POGZ variants in neurodevelopmental delay: a case series on phenotype-genotype correlation

Introduction

Neurodevelopmental delay (NDD) encompasses a group of disorders that typically begins in early childhood, primarily characterized by cognitive and behavioral impairments (1). Genetic factors play a significant role in the pathogenesis of NDD (2). POGO transposable element with ZNF domain (POGZ) protein is expressed in the brain throughout the development and involved in regulating synaptic function and gene expression, which plays an important role in neuronal development (3). POGZ is located on chromosome 1q21.3, contains 19 exons and encodes a ubiquitous 1410-aa protein. There are multiple functional domains in POGZ gene, one atypical and eight classical C₂H₂ zinc finger domains at its N-terminus (ZNF), a proline-rich (P-rich) domain, a helix-turn helix (HTH) domain also identified as a centromere protein (CENP) B-like DNA-binding domain, a putative DDE-1 transposase domain (DDE) and a coiled-coil motif at its C-terminus (4).

A small number of de novo protein-truncating variants (PTVs) and missense variants in POGZ were reported in the different cohorts of individuals with intellectual disabilities (ID), developmental delay (DD), autism spectrum disorder (ASD), schizophrenia or microcephaly (5-22). White-Sutton syndrome (WHSUS, Online Mendelian Inheritance in Man, OMIM 616364) was first described as an identifiable syndrome of neurodevelopmental disorders with specific phenotypic traits caused by heterozygous POGZ PTVs, resulting in loss-of-function (LoF) protein (23,24). In contrast to PTVs, the missense variants have been reported less frequently in patients with features of WHSUS (24), which seem to be more associated with a behavioral phenotype, including ASD or autistic-like features (25-27). In many studies of POGZ-related disorders, phenotypic reporting is likely varied between different series. Nagy et al. found that the types and locations of the variants predicting the POGZ protein dysfunction may play an important role in the severity of manifestations of POGZ-associated neurodevelopmental disorders (28).

Interpreting the pathogenicity of gene variants has been challenging due to the extensive genetic heterogeneity in POGZ. Previous research indicates that numerous putative pathogenic variants converge in similar protein functional domains, possibly accounting for overlapping phenotypic traits (27). In this study, we described five heterozygous POGZ variants identified in our patients, two PTVs and three missense variants. Clinical and molecular data of POGZ variants reported in previous literature were also reviewed to further delineate the phenotype related to POGZ variants. We present this article in accordance with the AME Case Series reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-477/rc).

Case presentation

Case series report

All procedures performed in this study were in accordance with the ethical standards of the Independent Ethics Committee of Beijing Children’s Hospital (No. [2021]-E-234-Y), and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from all adult participants and from the parents or legal guardians of all minor participants for publication of this case series. For children aged 8 years and older, assent was also obtained. A copy of the written consent is available for review by the editorial office of this journal. Five patients with DD/ASD in Pediatric Developmental Behavior Clinic were found to have POGZ gene variants in this retrospective study. Except for the maternal in individual 3, all family members underwent whole exome sequencing (WES) and copy number variation (CNV) testing. POGZ variants based on the transcript NM_015100.4. were classified using the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology guidelines (29). Five variants detected in our cohort were two PTVs and three missense variants in the POGZ gene (Figure 1). Two POGZ PTVs were of de novo origin, c.1180_1181del (p.Met394Valfs*Ter9) in individual 1 and c.1185+6 T>A (slicing) in individual 2, creating a premature stop codon and predicted to truncate the protein. The other probands all had missense variants. In Individual 3 with the novel variant c.3715G>A (p.Val1239Ile), his father did not carry this variant, but his mother was not available for the genetic testing. Individual 4 with c.1427G>A (p.Arg476Gln) and Individual 5 with c.1375G>A (p.Asp459Asn) were inherited maternally. Among these three missense variants, only individual 3 located in exon 19, individual 4 and 5 in exon 9. Two inherited missense variants were reported in a cohort of patients with ASD (30). We classified the variants according to the standards and guidelines for interpreting sequence variants from the ACMG (29) and provided the detail information in Table 1.

Figure 1 Exon and protein models of POGZ showing location of the variants (Figures S1-S5). On top is an exonic model of POGZ (the first exon is non-coding). Below is the POGZ protein which contains a series of zinc finger domains (C₂H₂-type ZN_FING), PRO, helix-turn-helix centromere protein-B-like DNA-binding domain (HTH), a DDE superfamily endonuclease domain (DDE). Below the protein model are variants reported in this series. DDE, DDE-1 transposase domain; HTH, helix-turn helix; POGZ, POGO transposable element with ZNF domain; PRO, proline-rich domain; ZNF, C₂H₂ zinc finger domains.

Each patient had been consulted by the neuropsychologist or developmental behavioral pediatrician for observation and assessment. Retrospective reappraisal of detailed clinical phenotypes was collected through medical records and telephone consultations with their families. Distinctive facial features were collected by the referring physician, and some of them underwent the neuropsychological assessment. The severity of developmental delay was determined using the Gesell Development Diagnosis Scales (China-version). Development quotient (DQ) scores are categorized into the following ranges: mild DD (score: 55–75), moderate DD (score: 40–54), severe DD (score: 25–39), and profound DD (score: <25). Some patients’ behavioral and social skill were screened by Autism Behavior Checklist (ABC) (31) and Modified Checklist for Autism in Toddlers (M-Chat) (32). The clinical features of the five probands with PTVs or missense variants in POGZ were summarized in Table 2. The detailed description can be reached in Appendix 1 and Table S2. Two sporadic probands with POGZ PTVs exhibited WHSUS-like symptoms. Distinctive facial features were found in them, including abnormal midface morphology, highly arched eyebrow, down slanted palpebral fissures, low-set ears, wide and depressed nasal bridge, short philtrum, tented upper lip vermilion, downturned corners of mouth, and short neck. Individual 1 also exhibited short stature and obesity trait. Consistent with previous reports, visual problems were a common finding. Both were found to have hyperopia and astigmatism in the version screening. Hearing problems were also reported in individual 2. These two males presented with moderate to severe general developmental delay, motor developmental delay, and speech delay. They showed repetitive hand movements, stereotyped behaviors, poor eye contact, limited communication, and were diagnosed with ASD. Other systemic features were not reported, except that individual 2 had mild feeding difficulties in his early childhood. Two patients had no epilepsy and no abnormalities on electroencephalography (EEG) examination. Individual 2 was found to have mild abnormalities on brain magnetic resonance imaging (MRI). No abnormality was found in the blood examination, including biochemical, hematological, endocrine, and hormonal tests.

The other three probands with missense variants exhibited mild to moderate DD. Individuals 4 and 5 were diagnosed with ASD, Individual 3 only presented with the limited social communication at preschool age. Except for individual 3, who was reported short stature, we did not record any abnormalities in facial features, other systemic features, hearing and visual function, EEG, brain MRI and blood tests. The mother with POGZ missense variant (p.Asp459Asn) reported she had no other significant clinical manifestations, except her poor academic performance in childhood. The mother with the POGZ missense variant (p.Arg476Gln) did not provide any valuable information about clinical symptoms during the telephone follow-up.

Literature reviews

A literatures review of POGZ gene variants and cases was conducted by searching the Human Gene Mutation Database (HGMD^®) and all cases published up to January, 2022 using the keyword “POGZ gene” and “variant or mutation” in databases including PubMed, Medline. We included English-language case reports/series describing patients with likely pathogenic variants in POGZ gene (5-9,33-37). Reviews and non-English papers were excluded. A total of 52 papers, including 201 cases with POGZ variants and the clinical features of these patients, were reviewed (38-62). A detailed description can be reached at https://cdn.amegroups.cn/static/public/TP-2025-477-1.xlsx.

We counted the frequency of PTVs and missense variations in each exon. The results showed that PTVs were highly concentrated in the C-terminal of the POGZ gene, whereas missense variants were relatively dispersed from exons 3–19 (Figure 2). Further analyzing the frequency of symptoms associated with variants located in different exons, PTVs displayed a wider range of phenotypic features (Figure 3). Individuals with PTVs distributed in exons 3–17 all presented varying degrees of symptoms, including DD, speech delay, motor development delay, ASD-like symptoms, facial dysmorphism, short stature, microcephaly, GI problems, hearing problems, visual disorders and obesity. A high frequency of these clinical features occurred in individuals with PTVs in exons 8, 10–11, and 17–19. While autism-like symptoms and DD were the main manifestations for individuals with missense variants, these were more frequently described in individuals with missense variants in exons 9–12 and 19.

Figure 2 Distribution of variations within each exon. Distribution of PTVs and missense variations was shown on the POGZ exon. Each column presented frequency of different variants in certain exon. The depth of gray color was showed according to the number of cases with variations in certain exon. POGZ, POGO transposable element with ZNF domain; PTVs, protein-truncating variants.

Figure 3 Distribution of pathogenic variants and associated clinical phenotypes. (A) Distribution of PTVs and their phenotypic associations. (B) Distribution of missense variants and their phenotypic associations. Each column in the heatmap represents the positive ratio of patients with variants located in a specific exon, and each row corresponds to a clinical phenotype derived from patient surveys in the literature. DD, developmental delay; GI, gastrointestinal tract; ID, intellectual disabilities; PTVs, protein-truncating variants.

We analyzed the range of phenotypes and variants found in our series and compared them with those previously reported in the literature. The frequency of features is shown in Table 3. The results showed that facial dysmorphism, ID/DD, speech delay, motor development delay, ASD-like features and visual disorders were common phenotypes (more than 50% of patients reported these clinical manifestations) in POGZ variant carriers, including PTVs and missense variants. Nevertheless, the incidences of ID/DD (96.8%, 121/125 vs. 86.8%, 33/38, P<0.05), speech delay (98.0%, 99/101 vs. 78.9%, 15/19, P<0.05) and motor developmental delay (91.5%, 86/94 vs. 60.0%, 12/20, P<0.05) were significantly higher in patients with PTVs than in those with missense variants, while the incidence of ASD was higher in patients with PTVs than in those with missense variants (76.9%, 30/39 vs. 53.8%, 56/104, P<0.05). In addition, microcephaly (61.4%, 54/88 vs. 20.0%, 3/15, P<0.05), gastrointestinal (GI) problems (56.5%, 52/92 vs. 36.4%, 4/11, P>0.05), brain MRI abnormalities (59.7%, 40/67 vs. 18.2%, 2/11 P<0.05) and obesity (42.3%, 41/97 vs. 23.1%, 3/13, P>0.05) were more frequently reported in patients with PTVs.

We further explored the different phenotypes between patients with PTVs in the last two exons and other exons (Table 4). Facial dysmorphism (92.5%, 37/40 vs. 70.8%, 34/48, P<0.05), GI problems (88.2%, 30/34 vs. 45.7%, 16/35, P<0.05), brain MRI abnormalities (78.8%, 26/33 vs. 43.8%, 14/32, P<0.05) and hearing problems (48.6%, 17/35 vs. 23.8%, 10/42, P<0.05) were found more frequently in individuals with PTVs in the last two exons. In addition, higher incidence rates of severe ID/DD (36.4%, 12/33 vs. 18.2%, 5/38, P<0.05) and severe speech delay symptoms (56.1%, 23/41 vs. 36.7%, 11/30, P<0.05) were found, compared to individuals with a PTV in or before exon 17, although both PTVs and missense variants caused high incidence rates of ID/DD (98.2%, 56/57 vs. 95.5%, 63/66, P>0.05) and speech delay (100.0%, 47/47 vs. 98.1%, 51/52).

Discussion

Here we presented detailed clinical and genetic findings from five individuals with POGZ variants (Figure 1). The variant c.1180_1181del had been determined to be pathogenic in Clinvar database. The novel variants c.1185+6 T>A was predicted to be pathogenic and possibly pathogenic, according to the ACMG guidelines. In contrast, the three missense variants (individuals 3, 4, and 5) were interpreted as variants of uncertain significance (VUS) with a predicted benign effect, supported by Rare Exome Variant Ensemble Learner (REVEL) and Combined Annotation Dependent Depletion (CADD) scores indicating benign or tolerated outcomes. Three POGZ missense variants in our patients, p.Val1239Ile, were located in the DDE domain of exon 19, while two inherited missense variants, p.Arg476Gln and p.Asp459Asn, and were located in the adjacent regions on the same exon, which were previously in close proximity to the ZNF domain. Two other inherited missense variants had been reported in previous cohort studies of ASD patients and were reported as unconfirmed variants in patients with developmental delay in the Clinvar database. Furthermore, the variant p.Asp459Tyr in the POGZ gene, with a different missense change in the same amino acid residue of p.Asp459Asn, was confirmed as a partial LoF variant in the functional study, affecting the cellular localization of POGZ and regulating neurite and dendritic spine development (26). Previous studies indicated that an altered excitation-inhibition (E/I) balance within neural circuits may lead to social and cognitive deficits, contributing to ASD pathogenesis (3,63,64). Matsumura et al. also reported that the two sporadic-ASD-associated de novo heterozygous missense variants within the HTH domain impaired the cellular localization of the POGZ protein and hindered cortical neuronal development, altered transcriptional networks controlling neuronal differentiation, and induced the excitatory shift in the cellular E/I balance of the cerebral cortex (27). Further evidence from detailed clinical data and functional studies will be needed to fully establish the contribution of missense variants in POGZ-associated neurodevelopment disorders.

According to our review, more PTVs (70.0%, 109/158) were reported than missense variants (30.0%, 59/158). Patients with PTVs exhibited more severe phenotypes than those with missense variants. In addition to ID/DD, microcephaly, GI problems, brain MRI abnormalities, and obesity were more commonly reported in patients with PTVs. Some previous studies also showed that most of de novo POGZ variants identified in patients with DD were nonsense and frameshift variants. POGZ was revealed to interact with HP1α, which played an essential role in heterochromatin formation and mitotic progression through interaction with several cell cycle proteins (4,65). It was also reported to play an important role in homology-directed DNA repair and the maintenance of genome stability (4). Almost all PTVs truncating variants in POGZ, likely resulting in LoF alleles, were reported to be pathogenic, including inherited PTVs. Therefore, it was recommended that the inherited POGZ variants should not be overlooked when interpreting WES or genome data. POGZ haplo-insufficient mice also display a significant growth defect, a deficit in intellectual abilities, hyperactive behavior, and multi-system disorder (66). We summarized the phenotypic diversity in patients with PTVs (Figure 3), which supported that WHSUS may be multi-factorial, with a potential “genome instability” component, caused by LoF of the POGZ protein.

In contrast to PTVs, missense variants in the POGZ gene were more frequently found in a cohort of people with ASD, DD microcephaly, speech delay, or other developmental delay. So far, only a small number of missense variants have been reported in the literature. In addition, only a few cases were described with a detailed phenotype because most des novo and inherited missense variants were first reported in some cohort studies. Moreover, some of them were identified in unaffected controls. From the perspective of our review, missense variants in POGZ were less frequently reported in patients with features of WHSUS, which may have milder deleterious effects than PTVs. The missense variants were not clearly associated with DD, and seemed to be associated with ASD or autistic-like features, speech delay, etc. (10,44,66,67). We analyzed the incidences of DD, speech delay and motor development delay of patients with missense variations, which were significantly lower than those in patients with PTVs, whereas the incidence of ASD in patients with missense variations was higher than that in patients with PTVs (Table 3). In contrast, PTVs were highly concentrated in the C-terminus of the POGZ gene, missense variants were scattered in the protein, and no significant cluster was involved. Autism-like symptoms and DD were the main manifestations in individuals with missense variants, which were more frequently described in individuals with missense variants in exons 9–12 and exon 19 (Figure 3). The ZNF domain is enriched in exons 9–13, which interacts with HP1α and activates Aurora B kinase (65).

Our study has several important limitations. The aggregation of data from published literature inherently introduces biases, such as heterogeneous clinical assessments and the overrepresentation of severe phenotypes due to ascertainment bias. These factors constrain the interpretability of the pooled data. Furthermore, this heterogeneity, combined with the significant phenotypic overlap observed in our cohort, constitutes a central challenge: it precludes a definitive conclusion on whether PTVs and missense variants confer categorically distinct manifestations or differ primarily in severity. Resolving this fundamental question is critical for improving prognosis and clinical management. We propose that future genotype-first studies employing standardized, deep phenotyping protocols are necessary to generate the evidence required to distinguish between these possibilities.

Conclusions

In summary, we reported five new individuals with variants in POGZ. We combined clinical data from these individuals with previously reported individuals and found some correlations between phenotypes and genotypes of POGZ variants, highlighting that clinical analysis for POGZ variant-associated phenotypic features should be considered. This is particularly true for recurrently-mutated loci where phenotypic homogeneity can be expected. The increasing emergence of candidate genes for different disorders requires genotype-driven approaches to describe associated phenotypic spectrums, which will help to further delineate and isolate the POGZ-related traits.

Acknowledgments

The authors would like to thank the participants and their families for participating in the study.

Footnote

Reporting Checklist: The authors have completed the AME Case Series reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-477/rc

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-477/prf

Funding: This work was supported in part by the Science and Technology Innovation Development Project, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health (No. YN2020408).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-477/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the Independent Ethics Committee of Beijing Children’s Hospital (No. [2021]-E-234-Y), and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from all adult participants and from the parents or legal guardians of all minor participants for publication of this case series. For children aged 8 years and older, assent was also obtained. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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