White-Sutton syndrome and congenital heart disease: case report and literature review
BMC Pediatrics volume 23, Article number: 158 (2023)
White-Sutton syndrome is an autosomal dominant neurodevelopmental disorder caused by heterozygous mutation in POGZ (Pogo Transposable Element Derived with ZNF Domain). This syndrome is characterized by delayed psychomotor development apparent in infancy and abnormal facial features. To date, 80 cases have been reported in the literature; however, the phenotypic characterizations remain incomplete.
We herein describe a 2-year-old girl harboring a novel frameshift de novo POGZ variant: c.2746del (p.Thr916ProfsTer12). This patient presented with multisystem abnormalities affecting the digestive tract and neurological functioning, as well as congenital heart disease, which involved an atrial septal defect (18 × 23 × 22 mm) with pulmonary arterial hypertension (42 mmHg). The relationship between congenital heart disease and White-Sutton syndrome as described in both the GeneReview and OMIM databases (#616,364) remains unclear. A review of the current literature revealed 18 cases of White-Sutton syndrome with POGZ variants and congenital heart disease, and we summarize their clinical features in this study.
Our findings based on the present case and those in the literature indicate a relationship between POGZ mutation and congenital heart disease.
POGZ encodes a zinc finger protein that is mainly found in the nucleus  and known to be involved in neuronal proliferation, chromatin remodeling, cell cycle progression and gene transcription regulation [2, 3]. Previous research has shown that POGZ is enriched in cerebrocortical and hippocampal neurons of early mouse embryos and regulates cortical neuronal development by promoting neuronal differentiation . De novo disruptive mutations of POGZ are associated with White-Sutton syndrome, a syndromic neurodevelopmental disorder characterized by developmental delay, cerebral malformation, hearing loss, facial dimorphisms, and seizures [5, 6]. To date, 80 cases of White-Sutton syndrome have been reported [5,6,7,8,9,10,11,12,13,14,15,16,17,18,19]. However, the phenotypic characterizations of this syndrome remain incomplete.
Herein, we present a case of White-Sutton syndrome with a novel POGZ frameshift mutation. The patient presented multisystem manifestations, including developmental delay, hypokalemia, congenital heart disease, incomplete intestinal obstruction, and dystonia. A review of the existing literature returned 18 additional cases of White-Sutton syndrome with de novo POGZ variants that presented with congenital heart disease. The findings of the present case and literature analysis provide insight for further establishing the phenotypic spectrum of White-Sutton syndrome.
We report a case of White-Sutton syndrome in a 2-year-old girl. She was the second child of healthy and unrelated Chinese parents. She was born at 39 weeks of gestation by cesarean section, with a birth weight of 2840 g. The mother had gestational diabetes mellitus. The patient had a 20-year-old brother who was healthy, and her family history was negative for heart disease, epilepsy, and other neurological disorders. Nineteen hours after delivery, the girl was admitted to the neonatal unit due to repeated vomiting and diagnosed with digestive tract bleeding, which was managed with fasting and thrombin. The passage of meconium was not delayed, but abdominal distension was observed from 4 days after birth and persisted. Abdominal ultrasound showed a dilated bowel and bowel gas. Abdominal distension recurred several times over the next 2 years, culminating in mechanical ileus (Fig. 1) at the age of 1 year. Mechanical ileus was improved by fasting, gastrointestinal decompression, and glycerin enema.
At the age of 5 months, the patient was diagnosed with an atrial septal defect (18 × 23 × 22 mm), and pulmonary arterial hypertension (42 mmHg) was recorded for the first time. Atrial septal defect closure surgery was performed when the patient was 5 months of age, and the patient was treated with digoxin (0.1 mg/kg.d), spironolactone (2.4 mg/kg.d), and hydrochlorothiazide (0.8 mg/kg.d) after surgery. The patient had recurrent pneumonia after surgery and was admitted to the ICU 6 months after surgery for heart failure. Her left ventricular ejection fraction dropped to 22% at the lowest recording. At the 1-year follow-up after ICU discharge, the patient’s left ventricular ejection fraction ranged from 47 to 55%.
At the age of 9 months, she presented with epileptic spasm with hypsarrhythmia several times a day. She was successively treated with courses of topiramate (TPM; maximum dosage of 5 mg/kg.d), valproate (VPA; maximum dosage of 24 mg/kg.d), and cocktail therapy. No obvious seizure attack was observed between the ages of 13 and 19 months after combined treatment with TPM, VPA and cocktail therapy, which was a combination nutraceutical therapy consisting of vitamin B1 50 mg/d, vitamin B2 100 mg/d, vitamin C 200 mg/d, vitamin E 100 mg/d, L-carnitine 1000 mg/d, and coenzyme Q10 100 mg/d. At 19 months old, seizure returned, occurring several times a day, and did not improve with successively administered courses of levetiracetam (LEV; maximum dosage of 20 mg/kg.d), vigabatrin (VGB: the maximum dosage of 160 mg/kg.d), nitrazepam (NZP: the maximum dosage of 0.07 mg/kg.d) and clobazam (CLB; maximum dosage of 0.27 mg/kg.d). Adrenocorticotropic hormone (ATCH, 1.5 IU/kg) was added to the combined levetiracetam, vigabatrin and cocktail therapy for 2 weeks when the patient was 1 year and 10 months old. Thereafter, prednisone was continued before being gradually reduced and withdrawn over 1 month. The frequency of seizures decreased to two times per week.
From 1 year of age, the patient suffered from sleep disturbance, which mainly manifested as light sleep, often crying in sleep, and being difficult to soothe. The patient had several dysmorphic features, including a high-arched palate, frontal bossing, a congenital preauricular fistula, a tented mouth, a broad nasal root, a flat nasal bridge, and tongue protrusion. Brain magnetic resonance imaging performed at 1 year showed cerebral atrophy associated with enlargement of the supratentorial ventricles, thinned corpus callosum, and delayed myelination. She did not pass the newborn hearing screening conducted with otoacoustic emissions testing, and hearing loss was confirmed by otoacoustic emissions testing at the age of 1 year.
Peripheral venous blood samples were collected from the proband and her parents with their informed consent. Chromosomal microarray analysis for the proband was performed using Affymetrix Cytoscan 750 K. The results of the chromosomal microarray analysis and mitochondrial genetic testing for the proband were normal. The results of prenatal karyotype analysis on a cord blood sample also were normal. Trio-based WES revealed that the POGZ gene had a de novo heterozygous frameshift mutation [NM_015100.4:c.2746delA (p.Thr916ProfsTer12)], which was not found in current population databases (dbSNP, GnomAD, and ExAC). Most previously reported mutations in the POGZ gene are null variant [5, 7, 20]. According to the guidelines of the American College of Medical Genetics and Genomics (ACMG) and the Association of Molecular Pathology (AMP), the variant identified in the present case is considered pathogenic.
At the last follow-up at 2 years of age, the patient was experiencing a seizure every 3–5 days. Her parents had stopped all anti-seizure medications against medical advice, and she was receiving traditional Chinese massage. Developmentally, she could turn over, sit without support, make eye contact, and laugh, but could not stand or speak.
Discussion and conclusions
The clinical spectrum of White-Sutton Syndrome is relatively wide, with known manifestations including autism spectrum disorder, developmental delays, and intellectual disability [5, 7, 17, 20, 21]. Additional commonly reported features include feeding and gastrointestinal problems, seizures, sleep problems, hearing loss, vision problems and genitourinary abnormalities. However, the association of congenital heart disease with POGZ haploinsufficiency has not been well characterized in the previous literature. As a result, the relationship between heart disease and White-Sutton syndrome as described in both the GeneReview  and OMIM databases (#616,364) remains unclear. The present case report describes a new patient with a pathogenic variant of the POGZ gene who presented with congenital heart disease. This case was then compared to all cases of patients with POGZ mutations and heart disease that were found in the literature.
Peer-reviewed articles were identified by searching PubMed with the search terms: “POGZ” and “White-Sutton syndrome.” A total of 141 cases of White-Sutton syndrome caused by mutation of POGZ were identified [5,6,7,8,9,10,11,12,13,14,15,16,17,18,19, 22,23,24,25,26,27,28,29,30,31,32,33,34,35,36] (Supplementary Table 1, Fig. 2). The types of mutations in these cases included frameshift mutation (61/141, 43.3%), nonsense mutation (49/141, 34.8%), splicing mutation (9/141, 5.6%), large deletion (3/141, 2.5%), missense mutation (17/141, 12.1%), intronic mutation (1/141, 0.7%) and in-frame deletion (1/141, 0.7%). Overall, 80.1% of the reported mutations were null variants, which suggests that loss of function is the main mechanism of pathogenicity. A previous function study revealed that de novo mutations Q1042R and R1008X in POGZ disrupt its DNA-binding activity, and a de novo missense mutation (Q1042R) is associated with an approximately 60% reduction in the DNA-binding activity of POGZ , which further proves that loss of function is the pathogenic mechanism. The mutation identified in the present case is a novel frameshift mutation, which is a common type of loss-of-function mutation.
The clinical descriptions of the 141 cases included varying phenotypic details, and a relatively detailed phenotype information was provided for 125 cases. Among those 125 cases, 16 cases (16/125, 12.5%) had previously received a diagnosis of congenital heart disease [5, 11, 14, 17, 19, 22, 24, 25, 27, 29, 31, 36]. In addition, we found in the Decipher database (https://decipher.sanger.ac.uk/) two cases (Patients: 333,151 and 284,226) with heart disease and a pathogenic mutation in the POGZ gene to which the patients’ whole phenotype was attributed. Therefore, we found a total of 19 cases (including the present case) with congenital heart disease (Tables 1 and 2). Among these 19 cases with a cardiovascular defect, clinical exome sequencing was performed for 6 cases, Trio-WES for 4 cases, both Trio-WGS and microarray analysis for 1 case, and both Trio-WES and microarray analysis for 4 cases. As such, the patients’ genetic test results were relatively comprehensive. However, no other suspected pathogenic mutations were reported in these cases. In particular, four of the cases were reported in studies on congenital heart disease [11, 19, 22], and no other disease-causing mutations were found in genes associated with congenital heart disease. In conclusion, we believe the likelihood of other another underlying genetic etiology causing congenital heart disease in these patients with White-Sutton syndrome is low. In addition, according to the cases we reviewed, the incidence of congenital heart disease in patients with POGZ mutation was 12.5%, compared with only 0.8 ~ 1% in all newborns [38, 39]. This finding suggests that the incidence of congenital heart disease is significantly higher in patients with POGZ mutation than in the general population and supports the hypothesis that congenital heart disease is a relatively uncommon feature in White-Sutton syndrome.
All of the variants in cases with congenital heart disease were truncation variants (i.e., frameshift, nonsense, splicing and large deletion mutation) except for c.1838 A > G (p.His613Arg). The only missense mutation, c.1838 A > G reported by Homsy et al. , was identified de novo in a case without neurodevelopmental disabilities. According to the Sequence Variant Interpretation Working Group (SVI WG) general recommendations for using ACMG/AMP criteria (https://clinicalgenome.org/working-groups/sequence-variant-interpretation/), c.1838 A > G was reclassified as a variant of uncertain significance, and this patient lacked other pathogenomic features (specifically neurodevelopmental disabilities) of White-Sutton syndrome. Thus, we believe that the pathogenicity of c.1838 A > G is dubious, and more evidence is needed to support it. Therefore, we only discuss the remaining 18 cases when considering the relationship between congenital heart disease and White-Sutton syndrome. The variants in these cases were scattered across genes and not concentrated in specific domains (Fig. 2). Moreover, two mutations, c.2545 + 1del and c.1180_1181del, have been reported in patients with and without congenital heart disease. Therefore, no significant difference was found in the type or distribution of variants between patients with and without congenital heart disease. In terms of the type of cardiac abnormalities, two of these 18 cases had no detailed phenotype of congenital heart disease. The cardiac abnormalities in the remaining 16 cases varied widely and included many types of congenital heart disease (Table 1). It is worth noting that atrial septal defects were presented in 8 cases (8/16, 50%) (including the present case), making this the most common defect type.
Animal models are an important tool for understanding the relationship between genes and disease. A mouse model with a heterozygous or homozygous nervous system-specific deletion of the Pogz gene mimicked several of the human symptoms, showing microcephaly, growth impairment, increased sociability, and learning and motor deficits . Mice heterozygous for the Q1038R mutation exhibited decreased brain size, decreased cortical thickness, and ASD-related behavioral abnormalities . Significantly, Complete knockout of Pogz  or homozygosity for the Q1038R mutation in mice  both cause early embryonic lethality. Micro computed tomography (CT) scanning of Q1038R homozygous mouse embryos (E15.5) showed a ventricular septal defect, which was suspected to result in embryonic lethality. This finding in a mouse model further supports the relationship between congenital heart disease and POGZ mutation.
In summary, we herein described a new White-Sutton syndrome patient with a novel frameshift de novo POGZ variant, c.2746delA (p.Thr916ProfsTer12). Furthermore, we reviewed all previously reported cases of White-Sutton syndrome with POGZ mutation and focused on patients with congenital heart disease. Our findings suggest that the White-Sutton syndrome phenotype may align with congenital heart disease. More cases showing a similar presentation would support our findings. In addition, the role of POGZ in cardiac development has not been functionally verified, and such analysis may be needed in the future.
Availability of data and materials
The datasets for this article are not publicly available due to concerns regarding participant/patient anonymity. Requests to access the datasets should be directed to the corresponding author.
Ibaraki K, Hamada N, Iwamoto I, Ito H, Kawamura N, Morishita R, et al. Expression analyses of POGZ, a responsible gene for Neurodevelopmental Disorders, during mouse Brain Development. Dev Neurosci. 2019;41(1–2):139–48.
Zhao W, Quan Y, Wu H, Han L, Bai T, Ma L, et al. POGZ de novo missense variants in neuropsychiatric disorders. Mol Genet Genomic Med. 2019;7(9):e900.
Zhao W, Tan J, Zhu T, Ou J, Li Y, Shen L, et al. Rare inherited missense variants of POGZ associate with autism risk and disrupt neuronal development. J Genet Genomics. 2019;46(5):247–57.
Matsumura K, Seiriki K, Okada S, Nagase M, Ayabe S, Yamada I, et al. Pathogenic POGZ mutation causes impaired cortical development and reversible autism-like phenotypes. Nat Commun. 2020;11(1):859.
Assia Batzir N, Posey JE, Song X, Akdemir ZC, Rosenfeld JA, Brown CW, et al. Phenotypic expansion of POGZ-related intellectual disability syndrome (White-Sutton syndrome). Am J Med Genet A. 2020;182(1):38–52.
Ferretti A, Barresi S, Trivisano M, Ciolfi A, Dentici ML, Radio FC, et al. POGZ-related epilepsy: case report and review of the literature. Am J Med Genet A. 2019;179(8):1631–6.
Stessman HAF, Willemsen MH, Fenckova M, Penn O, Hoischen A, Xiong B, et al. Disruption of POGZ is Associated with Intellectual Disability and Autism Spectrum Disorders. Am J Hum Genet. 2016;98(3):541–52.
Iossifov I, O’Roak BJ, Sanders SJ, Ronemus M, Krumm N, Levy D, et al. The contribution of de novo coding mutations to autism spectrum disorder. Nature. 2014;515(7526):216–21.
Deciphering Developmental Disorders S. Large-scale discovery of novel genetic causes of developmental disorders. Nature. 2015;519(7542):223–8.
Fukai R, Hiraki Y, Yofune H, Tsurusaki Y, Nakashima M, Saitsu H, et al. A case of autism spectrum disorder arising from a de novo missense mutation in POGZ. J Hum Genet. 2015;60(5):277–9.
Reuter MS, Chaturvedi RR, Liston E, Manshaei R, Aul RB, Bowdin S, et al. The Cardiac Genome Clinic: implementing genome sequencing in pediatric heart disease. Genet Med. 2020;22(6):1015–24.
Samanta D, Ramakrishnaiah R, Schaefer B. The neurological aspects related to POGZ mutation: case report and review of CNS malformations and epilepsy. Acta Neurol Belg. 2020;120(2):447–50.
Du X, Gao X, Liu X, Shen L, Wang K, Fan Y, et al. Genetic diagnostic evaluation of Trio-Based whole exome sequencing among children with diagnosed or suspected Autism Spectrum Disorder. Front Genet. 2018;9:594.
Dentici ML, Niceta M, Pantaleoni F, Barresi S, Bencivenga P, Dallapiccola B, et al. Expanding the phenotypic spectrum of truncating POGZ mutations: Association with CNS malformations, skeletal abnormalities, and distinctive facial dysmorphism. Am J Med Genet A. 2017;173(7):1965–9.
Wang T, Guo H, Xiong B, Stessman HA, Wu H, Coe BP, et al. De novo genic mutations among a chinese autism spectrum disorder cohort. Nat Commun. 2016;7:13316.
Tan B, Zou Y, Zhang Y, Zhang R, Ou J, Shen Y, et al. A novel de novo POGZ mutation in a patient with intellectual disability. J Hum Genet. 2016;61(4):357–9.
White J, Beck CR, Harel T, Posey JE, Jhangiani SN, Tang S, et al. POGZ truncating alleles cause syndromic intellectual disability. Genome Med. 2016;8(1):3.
Hildebrand MS, Jackson VE, Scerri TS, Van Reyk O, Coleman M, Braden RO, et al. Severe childhood speech disorder: gene discovery highlights transcriptional dysregulation. Neurology. 2020;94(20):e2148–e67.
Jin SC, Homsy J, Zaidi S, Lu Q, Morton S, DePalma SR, et al. Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands. Nat Genet. 2017;49(11):1593–601.
Ye Y, Cho MT, Retterer K, Alexander N, Ben-Omran T, Al-Mureikhi M, et al. De novo POGZ mutations are associated with neurodevelopmental disorders and microcephaly. Cold Spring Harb Mol Case Stud. 2015;1(1):a000455.
Assia Batzir N, White J, Sutton VR. White-Sutton Syndrome. 2021 Sep 16. In: Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle: University of Washington; 1993–2023.
Homsy J, Zaidi S, Shen Y, Ware JS, Samocha KE, Karczewski KJ, et al. De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies. Science. 2015;350(6265):1262–6.
Longoni M, High FA, Qi H, Joy MP, Hila R, Coletti CM, et al. Genome-wide enrichment of damaging de novo variants in patients with isolated and complex congenital diaphragmatic hernia. Hum Genet. 2017;136(6):679–91.
Nagy D, Verheyen S, Wigby KM, et al. Genotype-phenotype comparison in POGZ-related neurodevelopmental disorders by using clinical scoring. Genes (Basel).2022;13(1):154.
Murch O, Jain V, Benneche A, Metcalfe K, Hobson E, Prescott K, et al. Further delineation of the clinical spectrum of White-Sutton syndrome: 12 new individuals and a review of the literature. Eur J Hum Genet. 2022;30(1):95–100.
Villalba MF, Chang TC. Congenital corneal opacities as a new feature in an unusual case of White-Sutton syndrome. J AAPOS. 2022;26(5):265–268.
Garde A, Cornaton J, Sorlin A, Moutton S, Nicolas C, Juif C, et al. Neuropsychological study in 19 french patients with White-Sutton syndrome and POGZ mutations. Clin Genet. 2021;99(3):407–17.
Mahjani B, De Rubeis S, Gustavsson Mahjani C, Mulhern M, Xu X, Klei L, et al. Prevalence and phenotypic impact of rare potentially damaging variants in autism spectrum disorder. Mol Autism. 2021;12(1):65.
Dal S, Hopper B, du Chattel MVR, Goel H. A case of White-Sutton syndrome with previously described loss-of-function variant in DDE domain of POGZ (p.Arg1211*) and Kartagener syndrome. Am J Med Genet A. 2021;185(3):1006–7.
Giraldo-Ocampo S, Pacheco-Orozco RA, Pachajoa H. A novel POGZ variant in a patient with intellectual disability and obesity. Appl Clin Genet. 2022;15:63–8.
Trimarchi G, Caraffi SG, Radio FC, et al. Adducted thumb and peripheral polyneuropathy: diagnostic supports in suspecting white-sutton syndrome:case report and review of the literature. Genes (Basel). 2021;12(7):950.
Wright CM, Guter SJ, Cook EH. Case Report: Association of Comorbid Psychiatric Disorders and Sigmoid Prolapse with de novo POGZ mutation. J Autism Dev Disord. 2022;52(3):1408–11.
Donnarumma B, Riccio MP, Terrone G, Palma M, Strisciuglio P, Scala I. Expanding the neurological and behavioral phenotype of White-Sutton syndrome: a case report. Ital J Pediatr. 2021;47(1):148.
Bruno LP, Doddato G, Valentino F, et al. New Candidates for Autism/Intellectual Disability Identified by Whole-Exome Sequencing. Int J Mol Sci. 2021;22(24):13439.
Merriweather A, Murdock DR, Rosenfeld JA, Dai H, Ketkar S, Emrick L, et al. A novel, de novo intronic variant in POGZ causes White-Sutton syndrome. Am J Med Genet A. 2022;188(7):2198–203.
Pascolini G, Agolini E, Fleischer N, Gulotta E, Cesario C, D’Elia G, et al. A novel patient with White-Sutton syndrome refines the mutational and clinical repertoire of the POGZ-related phenotype and suggests further observations. Am J Med Genet A. 2020;182(7):1791–5.
Matsumura K, Nakazawa T, Nagayasu K, Gotoda-Nishimura N, Kasai A, Hayata-Takano A, et al. De novo POGZ mutations in sporadic autism disrupt the DNA-binding activity of POGZ. J Mol Psychiatry. 2016;4:1.
Williams K, Carson J, Lo C. Genetics of Congenital Heart Disease. Biomolecules. 2019;9(12):879.
van der Bom T, Zomer AC, Zwinderman AH, Meijboom FJ, Bouma BJ, Mulder BJ. The changing epidemiology of congenital heart disease. Nat Rev Cardiol. 2011;8(1):50–60.
Suliman-Lavie R, Title B, Cohen Y, Hamada N, Tal M, Tal N, et al. Pogz deficiency leads to transcription dysregulation and impaired cerebellar activity underlying autism-like behavior in mice. Nat Commun. 2020;11(1):5836.
Gudmundsdottir B, Gudmundsson KO, Klarmann KD, Singh SK, Sun L, Singh S, et al. POGZ is required for silencing mouse embryonic beta-like hemoglobin and human fetal hemoglobin expression. Cell Rep. 2018;23(11):3236–48.
We thank the patient and her parents for their participation and cooperation.
This work was supported by the Sanming Project of Medicine in Shenzhen (SZSM201812005); Shenzhen Fund for Guangdong Provincial High Level Clinical Key Specialties (No. SZGSP012); Shenzhen Key Medical Discipline Construction Fund (No. SZXK033); and Brain cognition and Brain disease institute Fund (No. NYKFKT20190014). The funding bodies had no role in the design of the study; the collection, analysis, or interpretation of the data; or the writing the manuscript.
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The studies involving human participants were reviewed and approved by ethics committee of Shenzhen Children’s Hospital. Written informed consent was obtained from the parents of the patient.
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Written informed consent was obtained from the parents of the patient for publication of this case report.
CL was employed by the Berry Genomics Co. Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Duan, J., Ye, Y., Liao, J. et al. White-Sutton syndrome and congenital heart disease: case report and literature review. BMC Pediatr 23, 158 (2023). https://doi.org/10.1186/s12887-023-03972-9