The results of ATP7B gene screening in 38,158 neonates and the clinical and variants characteristics of 14 cases with Wilson’s disease

Introduction

Wilson’s disease (WD; OMIM 277900) was first described by Samuel Alexander Kinnier Wilson in 1912 as hepatolenticular degeneration (1), which is an autosomal recessively inherited copper metabolism disorder (2). The ATP7B gene variants lead to a reduction in the activity of the P-type copper transport ATP enzyme that it encodes, thereby impairing the synthesis of plasma ceruloplasmin. Consequently, excess copper ions accumulate in the liver, kidneys, brain, and other organs, resulting in multi-organ damage (3). Typical features of WD include hepatic dysfunction, neurological disorders, psychiatric symptoms, corneal Kayser-Fleischer (K-F) rings, and low serum ceruloplasmin levels (4). WD can manifest at any age, but it is predominantly observed in children and adolescents, with a higher prevalence noted between the ages of 5 and 35 years (5). The global prevalence of this disease ranges from (0.25–4)/10,000 individuals, and the carrier rate of the responsible gene is approximately 1/90 (6). In China, national epidemiological data are lacking; however, some scholars have estimated the prevalence of WD in the country to be 0.587/10,000 (7), and the carriage rate was 2.43% (8). This condition is one of the genetic disorders that can be effectively managed through treatment, which primarily involves long-term copper chelation therapy, adherence to a low-copper diet, and liver transplantation (9). Upon diagnosis, lifelong treatment and continuous monitoring are essential. WD presents with a broad spectrum of clinical manifestations and atypical symptoms, increasing the risk of misdiagnosis or missed diagnosis, which can potentially delay the optimal treatment window (10). Consequently, early detection, accurate diagnosis, and timely intervention are of significant clinical importance.

This study seeks to elucidate the P hotspots of the ATP7B gene within this region by examining the detection rate of the ATP7B gene and conducting familial verification of potentially positive samples derived from the genetic screening data of 38,158 newborns in South China. Additionally, it retrospectively analyzes and synthesizes the clinical data of 14 patients diagnosed with WD to investigate the clinical manifestations and genetic characteristics associated with WD. The ultimate goal is to furnish a foundation for clinical diagnosis and genetic counseling. We present this article in accordance with the STROBE reporting checklist (available at https://jlpm.amegroups.org/article/view/10.21037/jlpm-25-21/rc).

Methods

Study population and data collection

Between November 2019 and December 2023, 38,158 neonates who received genetic screening were enrolled in South China (mainly including Guangdong, Yunnan, Guangxi, Guizhou, and other provinces in China). Fully informed written consent was obtained from the neonates’ parents or guardians. We conducted a retrospective analysis of the clinical presentations, biochemical profiles, and molecular genetics of 14 patients diagnosed with WD from 2017 to 2024 at South China Newborn Genetic Screening Alliance Hospital (Figure 1). Before the genetic studies, informed consent was obtained from the parents.

Figure 1 Enrollment of neonatal genetic screening cohort and WD cohort. P/LP, pathogenic/likely pathogenic; WD, Wilson’s disease.

The inclusion and exclusion criteria for newborn genetic screening: (I) inclusion criteria: (i) newborns have undergone genetic screening; (ii) 0–28 days after birth; and (iii) gestational age: 37–42 weeks. (II) Exclusion criteria: (i) unclear clinical information; (ii) lack of core traceability information; and (iii) uninterpretable test results.

The inclusion and exclusion criteria for WD patients refer to the Leipzig score. A total score of ≥4 points can confirm the diagnosis, 3 points is a suspected diagnosis, and less than 2 points is excluded (11,12).

Genetic screening

Gene screening contains 133 genetic disorders (138 genes; table available at https://cdn.amegroups.cn/static/public/jlpm-25-21-1.xlsx) with high prevalence in South China. These include all metabolic disorders covered by current newborn mass spectrometry screening programs, such as amino acid metabolism disorders, organic acid disorders, and fatty acid disorders, along with other conditions not detectable through mass spectrometry but of significant clinical importance and social value for early detection. Notable disorders include lysosomal diseases, glycogen storage diseases, WD, hereditary deafness, and β-thalassemia.

Genomic DNA was extracted from diameter of 5 mm dried blood spot specimens using the magnetic bead method (magnetic bead-based blood spot and blood card genomic DNA extraction kit, magnetic bead-based nucleic acid extraction instrument). Using target gene sequence was captured by multiplex polymerase chain reaction (PCR) amplification, covering all exon regions and adjacent intron regions (±50 bp). The target sequence library was obtained by amplification purification. Qubit^® 3.0 fluorescence quantifier (Thermo Fisher Scientific, Waltham, MA, USA) was used for library quantification, and Agilent 2100 biological analyzer (Santa Clara, CA, USA) was used for library length determination.

Diluted libraries with sequencing primers were sequenced on an Illumina NextSeq 500/550 platform (PE150; San Diego, CA, USA). The Raw sequencing image Data files were converted into Raw sequencing sequence (Raw data or Raw reads) FASTQ files by base calling analysis, and then filtered to remove connectors and low-quality sequences. Valid sequencing data were compared to the human reference genome (Human_B37) using the Burrows-Wheeler Aligner (BWA) software. Genome Analysis Toolkit (GATK) software was used to analyze the variation information, and ANNOVAR software was used for variation annotations, including the database of single-nucleotide polymorphism (dbSNP), Thousand Genomes Project, and other annotated information from existing databases. The annotated content covered pathogenicity classification information, such as population frequency, variation type, function prediction (SIFT, Polyphen2, Mutation Taster, etc.), human genome mutation database (HGMD), and ClinVar. The interpretation of genetic variation pathogenicity was based on the Classification Standards and Guidelines of Genetic Variation, which were divided into five categories: pathogenic (P), likely pathogenic (LP), variant of uncertain significance (VUS), limited benign (LB), and benign (B).

If two variants are detected in the ATP7B gene, the parents are contacted for blood sampling, and Sanger sequencing is conducted to determine the infant’s genotype.

Statistical analysis

The genetic screening data for 38,158 neonates were analyzed, and statistics were conducted. Statistical analyses were performed using SPSS 26.0 version (IBM Corporation, Armonk, NY, USA). The number of detectors of the variants is expressed as a percentage, calculated as the ratio of variant cases to the total number of individuals with detected variations (percentage = variant cases/n, where n represents the number of individuals with detected variations). Morbidity percentage = patients/n, where n represents 38,158 neonates. The carrier frequency of each variant gene was calculated by the percentage of subjects with the gene variant in 38,158 neonates.

Ethical consideration

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Ethics Committee of The First People’s Hospital of Yunnan Province (No. KHLL023-KY014) and The Sixth Affiliated Hospital, Sun Yat-sen University (No. 2023ZSLYEC-657). Given the retrospective nature of the analysis, the requirement for individual informed consent was waived.

Results

Neonatal genetic screening

The genetic screening data of 38,158 newborns, with a male-to-female ratio of 20,894 to 17,264, revealed 1,015 cases with variants in the ATP7B gene locus classified as P/LP (table available at https://cdn.amegroups.cn/static/public/jlpm-25-21-2.xlsx), resulting in a population detection rate of 2.66%. Among these, 37 cases exhibited two P/LP variants in the ATP7B gene, categorized as suspicious positive cases. Five cases refused family verification. In the 32 cases that underwent pedigree verification, five newborns were preliminarily diagnosed with WD (composite heterozygous variation). The remaining 27 newborns were identified as carriers of c.3316G>A/c.588C>A (26/27) or c.3207C>G/c.3443T>C (1/27) variants in cis-arrangement. We also detected a patient with a homozygous variant. In total, six patients with WD were detected, with a morbidity rate of 0.0157% (five neonates refused Sanger sequencing, who were detected with two variants in the ATP7B gene, so it is speculated that the morbidity rate of WD in this region may be higher than this value). One thousand and four carriers of ATP7B gene variants were identified, comprising 236 individuals with one LP variant, 741 with one P variant, and 27 with two P variants. It resulted in a population detection rate of 2.66%. A total of 90 variants were detected (Figures 1,2 and table available at https://cdn.amegroups.cn/static/public/jlpm-25-21-2.xlsx), with the most frequent variants being c.3316G>A, c.2333G>T, c.3443T>C, c.2755C>G, and c.2804C>T.

Figure 2 Distribution of ATP7B gene detection in neonatal genetic screening. Proportion of detected variants = the number of detected variants/total number of detected variants (n=1,053, confirmed patients are calculated according to two detected variants).

Clinical characteristics and genetic molecules of 14 patients with WD

In the cohort of 14 patients diagnosed with WD, an equal distribution of seven males and seven females was observed, with ages at initial consultation ranging from 1 month to 9 years. Among these, 11 patients were diagnosed with confirmation achieved through genetic screening or familial verification; however, the timing of their families’ consultations at the hospital varied. Patients 04, 09, and 14 received their diagnoses following the detection of abnormal liver function during routine physical examinations. Patient 07, the sibling of patient 06, was similarly confirmed through familial verification. A total of 17 genetic variants were identified, including c.3316G>A (n=4), c.3443T>C (n=4), c.1543+1G>T (n=2), c.2333G>T (n=2), and c.3859G>A (n=2). The remaining variants, each detected once, included c.2304dup, c.2509G>T, c.2549C>T, c.2755C>G, c.2804C>T, c.3451C>T, c.3517G>A, c.3700del, c.3877G>A, c.3884C>T, c.4112T>C, and c.970A>T, as detailed in Table 1.

Copper blue protein decreased in all 14 (100%) patients, and blood copper decreased in 12 (85.7%) patients. The 24-hour urine-copper was increased in a patient (only 3 patients were tested), and liver function was abnormal in 3 patients (21.4%). Post-diagnosis, all 14 WD patients were prescribed a low-copper diet in conjunction with treatment regimens involving penicillamine and zinc gluconate tablets for copper chelation. In the follow-up, we tested the liver function, ceruloplasmin, blood copper, and other indicators of the WD patients in the cohort. Unfortunately, most families refused to test 24-hour urine copper due to the difficulty of operation. Notably, patients diagnosed before 1 year of age did not exhibit significant liver function abnormalities during the early stages of the disease. Subsequent evaluations indicated that liver function temporarily remained within normal parameters, as detailed in Table 2. However, due to delayed diagnosis, patients 04 and 14 presented with increased liver parenchymal echogenicity on ultrasound and the presence of K-F rings upon fundus examination.

Discussion

WD is a multisystem disorder with a wide range of clinical presentations. Hepatic involvement is common, with symptoms ranging from asymptomatic (13) to acute liver failure. Characteristic manifestations of WD encompass hepatic dysfunction, neurological disturbances, psychiatric symptoms, the presence of corneal K-F rings, and reduced serum ceruloplasmin levels (4). Symptoms, age of onset, and prognosis can also be influenced by external factors (environment, diet, etc.) and the personal characteristics of the patient’s body (epigenetics, other congenital diseases). In addition, early neurological deteriorations also affect the WD outcomes sometimes (14).

WD is an autosomal recessive genetic disorder. Early diagnosis and initiation of appropriate therapy can significantly improve outcomes, with many patients achieving normal life expectancy (15). Currently, all medical treatments for WD, including a low-copper diet, zinc salts, and D-penicillamine, necessitate lifelong adherence to maintain patient health (16). Zinc salts, such as zinc acetate, work by inhibiting copper absorption in the gastrointestinal tract. They are generally well-tolerated and have a favorable safety profile, making them suitable for long-term use (17). D-penicillamine is a chelating agent that binds to copper and facilitates its excretion through urine. However, it is associated with allergic reactions and hematologic abnormalities (18). Advances in science and technology have led to significant progress in therapeutic techniques for WD. In the realm of pharmacotherapy, N,N’-bis(2-mercaptoethyl)isophthalamide (NBMI) has emerged as a novel chelator for WD (19). Emerging technologies, such as CRISPR/Cas9 genome editing and induced pluripotent stem cell (iPSC)-derived hepatocytes (iHeps), hold significant promise for the treatment of WD (20).

The availability of straightforward and efficacious treatments underscores the importance of early and accurate diagnosis of WD (21). Timely diagnosis and effective therapeutic interventions can arrest disease progression in symptomatic individuals and avert the onset of symptoms in presymptomatic individuals (22). Currently, over 800 P variants in the ATP7B gene have been documented (23). The distribution of ATP7B hotspot variants exhibits geographical variability (16). Genetic screening data from 38,158 newborns in South China revealed a population detection rate of P/LP variants for the ATP7B gene of approximately 2.66%, with a morbidity rate of 0.0157%. However, five neonates refused Sanger sequencing who were detected with two variants in the ATP7B gene, so it is speculated that the morbidity rate of WD in South China may be higher than this value. Meanwhile, our study excluded neonates admitted to the neonatal intensive care unit (NICU), which could have introduced a bias by potentially excluding more severe cases. These rates are higher than previously reported carrier rates of 2.43% (8) and a prevalence rate of 0.587/10,000 (7), which may be attributed to the regional and quantitative characteristics of the tested population.

Previous studies identified three high-frequency P variants (c.2333G>T, c.2975C>T, and c.2804C>T) in Chinese WD patients, accounting for 50–60% of all P variants (24). However, this study detected a total of 90 variants, with the most prevalent variants being c.3316G>A, c.2333G>T, c.3443T>C, c.2755C>G, and c.2804C>T. Our study identified the c.3316G>A variant as a high-frequency variant in the newborns of South China (Figure 2). This finding indicates potential regional differences in WD gene variants. Furthermore, the frequency of this variant in our study population differed from that observed in the East Asian population according to the gnomAD database. This suggests that different regional populations exhibit distinct variant preferences, with some variations identified in our study not being represented in the database. These findings could provide a foundation for further research, including the expansion of genetic databases.

With the development of genetic testing, more and more variants in the ATP7B gene were described. However, other papers highlighted that a small part of clinically and biochemically diagnosed WD patients could be carriers of a single variant in the ATP7B gene or no variants at all (4,25). Patients carrying only a single P/LP variant in the ATP7B gene pose a diagnostic challenge, so the current diagnosis of WD is based on the Leipzig score (11,12). In the absence of a second identified variant, the diagnosis of WD cannot be definitively confirmed through genetic testing alone. However, these patients may still exhibit clinical features suggestive of WD (26). In such cases, a combination of clinical evaluation, biochemical testing, and imaging studies can be used to support the diagnosis. Long-term follow-up is recommended to monitor for the development of WD-related symptoms and to assess the need for treatment. The presence of a family history of WD can serve as an important auxiliary diagnostic criterion, especially in patients with a single P variant.

Among the cohort of 14 patients diagnosed with WD, 11 were identified through newborn genetic screening or family verification, while three were diagnosed following the detection of abnormal liver function during physical examinations, which was subsequently confirmed through genetic testing. In our study, liver damage and related symptoms were observed in 21.4% (3/14) of patients with WD. This proportion is significantly lower than the 81.72% reported in previous studies (4). The discrepancy may be attributed to the relatively small sample size in our study and the fact that the majority of our patients were diagnosed through early genetic screening. Post-diagnosis, all patients received intervention (zinc gluconate + D-penicillamine + low-copper diet). Notably, patients diagnosed before 1 year of age did not exhibit significant liver function abnormalities during the early stages of the disease. Subsequent evaluations indicated that liver function temporarily remained within normal parameters, aligning with previous reports (12,27). Interestingly, we found that the liver function of patient 04 was elevated again after the follow-up after the administration of the intervention, which may be due to the irregular medication of the patient or the combination of other diseases during the period, because the liver function could be reduced to the baseline level in the later monitoring. This suggests that early diagnosis and effective treatment can prevent disease progression in symptomatic patients and avert symptom development in presymptomatic individuals (22). But in the context of WD, retrospective studies may not capture the full spectrum of disease presentation or treatment outcomes, as they are often based on medical records that may lack detailed information. Therefore, while retrospective studies provide important insights, prospective studies with well-defined cohorts and standardized protocols are essential for generating robust and reliable data. Among the 14 confirmed cases of WD, the c.3316G>A and c.3443T>C genetic variants were identified in four patients. Although the data on WD patients were somewhat limited, when combined with neonatal genetic screening data (Figure 2), it was evident that c.3316G>A and c.3443T>C are prevalent variants in the neonatal population of South China.

Understanding the relationship between specific ATP7B gene variants and clinical phenotypes is essential for accurate diagnosis and effective management of WD. In our study, we identified high-frequency variants in the ATP7B gene through genetic screening of a neonatal cohort and a cohort of patients with WD. The identification of these variants highlights the genetic heterogeneity of WD and underscores the importance of comprehensive genetic analysis in diagnosing this disorder. However, due to the limited sample size of our WD cohort, we were unable to robustly assess the correlation between these variants and specific phenotypes. Previous studies have reported that the c.2333G>T (p.Arg778Leu) variant in the ATP7B gene is highly associated with hepatic manifestations of WD (4), so early identification and monitoring of liver function in individuals carrying this variant are crucial for timely intervention and management. The c.3207C>G (p.His1069Gln) variant has been reported to be associated with neurologic and psychiatric symptoms, particularly in patients who present after puberty (28,29).

Conclusions

This study offers a large-scale analysis of the carrier rates and incidence of P/LP variants in the ATP7B gene within newborn cohorts in South China. It identifies specific hotspots of ATP7B gene variants, thereby providing essential foundational data to support the integration of ATP7B into newborn genetic screening programs. Additionally, longitudinal monitoring of 14 patients diagnosed with WD underscores the critical importance of early diagnosis and intervention.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jlpm.amegroups.com/article/view/10.21037/jlpm-25-21/rc

Data Sharing Statement: Available at https://jlpm.amegroups.com/article/view/10.21037/jlpm-25-21/dss

Peer Review File: Available at https://jlpm.amegroups.com/article/view/10.21037/jlpm-25-21/prf

Funding: This study was supported by the Yunnan Province Ten Thousand Talents Plan-Famous Doctor Special Fund (No. YNWR-MY-017).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jlpm.amegroups.com/article/view/10.21037/jlpm-25-21/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. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Ethics Committee of The First People’s Hospital of Yunnan Province (No. KHLL023-KY014) and The Sixth Affiliated Hospital, Sun Yat-sen University (No. 2023ZSLYEC-657). Given the retrospective nature of the analysis, the requirement for individual informed consent was waived.

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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