Novel variants in ZNF462 and phenotype update in patients with Weiss-Kruszka syndrome: a case series

Abstract

Background

Weiss-Kruszka syndrome (WSKA) is a neurodevelopmental disorder caused by loss-of-function variants in ZNF462, a zinc-finger transcription factor critical for embryonic morphogenesis. Characterized by intellectual disability, facial dysmorphism, muscle tone abnormalities, and congenital malformations, WSKA exhibits significant phenotypic heterogeneity. Despite over 40 cases reported globally, existing studies rarely report the clinical manifestations of this disease in Chinese patients.

Case Description

Six patients harboring pathogenic ZNF462 variants were included and clinically evaluated at Shanghai Children’s Medical Center. Comprehensive phenotyping included detailed dysmorphology assessments, neurodevelopmental testing, and targeted organ system evaluations. Whole-exome sequencing (WES) with Sanger confirmation identified pathogenic ZNF462 variants. Additionally, phenotypic data from prior published cases were systematically reviewed. WES confirmed the diagnosis of WSKA in six patients from five pedigrees, revealing five novel ZNF462 variants. Phenotypic information in our Chinese patient cohort revealed similar neurodevelopmental abnormalities and dysmorphic facial features. Other clinical features, including growth hormone deficiency, limb anomalies, and abnormal gonadal development, were also observed within different individuals in our cohort, suggesting phenotypic variability and heterogeneity among different ethnic origins.

Conclusions

Identifying novel pathogenic variants in ZNF462 and compiling a comprehensive clinical phenotype spectrum of patients could provide crucial information for the precise diagnosis and treatment of WSKA in Han Chinese individuals. Our findings underscore the necessity of ethnicity-specific diagnostic criteria.

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Key findings

• We identified five previously unreported variants of ZNF462 in six patients across five pedigrees. Phenotypic information in our Chinese patient cohort revealed similar neurodevelopmental abnormalities and dysmorphic facial features. Other clinical features, including growth hormone deficiency, limb anomalies, and abnormal gonadal development, were also observed within different individuals in our cohort, suggesting phenotypic variability and heterogeneity among different ethnic origins.

What is known and what is new?

• To date, 47 cases of Weiss-Kruszka syndrome caused by ZNF462 abnormalities have been reported, with only 4 cases of Chinese Han origin.

• We added clinical presentation and new gene variants from 6 patients. The similarities and differences in clinical manifestations of the same disease between Chinese and other countries were expounded, and the spectrum of variation was expanded.

What is the implication, and what should change now?

• This means ZNF462 shows different phenotypes in different races and different individuals. This disease requires clinicians to closely combine whole-exome sequencing for clinical diagnosis and genetic counseling.

Introduction

Weiss-Kruszka syndrome (WSKA, MIM:618619) is a dominantly inherited disorder caused by variants in ZNF462. Most individuals are affected by de novo mutations in ZNF462. Patients with WSKA exhibit recognizable clinical phenotypic features, including metopic ridge/craniosynostosis, ptosis, developmental delay, downward-slanting palpebral fissures, a prominent Cupid’s bow, arched eyebrows, and ear abnormalities. Other features include cryptorchidism, attention deficits, agenesis of the corpus callosum, autism, hypotonia, and a short-upturned nose with a bulbous tip (1). This genetic abnormality can also cause other skeletal abnormalities, such as scoliosis and pectus (2).

ZNF462, located on chromosome 9q31.2, encodes a transcription factor belonging to the C2H2-type zinc finger (ZNF) family of proteins, which plays important roles in embryonic development and neuronal differentiation (3,4). ZNFs are crucial for the interaction between ZNF proteins and DNA targets, as well as for the regulation of gene expression. The pathogenic mechanism of ZNF462 is loss of function (5,6). Currently, 47 cases of WSKA have been reported (1,2,5-15) (Table 1): 13 female and 34 male patients, aged 7 months to 41 years. There are 20 frameshift mutations, 17 nonsense mutations, 1 splice-site mutation, 2 translocation mutations, and 7 copy number variations, with mutations concentrated in exon 3. De novo mutations account for 68% of the cases. In terms of clinical phenotypes, ptosis, developmental delay, arched eyebrows, downward-slanting palpebral fissures, and a short-upturned nose with a bulbous tip are more common, accounting for 83%, 77%, 60%, 55%, and 53% of the cases, respectively. Among the other phenotypes, ear abnormalities may be more common. Heart disease, limb abnormalities, feeding difficulties, and autism spectrum disorders are relatively rare.

Table 1. Common clinical manifestations and frequency of WSKA patients.

Case features	Patient 1	Patient 2	Patient 3	Patient 4	Patient 5	Patient 6	This study (N=6)	Published patients before (N=47)	This study and published patients before (N=53)
Sex	Female	Male	Male	Female	Female	Male	3 females/3 males	13 females/34 males	16 females/37 males
Age at last review	6 years 8 months	1 year 9 months	12 years 8 months	11 years 6 months	About 35 years	2 years 5 months	21 months to about 35 years	7 months to 41 years	7 months to 41 years
ZNF462 variant	c.370del	c.876_877dup	c.6449del	c.1304del	c.1304del	c.7190-1G>A	5 frame shift; 1 splice	20 (43%) frame shift; 17 (36%) nonsense; 1 (2%) splice; 2 (4%) translocation; 7 (15%) copy number change	24 (45%) frame shift; 18 (34%) nonsense; 2 (4%) splice; 2 (4%) translocation; 7 (13%) copy number change
	p.Ile124*	p.Ala293Valfs*12	p.Pro2150Glnfs*7	p.Phe435Serfs*2	p.Phe435Serfs*2
Inheritance	De novo	De novo	De novo	Maternally	Unknown	De novo	De novo 4/6, inherited 1/6	De novo 32/47 (68%); inherited 7/47 (15%)	De novo 36/53 (68%); inherited 8/53 (15%)
Reported height	115 cm (10th)	85.5 cm (50th)	155 cm (45th)	150 cm (50th)	165 cm	77 cm (<3rd)	<3rd–50th	<3rd–97th	<3rd–97th
Cranial MRI	Midline lipoma	−	Thin pituitary gland	−	Unknown	Unknown	2/6	10/47 (21%)	12/53 (23%)
Developmental delay	+	−	+	+	−	Speech/motor	4/6	36/47 (77%)	40/53 (75%)
Intellectual disability	−	−	+	+	Mild	+	4/6	25/47 (53%)	29/53 (55%)
ASD	−	−	+	−	−	Unknown	1/6	17/47 (36%)	18/53 (34%)
Hypotonia	−	−	−	−	−	Unknown	0/6	16/47 (34%)	16/53 (30%)
Metopic ridge/craniosynostosis	−	−	−	−	−	+	1/6	22/47 (47%)	23/53 (43%)
Ptosis	−	−	−	−	−	+	1/6	39/47 (83%)	40/53 (75%)
Down slanting palpebral fissures	−	+	+	+	−	+	4/6	26/47 (55%)	30/53 (57%)
Arched eyebrows	+	+	+	+	−	+	4/6	28/47 (60%)	32/53 (60%)
Epicanthal folds	+	−	+	+	−	+	4/6	16/47 (34%)	20/53 (38%)
Short up turned nose with bulbous tip	+	−	−	−	−	+	2/6	25/47 (53%)	27/53 (51%)
Exaggerated cupid bow/wide philtrum	+	+	+	+	−	+	5/6	24/47 (51%)	29/53 (55%)
Feeding issues	−	−	−	−	−	−	0/6	16/47 (34%)	16/53 (30%)
Congenital heart disease	+	−	−	+	−	+	3/6	14/47 (30%)	17/53 (32%)
Limb anomalies	−	−	Fifth finger clinodactyly	−	−	Six fingers on each hand, six toes on the right foot	2/6	12/47 (26%)	14/53 (26%)
Ears	−	−	Low-set ears	Low-set ears	−	Low-set ears/Ear malformation	3/6	24/47 (51%)	27/53 (51%)
Other	GHD	Small penis/cryptorchid	Attention disorder/teeth loss/nail biting	GHD	−	Hypospadias/Ascites/Teeth loss	−	−	−

“+” denotes the presence of a specific clinical manifestation or structural abnormality, while “−” indicates the absence of the corresponding phenotypic feature. ASD, autism spectrum disorder; GHD, growth hormone deficiency; WSKA, Weiss-Kruszka syndrome.

WSKA is a rare disease with a very low incidence, and clinicians have limited knowledge of its clinical phenotype. It is necessary to establish a complete genotype-phenotype association database. Variations in different types and gene locations may correspond to different severity of clinical manifestations, and a large amount of data accumulation is still needed.

In this study, we identified five previously unreported rare mutations in ZNF462. The patients in our cohort exhibited similar facial features but demonstrated clinical heterogeneity. Our findings expand the phenotypic and genetic spectrum of ZNF462. Although more data from Chinese patients are needed to support it, our study may lay a foundation for a more comprehensive identification of diseases caused by abnormalities in this gene and in turn, contribute to the improvement of clinical diagnosis and management. Standardized abbreviations (e.g., WES for whole-exome sequencing) are expanded at initial use. A master reference of all abbreviations is provided in Table S1. We present this article in accordance with the AME Case Series and STROBE reporting checklists (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-274/rc).

Case presentation

Patients

Five Han Chinese families were included for this study. They had different variations in the same gene and exhibited similar, but not entirely identical, phenotypes. All procedures performed in this study were in accordance with the ethical standards of the Ethics Committee of Shanghai Children’s Medical Center (No. SCMCIRB-K2020060-1) and with the Helsinki Declaration and its subsequent amendments. Informed consent was obtained from all the patients’ guardians for publication of this article and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Patient II-2 in family 1 (patient 1)

Patient 1 was a girl with a normal birth weight. At 1 month of age, she was diagnosed with a complete atrioventricular septal defect (AVSD), atrial septal defect, mild-to-moderate atrioventricular valve regurgitation, pulmonary arterial hypertension, and residual left superior vena cava. The patient underwent corrective surgery for a congenital heart defect at 6 months of age. At one and a half years of age, she could speak and walk, but her expressive abilities were weak and articulation was unclear. She had a high-arched palate, excessive body hair, an extroverted personality, and asthma. The patient’s facial features included mild frontal bossing, a prominent chin, a high-arched palate, excessive body hair, arched eyebrows, epicanthal folds, a short-upturned nose, and an exaggerated Cupid’s bow. Additionally, the patient’s teeth were uneven and had cavities. Neurocognitive testing results showed that her total intelligence quotient (IQ) was within the normal range [105] on the Wechsler Preschool and Primary Scale of Intelligence test in 2022. However, on the Wechsler Intelligence Scale for Children Revised test in 2023, her total IQ was at a borderline intellectual functioning level [88]. She exhibited slow growth in height. By the age of 6 years and 8 months, her height and weight were 115 cm and 23 kg, respectively.

Patient II-1 in family 2 (patient 2)

Patient 2 was a boy with elevated levels of alanine aminotransferase, which normalized after taking hepatoprotective medication. At 1 year and 3 months of age, the patient had a height of 77.5 cm and a weight of 9.5 kg. Examination of the external genitalia showed a lax bilateral scrotum, a penis length of 1.5–2 cm and a circumference of 2.0 cm, and development consistent with the public hair stage 1. He had a significant number of Mongolian spots on his back. Electrocardiography revealed sinus tachycardia. Cardiac color Doppler ultrasonography and pituitary magnetic resonance imaging (MRI) revealed no abnormalities. The boy’s facial features included narrow-slanting palpebral fissures, downward-slanting arched eyebrows, and an exaggerated Cupid’s bow; however, his teeth were normal. As of November 2023, his testes had descended, but he still had a small penis.

Patient II-1 in family 3 (patient 3)

Patient 3 was a 12-year-old boy who started walking at one and a half years of age but had unclear speech during his kindergarten years. At the time of examination, he had poor academic performance in the 6th grade. He exhibited narrow, downward-slanting palpebral fissures, a high palate, arched eyebrows, an exaggerated Cupid’s bow, a protruding chin, and low-set ears. The patient had delayed intellectual (mental) development. By the age of 12 years and 8 months, his height had increased to 154.3 cm and weight to 45 kg. He experienced language impairment, poor academic performance, attention deficit, and stereotypical movements. The external appearance of male genitalia was normal. Pituitary MRI revealed a thin pituitary gland of 3.5 mm length and strong signal in the neurohypophysis behind the adenohypophysis. An anomaly was also detected in the coronary arteries, although no significant symptoms, such as exertional palpitations or shortness of breath, were observed. Dental abnormalities included two missing permanent teeth on both sides. He also had a tilted little finger and a nail-biting habit. His father’s height was 170 cm and mother’s height was 160.1 cm.

Patient II-1 and patient I-2 in family 4 (patient 4 and patient 5)

Patient 4 was a girl who visited the clinic at the age of eleven and a half years. At that time, her bilateral breasts had enlarged for 1 year, but she had not yet begun menstruating. We noted a yellowish discharge in her underwear. She had intellectual disabilities, poor memory, and unsatisfactory academic performance. The patient had undergone surgery for pulmonary artery stenosis in the past. Her facial features included a low hairline, low-set ears, arched eyebrows, a protruding chin, redundant skin on the inner corners of her eyes, and a prominent Cupid’s bow. Her height was 146.2 cm and weight was 46.1 kg. At the age of 12 years, she began menstruating, and her height increased to 150 cm, with a weight of 55 kg. Patient 5 was the mother of patient 4.

Patient II-1 in family 5 (patient 6)

Patient 6 visited the genetic counselling clinic of Shanghai Children’s Medical Center genetic counselling clinic on June 6, 2024. Prior to this, the patient had undergone AVSD repair surgery for a ventricular septal defect. At the time of the visit, the patient was 2 years and 5 months old and presented clinically with basic tooth loss, a height of 77 cm, and a weight of 9 kg. The patient exhibited stunted growth and developmental delays. The patient had six fingers on each hand, six toes on the right foot, and hypospadias. Unfortunately, the patient died after heart surgery.

DNA extraction and WES

DNA was obtained from peripheral blood samples of all patients, except patient 6. Patient 6 also underwent genetic testing elsewhere. WES was performed on patients 1–4 as previously described (16). A sequencing library was generated using the SureSelect XT Human All Exon V6 Reagent Kit (Agilent Technologies, Santa Clara, CA, USA). Sequencing was performed using the Illumina NovaSeq 6000 system (Illumina, San Diego, CA, USA). Sequence reads were aligned to the reference human genome (GRch37/hg19) using the GATK software (SoftGenetics, Broad Institute, USA). Biological analysis and interpretation of all single-nucleotide variants and indels were performed using TGex^TM (LifeMap Sciences, Inc., Walnut, CA, USA). Candidate mutations were confirmed using Sanger sequencing. The primers used for amplification are listed in Table S2. The pathogenicity of the identified candidate variants was evaluated based on the guidelines provided by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) (17). Variants were confirmed in the parental DNA using Sanger sequencing.

WES and Sanger sequencing validated ZNF462 variants

ZNF462 variants were identified using bioinformatic analysis after WES and confirmed using Sanger sequencing in all five families (data from family 5 were unavailable). Family trees are shown in Figure 1 and Sanger sequencing results are shown in Figure S1. Facial photographs of the patients are shown in Figure 2. Patient 1 harbored a de novo heterozygous nonsense variant NM_021224.6:c.370del(p.Ile124*). Patient 2 displayed a de novo heterozygous frameshift variant c.876_877dup(p.Ala293Valfs*12). Patient 3 harbored a de novo heterozygous variant, c.6449del(p.Pro2150Glnfs*7). Only patient 4 had the maternal variant c.1304del(p.Phe435Serfs*2). Patient 5, the mother of patient 4, had only mild intellectual disability, with no other clinical manifestations and no detailed examinations. The younger sister of patient 4 had high thyroid-stimulating hormone levels but was otherwise normal. Patient 6 had a de novo splicing variant, NM_021224.6:c.7190-1G>A, which was located at the junction of intron 11 and exon 12. The above five variants were novel variants that were not included in population databases, such as the Genome Aggregation Database v2.1.1 (gnomAD v2.1.1, http://gnomad-sg.org/), or reported in variant databases, including ClinVar (https://www.ncbi.nlm.nih.gov/clinvar) and Human Gene Mutation Database (http://www.hgmd.cf.ac.uk). These mutations, including four frameshift variants and one splicing variant, were loss-of-function mutations. Bioinformatic analysis predicted that they could lead to mRNA degradation through nonsense-mediated decay, resulting in a loss of protein function. According to the ACMG/AMP standards and guidelines for the interpretation of sequence variants, four de novo variants, c.370del(p.Ile124*), c.876_877dup(p.Ala293Valfs*12), c.6449del(p.Pro2150Glnfs*7), and c.7190-1G>A, were identified as pathogenic variants (PVS1+PM2_Supporting+PS2_ Moderate), while c.1304del(p.Phe435Serfs*2) was classified as likely pathogenic (PVS1+PM2_ Supporting). Patients 1–4 and patient 6 had no confirmed parental relationships.

Figure 1.

Five novel variants in five families. The contents are pedigrees and sequencing results for families 1–5. M, mutant allele.

Figure 2.

Facial photographs of patients with ZNF462 variants. P1: proband from family 1 at the age of 6 years 8 months; P2: proband from family 2 at the age of 1 year 9 months; P3: proband from family 3 at the age of 12 years 8 months; P4: proband from family 4 at the age of 12 years; P5: mother of P4; P6: proband from family 5 at the age of 2 years 5 months. These images are published with the consent from patients’ guardians.

Genotype and phenotype spectra

We reviewed the data on 53 patients at Shanghai Children’s Medical Center, as well as published data on patients with pathogenic ZNF462 variants. Information from previously reported patients and those in this study is summarized in Table 1, and further details are presented in Table S3. The variant information is shown in Figure 3. There were 46 non-repetitive variants in ZNF462, comprising nonsense variants (11/46, 24%), frameshift variants (24/46, 52%), splice-site variants (2/46, 4%), and structural variants (9/46, 20%). There were 37 point mutations distributed in exon 3 (n=28), exon 6 (n=2), exon 7 (n=1), exon 8 (n=3), exon 9 (n=1), intron 10 (n=1), and intron 11 (n=1). The mutation rate in exon 3 accounted for 76% of all mutations (28/37). When allowing for the presence of repetitive mutations, frameshift mutations accounted for 45% (24/53), which was higher than that in the 47 patients reported previously (43%). Nonsense mutations accounted for 34% of the mutations, which was lower than the percentage in the 47 patients. In this cohort, a splicing mutation was discovered, which increased the proportion of splicing mutations among patients. Balanced mutations were not observed in this cohort.

Figure 3.

ZNF462 point variants and structure variants. (A) A diagram showing the ZNF462 coding exons and introns (NM_021224.6). Black font indicates variants previously reported, while orange font indicates variants reported in this study. (B) This chart represents a schematic diagram of the location of the ZNF462 gene on chromosome 9.

Among all reported cases (incorporating both our cohort and prior literature cases), the proportion of de novo mutations was 68%. In terms of clinical phenotypes, neurodevelopmental delays and abnormal facial features occurred more frequently. Both developmental delay and ptosis accounted for 75%, arched eyebrows accounted for 60%, and downward-slanting palpebral fissures accounted for 57% of all phenotypes. Other features included an exaggerated Cupid’s bow/wide philtrum, intellectual disability, a short-upturned nose with a bulbous tip, malformed ears, metopic ridge/craniosynostosis, epicanthal folds, autism spectrum disorder, congenital heart disease, hypotonia, feeding issues, and limb anomalies. The clinical characteristics of our Chinese cohort included an exaggerated Cupid’s bow/wide philtrum (5/6), downward-slanting palpebral fissures (4/6), arched eyebrows (4/6), epicanthal folds (4/6), developmental delay (4/6), and intellectual disability (4/6). Other features included low-set ears, congenital heart disease, limb anomalies, and growth hormone deficiency.

Patient 1 presented with mild facial abnormalities and congenital heart disease. The MRI findings were different from those of previous patients with a midline lipoma. Previously, patients mostly presented with agenesis of the corpus callosum and dilated ventricles. Beyond the facial features, patient 2 displayed only minor clinical manifestations, specifically micropenis and cryptorchidism. Patient 3 also exhibited neurological and facial abnormalities, along with relatively prominent neurological features. This patient also had a thin pituitary gland and attention disorder, while also presented with skeletal abnormalities. Patient 4 represented the only case in which the pathogenic variant was inherited from her mother; Patient 5 harbored the variant c.1304del(p.Phe435Serfs*2). Among the previous cases, four had a family history, with the related variants being c.3787C>T(p.Arg1263*), c.2590C>T(p.Arg864*), c.6431C>A(p.Ser2144*), and c.3502dup(p.Arg1168Profs*15). The four variants were distributed in exon 3, and one variant was located in exon 8. Patient 6 showed relatively severe clinical manifestations with prominent facial and neurological features, congenital heart disease, six fingers on each hand, six toes on the right foot, ear abnormalities, tooth loss, hypospadias, and ascites. The patient exhibited abnormal thinness and a short stature. Among these patients with height in the 3rd percentile, Patient 6 showed an unusually severe phenotype.

Discussion

Clinical Genome Resource (ClinGen) curated 10 ZNF genes, including five Online Mendelian Inheritance in Man (OMIM) morbid genes. These genes were ZNF711, ZNF407, ZNF292, ZNF141, and ZNF462. Only ZNF462 has sufficient evidence of haploinsufficiency, and the pathogenic mechanisms of the other genes are still unclear. The relationship between ZNF141 and postaxial polydactyly type A requires further confirmation (18). ZNF462, ZNF711, ZNF407, and ZNF292 have detrimental effects on the nervous system and can cause mental retardation and autistic features. Various types of mutations in ZNF462 have been reported, including null variants as well as deletions or translocations involving the complete or partial loss of ZNF462 (1,5,7-9). Combining previous reports with the present cases, we identified a total of 16 female and 37 male patients. Nonsense and frameshift mutations accounted for a large proportion of cases (47% and 32%, respectively). Splice-site mutations accounted for the smallest proportion, at only 4%.

Testicular or penile abnormalities are rare phenotypic features reported in only four patients with WSKA. Patient 2 only exhibited facial dysmorphism and developmental anomalies in the reproductive organs, without any neurodevelopmental abnormalities. His growth and development were similar to those of normal individuals of the same age. The effect of ZNF462 on cryptorchidism and pubertal development has not yet been definitively studied. Furthermore, ZFP462 acts as a ZNF protein and represses the expression of mesendodermal genes in mouse embryonic stem cells by targeting the H3K9-specific histone methyltransferase complex G9A/GLP (19-21). This repression protects the neural lineage specification of mouse embryonic stem cells. Therefore, the loss of ZNF462 function can result in the aberrant activation of nonspecific lineage genes in the neural lineage (21). Lomniczi et al. investigated the epigenetic regulation of ZNF protein-mediated transcriptional repression during puberty and found downregulation of ZNFs, including GATAD1, ZNF573, and ZNF462, in agonadal male monkeys, and this was associated with the pubertal reactivation of gonadotropin secretion. It has been speculated that ZNF462 plays a role in inhibiting gene transcription during non-pubertal development (22).

To date, 47 cases of WSKA caused by ZNF462 abnormalities have been reported, with only 4 cases of Chinese Han origin. Most patients have been of Caucasian and European descent, with one from Korea. Herein, we analyzed data on six Chinese individuals and provided phenotypic information on WSKA in a Chinese population. Zhao et al. (13) reported a patient carrying a ZNF462 nonsense mutation inherited from the father, both of whom presented with unilateral ptosis and hearing impairment. The patient also had developmental delays, unlike her father; however, it is not clear whether cognitive testing was conducted. Zhou et al. (1) reported a patient with distinctive facial features, growth hormone deficiency, attention deficit hyperactivity disorder, and obstructive sleep apnea due to a ZNF462 abnormality. Hau et al. (2) reported a Chinese patient with facial dysmorphism, learning difficulties, developmental delays, and unilateral fifth finger clinodactyly. Combining these findings with the results from our cohort indicates that significant facial abnormalities and neurodevelopmental abnormalities also exist in the Chinese cohort. Other prominent features included growth hormone deficiency (3/10) and limb anomalies (3/10). Our findings provide initial characterization of WSKA manifestations in Chinese patients, but the relatively limited cohort size and scarcity of population-specific data necessitate expanded investigations. Future multi-center studies with larger Chinese cohorts are needed.

Patient 5, an adult aged approximately 35 years, exhibited only mild clinical manifestations, normal daily living, expressive abilities, and slight learning difficulties. She showed fewer and milder clinical manifestations of the disease than her daughter (patient 4) and other patients. This is consistent with the findings of Hau et al. (2), who reported that adult patients within families often exhibit fewer clinical manifestations. The clinical phenotypes of five patients over 30 years of age were analyzed. Apart from facial abnormalities, neurological developmental abnormalities and various other anomalies, such as a third pair of ribs, seizures, tooth loss, and umbilical hernia were observed in only one 33-year-old female patient (9). However, the variation in this patient was a copy number deletion involving 61 protein-coding genes, with ZNF462 being one of them. The possibility that other genes may have caused the patient’s phenotype cannot be ruled out. The other four patients carried point mutations and presented with facial and ear abnormalities, but no significant neurological abnormalities. These four patients included three male individuals and one female individual, indicating that the heterogeneity of the clinical phenotypes was unrelated to sex. The distribution of mutations included three in exon 3 and one in exon 8, which aligned with the distribution pattern of all mutations in this gene. Therefore, there may be no relationship between phenotypic heterogeneity and mutation distribution. Further research and case studies are needed to explore the heterogeneity of clinical phenotypes.

Conclusions

Accurate clinical diagnosis of WSKA remains challenging. Herein, we presented data from our cohort and summarized previously published data to provide a comprehensive coverage of the various phenotypes caused by ZNF462 mutations. The disease is associated with prominent facial features, such as an exaggerated Cupid’s bow, arched eyebrows, and ptosis; however, some patients may only exhibit mild facial characteristics and have other nonspecific phenotypes. Therefore, identification using WES is necessary for clinical diagnosis.

Supplementary

The article’s supplementary files as

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 Ethics Committee of Shanghai Children’s Medical Center (No. SCMCIRB-K2020060-1) and with the Helsinki Declaration and its subsequent amendments. Informed consent was obtained from all the patients’ guardians for publication of this article and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.