman et al. (2016) found that knockdown of the POGZ ortholog 'row' in Drosophila resulted in impaired learning in a habituation paradigm. The 'row' gene shares only about 10% identity with human POGZ, but both contain a well-conserved (25% identity) central zinc finger domain.
Assia Batzir, N., Posey, J. E., Song, X., Coban Akdemir, Z., Rosenfeld, J. A., Brown, C. W., Chen, E., Holtrop, S. G., Mizerik, E., Nieto Moreno, M., Payne, K., Raas-Rothschild, An., Scott, R., Vernon, H. J., Zadeh, N., Baylor-Hopkins Center for Mendelian Genomics, Lupski, J. R., Reid Suton, V. Phenotypic expansion of POGZ-related intellectual disability syndrome (White-Sutton syndrome). Am. J. Med. Genet. 182A: 38-52, 2020. [PubMed: 31782611] [Full Text: https://doi.org/10.1002/ajmg.a.61380]
Deciphering Developmental Disorders Study. Large-scale discovery of novel genetic causes of developmental disorders. Nature 519: 223-228, 2015. [PubMed: 25533962] [Full Text: https://doi.org/10.1038/nature14135]
Fromer, M., Pocklington, A. J., Kavanagh, D. H., Williams, H. J., Dwyer, S., Gormley, P., Georgieva, L., Rees, E., Palta, P., Ruderfer, D. M., Carrera, N., Humphreys, I., and 20 others. De novo mutations in schizophrenia implicate synaptic networks. Nature 506: 179-184, 2014. [PubMed: 24463507] [Full Text: https://doi.org/10.1038/nature12929]
Iossifov, I., Ronemus, M., Levy, D., Wang, Z., Hakker, I., Rosenbaum, J., Yamrom, B., Lee, Y., Narzisi, G., Leotta, A., Kendall, J., Grabowska, E., and 23 others. De novo gene disruptions in children on the autistic spectrum. Neuron 74: 285-299, 2012. [PubMed: 22542183] [Full Text: https://doi.org/10.1016/j.neuron.2012.04.009]
Neale, B. M., Kou, Y., Liu, L., Ma'ayan, A., Samocha, K. E., Sabo, A., Lin, C.-F., Stevens, C., Wang, L.-S., Makarov, V., Polak, P., Yoon, S., and 47 others. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 485: 242-245, 2012. [PubMed: 22495311] [Full Text: https://doi.org/10.1038/nature11011]
Stessman, H. A. F., Willemsen, M. H., Fenckova, M., Penn, O., Hoischen, A., Xiong, B., Wang, T., Hoekzema, K., Vives, L., Vogel, I., Brunner, H. G., van der Burgt, I., and 39 others. Disruption of POGZ is associated with intellectual disability and autism spectrum disorders. Am. J. Hum. Genet. 98: 541-552, 2016. [PubMed: 26942287] [Full Text: https://doi.org/10.1016/j.ajhg.2016.02.004]
Tan, B., Zou, Y., Zhang, Y., Zhang, R., Ou, J., Shen, Y., Zhao, J., Luo, X., Guo, J., Zeng, L., Hu, Y., Zheng, Y., Pan, Q., Liang, D., Wu, L. A novel de novo POGZ mutation in a patient with intellectual disability. J. Hum. Genet. 61: 357-359, 2016. [PubMed: 26763879] [Full Text: https://doi.org/10.1038/jhg.2015.156]
White, J., Beck, C. R., Harel, T., Posey, J. E., Jhangiani, S. N., Tang, S., Farwell, K. D., Powis, Z., Mendelsohn, N. J., Baker, J. A., Pollack, L., Mason, K. J., and 19 others. POGZ truncating alleles cause syndromic intellectual disability. Genome Med. 8: 3, 2016. Note: Electronic Article. [PubMed: 26739615] [Full Text: https://doi.org/10.1186/s13073-015-0253-0]