Carrier frequency and incidence of aromatic l-amino acid decarboxylase deficiency: a gnomad-based study

ABSTRACT BACKGROUND Aromatic L-amino acid decarboxylase (AADC) deficiency is an autosomal recessive neurotransmitter metabolism disorder and is clinically characterized by infancy hypotonia,

ophthalmic crisis, and developmental delay. With the emergence of gene therapy for AADC deficiency, accurate prediction of AADC deficiency is required. This study aimed to analyze the

carrier frequency and expected incidence of AADC deficiency using exome data from the Genome Aggregation Database (gnomAD). METHODS We analyzed 125,748 exomes from gnomAD, including 9197

East Asian exomes, for the _DDC_ gene. All identified variants were classified according to the 2015 American College of Medical Genetics and Genomics and the Association for Molecular

Pathology guidelines. RESULTS The worldwide carrier frequency of AADC deficiency was 0.17%; the highest frequency was observed in East Asians at 0.78%, and the lowest was in Latinos at

0.07%. The estimated incidence of AADC deficiency was 1 in 1,374,129 worldwide and 1 in 65,266 in East Asians. CONCLUSION The results demonstrated that East Asians have a higher carrier

frequency of AADC deficiency than other ethnic groups. The variant spectrum of _DDC_ genes in East Asian populations differed greatly from those of other ethnic groups. Our data will serve

as a reference for further investigation of AADC deficiency. IMPACT * This study analyzed exome data from the Genome Aggregation Database (gnomAD) to estimate the carrier frequency and

expected incidence of aromatic L-amino acid decarboxylase (AADC) deficiency. * The article provides updated carrier frequency and incidence estimates for AADC deficiency, particularly in

East Asian populations, and emphasizes the significant differences in the variant spectrum of DDC genes in this population compared to other ethnic groups. * The study provides important

information for accurate prediction and early diagnosis of AADC deficiency, particularly in high-risk populations, and may aid in the development of more effective targeted screening

programs and gene therapies for this disorder. You have full access to this article via your institution. Download PDF SIMILAR CONTENT BEING VIEWED BY OTHERS _ITSN1_: A NOVEL CANDIDATE GENE

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access 11 November 2024 INTRODUCTION Aromatic L-amino acid decarboxylase (AADC) (OMIM #608643), first described by Hyland et al. in 1990, is an autosomal recessive inherited disorder that is

an inborn error in neurotransmitter metabolism.1 AADC deficiency is clinically characterized by hypotonia, oculogyric crises, and dystonia, which are distinctive features, along with

developmental retardation in infancy.2 AADC deficiency is caused by a functional defect in the AADC enzyme, which is encoded by the _DDC_ gene. AACD is the final enzyme in the biosynthesis

of the monoamine neurotransmitters serotonin and dopamine. Thus, a deficiency of AACD results in a deficiency in serotonin and dopamine as well as catecholamines.3 Although the incidence of

AADC deficiency remains unclear, a recent study reported that the predictive birth rate was 1:90,000 in the US, 1:118,000 in the EU, and 1:182,000 in Japan.4 In another study, the incidence

of AADC deficiency predicted through newborn screening was reported to be 1:32,000 in Taiwan and 1:64,000 in the US.5,6 In a study of the at-risk population, the estimated prevalence was

reported to be approximately 1:900.6 Carrier frequency studies of AADC deficiency are quite rare. AACD deficiency has been known mainly in East Asians, and IVS6+4A>T is a founder variant

in Taiwan.7 In the study by Chien et al., the IVS6+4A>T variant was found in eight alleles in 1171 anonymous samples, and the allele frequency was approximately 0.34% and the converted

carrier frequency was 0.68%.5 With the recent emergence of gene therapy for AADC deficiency,8,9 rapid diagnosis and accurate prediction of AADC deficiency are required. The Genome

Aggregation Database (gnomAD) is a globally used genomic database, and gnomAD V2 consists of 125,748 exomes, including 9197 exosomes for East Asian populations.10 In open genome databases,

the genomic data of various ethnic groups are included, making these suitable for predicting carrier frequency and studying estimated incidence rates. In this study, we analyzed the global

carrier frequency and expected incidence of AADC deficiency by examining _DDC_ variants using exome data from using the widely used 2015 American College of Medical Genetics and Genomics and

the Association for Molecular Pathology (2015 ACMG/AMP) guidelines.11 METHODS GNOMAD POPULATION DATABASE Data for the _DDC_ gene were acquired from gnomAD (v2.1.1)

(https://gnomad.broadinstitute.org/). We analyzed 125,748 exomes, of which 9197 were East Asian, 8128 were African/African-American, 17,296 were Latino/Admixed American, 5040 were Ashkenazi

Jewish, 10,824 were Finnish, 56,885 were Non-Finnish European, 15,308 were South Asian and 3070 were other populations. Among the 9197 East Asian exomes, 1909 were Korean, 76 were Japanese,

and 7212 were other East Asians. The filtered variants that were flagged in gnomAD as failing “InbreedingCoeff,” “AC0,” or “RF” QC filters were excluded from the analysis. _DDC_ VARIANT

CLASSIFICATION AND STATISTICAL ANALYSIS All _DDC_ variants were interpreted using 2015 ACMG/AMP guidelines and Sequence Variant Interpretation general recommendations for ACMG/AMP Criteria

by ClinGen (https://clinicalgenome.org/working-groups/sequence-variant-interpretation/, accessed on June 15, 2022). The 2015 ACMG/AMP guidelines recommend the classification of variants into

five categories: pathogenic variants (PV), likely pathogenic variants (LPV), variants of uncertain significance, likely benign variants, and benign variants. REVEL12 and SpliceAI13 were

used to predict variant pathogenicity. All _DDC_ variants identified in gnomAD were compared with previously classified disease-causing variants from ClinVar, the Human Gene Mutation

Database (HGMD), and the Locus-Specific Database of Gene Variants Causing BH4 Deficiencies and related pediatric neurotransmitter disease (PNDdb), which are representative disease databases,

to identify overlap. ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/, accessed on June 20, 2022) is a freely available archive that provides a classification of variants interpreted by

clinical laboratories. The HGMD professional database (http://www.hgmd.org/, release 2022.01) is a comprehensive collection of germline variants categorized into six categories, of which we

analyzed only disease-causing mutations (DM). The PNDdb (http://www.biopku.org/pnddb/home.asp, accessed on May 9, 2023) is a disease database specifically focused on pediatric

neurotransmitter diseases-associated variants. Among the variants enrolled in the PNDdb, we included only those that were interpreted as PV or LPV by Himmelreich et al.14 AADC DEFICIENCY

CARRIER FREQUENCY AND INCIDENCE ESTIMATION AADC deficiency carrier frequencies were calculated for the _DDC_ gene using gnomAD. We used variants classified as PV and LPV according to the

2015 ACMG-AMP guideline interpretation, the DM in HGMD, and those classified as PV and LPV in ClinVar for carrier frequency analysis. We then estimated the incidence of AADC deficiency based

on the frequency and the Hardy–Weinberg equilibrium principle (1 = _p_2 + 2_pq_ + _q_2), in which the major allele is _p_ (non-disease), the minor allele is _q_ (disease), the major allele

_p_ is assumed to be approximately 1. 2_pq_ and represents the carrier, and _q_2 represents the disease. By calculating the _q_ value based on the carrier frequency obtained from gnomAD, the

estimated disease incidence _q_2 was predicted. MedCalc ver. 11.5.1.0 (MedCalc Software, Maiakerke, Belgium) was used for statistical analysis, and 95% confidence intervals were calculated

for each value. This study was approved by the Institutional Review Board of Hanyang University Guri Hospital (2021-06-029) and conducted in accordance with the Declaration of Helsinki.

RESULTS We analyzed 125,748 exomes including 9197 East Asian exomes in gnomAD for _DDC_ gene variants. The variants were classified according to the 2015 ACMG/AMP guidelines and three

disease classification databases, ClinVar, HGMD, and PNDdb (Table 1). According to the 2015 ACMG/AMP guidelines, the worldwide carrier frequency of AADC deficiency was 0.17%; the highest

carrier frequency of AADC deficiency was in East Asians at 0.78%, and the lowest was in Latinos at 0.07%. The estimated incidence of AADC deficiency was 1 in 1,374,129 worldwide and 1 in

65,266 in East Asians. Based on ClinVar, the carrier frequency was 0.09% worldwide and 0.72% in East Asians. The estimated incidences were 1 in 4,953,421 worldwide and l in 77,672 for East

Asians. Based on HGMD, the carrier frequency was 0.75% worldwide and 0.75% in East Asians; the estimated incidence values were 1 in 71,582 worldwide and 1 in 71,065 for East Asians. Based on

PNDdb, the carrier frequency was 0.15% worldwide and 0.77% in East Asians. The estimated incidences were 1 in 1,715,800 worldwide and 1 in 67,117 for East Asians. Among East Asian

populations, the carrier frequency of AADC deficiency in Koreans was 0.16% and the carrier frequency in other East Asian populations was 0.96% according to 2015 ACMG/AMP guidelines

(Supplementary Table 1). The estimated incidences were 1 in 1,619,680 for Koreans and 1 in 43,699 for other East Asians. PVs/LPVs in _DDC_ found in gnomAD are summarized in Table 2. The

c.714+4A>T variant (61 alleles) was most common worldwide and was identified only in East Asians. The next most common variants were c.367G>C, p.(Gly123Arg) (15 alleles) and

c.1040G>A, p.(Arg347Gln) (12 alleles); these variants were found in several ethnicities but not in East Asians. We compared the PVs/LPVs found in East Asians with those in other

ethnicities and found that PVs/LPVs identified in East Asians were not detected in other ethnicities except for Africans and Europeans (non-Finnish). Evaluations of PVs/LPVs among East

Asians showed that the variants found in Koreans were unique to Koreans and not found in other East Asians (Supplementary Table 2). DISCUSSION In this study, the carrier frequency and

estimated incidence of AADC deficiency were analyzed using gnomAD. The overall carrier frequency of AADC deficiency worldwide was 0.17% and the carrier frequency of East Asians was 0.78%.

Latinos had the lowest carrier frequency at 0.07%. Carrier frequency studies of AACD deficiency are rare and difficult to compare. The global carrier frequency (0.17%) in gnomAD was lower

than that of the IVS6+4A>T variant carrier frequency (0.68%) in the study by Chien et al., but the East Asian carrier frequency (0.78%) was similar or higher than the previous study.5 In

a comparison of the carrier frequency of other East Asians (0.96%), who are presumed to be of similar ethnicity to those of the Chien et al. study, the carrier frequency reported in this

study was much higher than that in the previous study. The carrier frequency of Koreans (0.16%) was lower than that of other East Asians, and it was similar to the global carrier frequency.

In the case of Japanese, it was difficult to accurately predict the carrier frequency because there were few Japanese exomes in gnomAD. In 2021, the ACMG published a practice resource

related to screening for autosomal recessive and X-linked conditions during pregnancy and preconception.15 In this practice tool, the conditions are differentiated from Tier 1 to Tier 4

according to the carrier frequency, and a gene list for each tier is proposed. The ACMG recommends all pregnant patients and those planning a pregnancy should be offered Tier 3 (carrier

frequency ≥1/200) carrier screening. In this recommendation, AADC deficiency is not included in the genes to be screened. However, according to this study, the global carrier frequency is

0.17%, while that in East Asians is 0.78%. Since the carrier frequency in other East Asians is as high as 0.96%, it is necessary to include AADC as a screening gene in East Asians. In this

study, the approximate incidence of AADC deficiency was estimated by calculating the Hardy–Weinberg equation. The estimated incidence of AACD deficiency was predicted to be 1/1,394,129 (0.07

per 100,000) worldwide and 1/65,266 (1.53 per 100,000) in East Asians. The worldwide estimated incidence of AACD deficiency was quite low compared to those reported in previous studies.

Although the prediction method is different for each study, in the study predicting incidence using newborn screening, the incidence rate in Taiwan was 1:32,000 and in the US was

1:64,000.5,6 According to data from the Korean Statistical Information Service (http://kosis.kr/; accessed on August 23, 2022), the total population of Korea in 2022 was 51.8 million with

272,337 births. Based on the carrier frequency in this study, the number of carriers is estimated to be 83,000 with 436 in newborns per year. The estimated incidence of AADC deficiency in

Korea based on the Hardy–Weinberg equilibrium is approximately 0.17 cases per year. The PVs/LPVs identified in this study were found to show different spectra of variation between

ethnicities. This phenomenon was particularly noticeable in East Asians. The c.714+4A>T variant was the most common variant worldwide, but it was only found in East Asians and not in

other ethnicities. The next most common variants worldwide were c.367G>C, p.(Gly123Arg) and c.1040G>A, p.(Arg347Gln); these variants were found in all ethnicities except East Asians.

Even among East Asians, Koreans exhibited different characteristics from other East Asians. The c.714+4A>T variant, which is the most common among East Asians, was not identified at all

in 1909 Korean exomes in gnomAD. In addition, the c.714+4A>T variant was not found in the Korean Reference Genome Database (http://152.99.75.168:9090/KRGDB/menuPages/introKor.jsp,

accessed on June 25, 2022), a genome database including 1722 Koreans. In addition, the Korean PV/LPV variants identified in gnomAD was the only variant that had not been reported in other

East Asians. These data suggest that Koreans, although in the East Asian region, have different genetic characteristics compared with other East Asian populations. Variants found in

Taiwanese AADC deficiency patients, in one of the largest studies of AADC deficiency patients,16 were compared with the East Asian variants identified in gnomAD. In patients with AADC

deficiency in Taiwan, variants were identified in the order of c.714+4A>T, c.1297dup, p.(Ile433AsnfsTer60), and c.1234C>T, p.(Arg412Trp), and these were commonly found in East Asian in

gnomAD in the same order. The results of this study indicate that carrier prediction through gnomAD is helpful in predicting the genetic spectrum of an actual patient. This study has

several limitations. We did not evaluate structural variations, including large deletions/insertions of the _DDC_ gene. To the best of our knowledge, only one case of AADC deficiency due to

a structural mutation in the _DDC_ gene has been reported so far.17 Second, according to the consensus guideline for the diagnosis and treatment of AADC deficiency, at least two of the

following three core diagnostic tests must be positive for AADC deficiency diagnosis: (1) low cerebrospinal fluid (CSF) levels of 5-HIAA, HVA, and MHPG, increased CSF levels of 3-OMD, L-Dopa

and 5-HTP, and normal CSF pterins, (2) compound heterozygous or homozygous PVs in the _DDC_ gene, and (3) decreased AADC enzyme activity in plasma.18 However, since this study predicted the

estimated incidence based only on genetic information, there is a possibility that the estimated incidence may be inaccurate. Nevertheless, this study identified significant results. This

study confirmed the carrier frequency and estimated incidence of AADC deficiency for all ethnicities. This study also reconfirmed that AADC deficiency is most common in East Asians, as shown

in patient cohort studies. In addition, this study confirmed that the variants identified in the patient cohort were similarly retained as carriers in the general population. With the

recent development of treatments for AADC deficiency, it will be particularly important to know the carrier frequency and incidence. CONCLUSION This study is the first to identify carrier

frequencies in East Asians, including subpopulations of East Asians, using gnomAD. Our findings confirmed that East Asians have a higher carrier frequency than other ethnic groups, and

Koreans have lower carrier frequencies than other East Asians, similar to the global carrier frequency. The variant spectrum of _DDC_ genes in East Asian and Korean populations differed

greatly from those of other ethnic groups. Our data may serve as a reference for further investigation of AADC deficiency. DATA AVAILABILITY All data are available by the corresponding

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Rare Dis._ 12, 12 (2017). Article  PubMed  PubMed Central  Google Scholar  Download references ACKNOWLEDGEMENTS The authors are grateful to those responsible for creating and maintaining

gnomAD, ClinVar, and HGMD database. FUNDING This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of

Education (NRF-2021R1I1A1A01049183) and the research fund of Hanyang University (HY-202300000001152). AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Laboratory Medicine, Hanyang

University Guri Hospital, Hanyang University College of Medicine, Guri, Republic of Korea Jong Eun Park * GC Genome, Yongin, Republic of Korea Taeheon Lee, Kyeongsu Ha & Chang-Seok Ki *

Department of Laboratory Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea Eun Hye Cho Authors * Jong Eun Park View author

publications You can also search for this author inPubMed Google Scholar * Taeheon Lee View author publications You can also search for this author inPubMed Google Scholar * Kyeongsu Ha View

author publications You can also search for this author inPubMed Google Scholar * Eun Hye Cho View author publications You can also search for this author inPubMed Google Scholar *

Chang-Seok Ki View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS J.E.P. participated in the analysis and interpretation of the data and the

drafting of the manuscript. E.H.C. participated in the analysis and interpretation of the data. T.L. and K.H. participated in the acquisition and analysis of data. C.-S.K. and J.E.P.

participated in the study concept and design, the drafting of the manuscript, and important intellectual content. CORRESPONDING AUTHOR Correspondence to Jong Eun Park. ETHICS DECLARATIONS

COMPETING INTERESTS The authors declare no competing interests. ETHICS APPROVAL This study was approved by the Institutional Review Board of Hanyang University Guri Hospital (2021-06-029)

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incidence of aromatic L-amino acid decarboxylase deficiency: a gnomAD-based study. _Pediatr Res_ 94, 1764–1770 (2023). https://doi.org/10.1038/s41390-023-02685-0 Download citation *

Received: 04 April 2023 * Revised: 14 May 2023 * Accepted: 21 May 2023 * Published: 07 June 2023 * Issue Date: November 2023 * DOI: https://doi.org/10.1038/s41390-023-02685-0 SHARE THIS

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