Carrier frequency and incidence of aromatic L-amino acid decarboxylase deficiency: a gnomAD-based study.

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.

Carrier frequency and incidence of alpha-mannosidosis: population database-based study-focus on the East Asian and Korean population.

Background: Alpha-mannosidosis caused by mutations in the MAN2B1 gene is a rare genetic disorder characterized by physical abnormalities and intellectual disabilities. The objective of this study was to analyze the carrier frequency and estimated incidence of alpha-mannosidosis in East Asian populations, as limited data exists on its incidence in this group. Methods: In this study, a total of 125,748 exomes from the gnomAD database was analyzed. Additionally, 5,305 data from the KOVA and 1,722 data from the KRGDB, both representing Korean populations, were included. Results: The global carrier frequency of alpha-mannosidosis in gnomAD was 0.23%; the highest carrier frequency was observed in the Finnish at 0.49%, and East Asians had the second highest carrier frequency at 0.30%. Globally, the approximate incidence of alpha-mannosidosis was calculated at 1 in 784,535, l in 166,801 Europeans (Finnish), and l in 431,689 East Asians. By integrating the data from the 8,936 Koreans in gnomAD Korean, KOVA and KRGDB, the carrier frequency of alpha-mannosidosis in the Korean population was 0.04% and estimated incidence was 1 in 19,963,024. Conclusion: This study is the first to investigate the carrier frequencies of alpha-mannosidosis in East Asians and Koreans, including specific subpopulations, utilizing gnomAD and the Korean genomic database. The variant spectrum of MAN2B1 genes in East Asians showed significant differences compared to other ethnic groups. Our data provide valuable reference information for future investigations into alpha-mannosidosis, aiding in understanding the genetic diversity and specific variants associated with the condition in East Asian populations.

Carrier frequency and incidence estimation of RPE65-associated inherited retinal diseases in East Asian population by population database-based analysis.

BACKGROUND: Inherited retinal diseases (IRDs) are clinically and genetically heterogenous disorders leading to visual impairment and blindness. Because gene therapy for RPE65-associated IRDs was recently approved, it is necessary to predict the carrier frequency and prevalence for RPE65-associated IRDs. This study aimed to analyze the carrier frequency and expected incidence of RPE65-associated IRDs in East Asians and Koreans using exome data from the Genome Aggregation Database (gnomAD) and the Korean Reference Genome Database (KRGDB). METHODS: We analyzed 9,197 exomes for East Asian populations from gnomAD comprising 1,909 Korean and 1,722 Korean genomes from KRGDB. All identified RPE65 variants were classified according to the 2015 American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines. RESULTS: The total carrier frequencies of East Asians and Koreans from both gnomAD and KRGDB were 0.10% (11/10,919) and 0.06% (2/3,631), respectively. The estimated incidence of RPE65-associated IRDs was 1/3,941,308 in East Asians and 1/13,184,161 in Koreans. CONCLUSION: This study identified carrier frequencies of RPE65-associated IRDs in East Asians and Koreans using gnomAD and KRGDB. We confirmed that the carrier frequency of RPE65-associated IRDs patients was low in Koreans among all East Asian populations, and the incidence was also predicted to be lower than in other East Asian populations. The variant spectrum of RPE65 gene in East Asian and Korean populations differed greatly from those of other ethnic groups.

Carrier frequency and incidence estimation of familial hemophagocytic lymphohistiocytosis in East Asian populations by genome aggregation database (gnomAD) based analysis.

Objectives: Hemophagocytic lymphohistiocytosis (HLH) is a clinical syndrome characterized by a life-threatening condition caused by severe hypercytokinemia. The hereditary forms of HLH, also called familial HLH (fHLH), have 4 different genes (PRF1, UNC13D, STX11, and STXBP2) and have been identified as being causative for fHLH. This study aimed to analyze the carrier frequency and expected incidence of fHLH in East Asians and Koreans using exome data from the Genome Aggregation Database (gnomAD). Methods: We analyzed 9,197 exomes for East Asian populations from gnomAD with 1,909 Korean for four fHLH genes. All identified variants were classified according to 2015 American College of Medical Genetics and Genomics and the Association for Molecular Pathology guideline. Results: 19 pathogenic variant/likely pathogenic variants (PV/LPVs) were identified in 30 East Asian individuals (0.33%). Among them, 7 PV/LPVs were identified in 17 Korean individuals (0.63%). The estimated incidence of fHLH was 1 in 1,105,652 for East Asians and l in 235,128 for Koreans. Conclusions: This study is the first to identify carrier frequencies in East Asian and Korean populations for fHLH using gnomAD. It was confirmed that the carrier frequency of fHLH patients was high in Koreans among East Asians and the incidence was also predicted to be higher than that of other East Asians. The variant spectrum of fHLH genes in East Asian and Korean populations differed greatly from those of other ethnic groups.

Carrier frequency and incidence estimation of Smith-Lemli-Opitz syndrome in East Asian populations by Genome Aggregation Database (gnomAD) based analysis.

BACKGROUND: Smith-Lemli-Opitz syndrome (SLOS) is an autosomal, recessively inherited congenital malformation syndrome characterized by multiple congenital anomalies such as microcephaly with mental defects, distinctive facial features, genital abnormalities, and 2-3 syndactyly of the toes. SLOS is caused by defective 7-dehydrocholesterol reductase, which is encoded by the DHCR7 gene. This study aimed to analyze the carrier frequency and expected incidence of SLOS in East Asians and Koreans using exome data from the Genome Aggregation Database (gnomAD) through the 2015 American College of Medical Genetics and Genomics and the Association for Molecular Pathology guideline (2015 ACMG-AMP guideline). METHODS: We analyzed 9197 exomes for East Asian populations from gnomAD, comprising 1909 Korean, 76 Japanese, and 7212 other East Asian populations. All identified variants were classified according to the 2015 ACMG-AMP guideline. RESULTS: According to the 2015 ACMG-AMP guideline, 15 pathogenic variant/likely pathogenic variant (PV/LPV) cases were identified in 33 East Asian individuals (33/9191 = 0.4%). Among them, four PVs/LPVs were identified in 19 Korean individuals (19/1909 = 1.0%). The predicted incidence, based upon the carrier rates of PV/LPV of DHCR7 alleles, is 1 in 310,688 in East Asians and l in 40,380 in Koreans. CONCLUSIONS: This study is the first to identify carrier frequencies in East Asians and Koreans using gnomAD. It was confirmed that East Asians (0.4%) had a lower carrier frequency than did other ethnicities (1-3%) and Koreans (1.0%) had similar or lower carrier frequencies than other ethnicities. The variant spectrums of DHCR7 in East Asian and Korean populations differed greatly from those of other ethnic groups.