Estimating carrier frequencies of newborn screening disorders using a whole-genome reference panel of 3552 Japanese individuals

Yamaguchi-Kabata, Yumi; Yasuda, Jun; Uruno, Akira; Shimokawa, Kuniyasu; Koshiba, S.; Suzuki, Yôichi; Fuse, Nobuo; Kawame, Hiroshi; Tadaka, Shu; Nagasaki, Masao; Kojima, Kazuyuki; Katsuoka, Fumiki; Kumada, Kazuki; Takahashi, Osamu; Tamiya, Gen; Yaegashi, Nobuo; Kinoshita, Kengo; Yamamoto, Masayuki; Kure, Shigeo

doi:10.1007/s00439-019-01998-7

Cited by 8 publications

(10 citation statements)

References 94 publications

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“…The estimated frequency of patients with citrin deficiency is 1/38000-7100 in Asia depending on the carrier frequency of pathogenic SLC25A13 variants ( Kobayashi et al, 2003 ; Tabata et al, 2008 ; Treepongkaruna et al, 2012 ; Lin et al, 2020 ). However, the total frequency of newborn screening with NICCD in our population was 1:82352, similar to the observed prevalence in Japan (1/84,782) ( Yamaguchi-Kabata et al, 2019 ). This indicated that not a few NICCD cases are missed in newborn screening and some of them develop symptoms during infancy.…”

Section: Discussionsupporting

confidence: 87%

Dynamic changes of metabolic characteristics in neonatal intrahepatic cholestasis caused by citrin deficiency

Zhang

Zhu²,

Miao³

et al. 2022

Front. Mol. Biosci.

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Introduction: Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) is a pan-ethnic complicated inborn error of metabolism but the specific mechanism is not fully understood.Methods: A total of 169 patients with NICCD who have biallelic pathogenic SLC25A13 variants detected by targeted next-generation sequencing were collected. They were divided into the “Newborn-screen Group” and “Clinical diagnosed Group” depending on the newborn screening results. Amino acid and acylcarnitine profiles were measured by MS/MS. The total bile acids, blood amino acids and acylcarnitines, general biochemistry, blood count, and coagulation parameters were monitored every 2–3 months. We compared the differences in metabolic indices and their dynamic changes between these two groups. The Mann–Whitney test and orthogonal partial least squares discrimination analysis (OPLS-DA) were used for statistical analysis.Results: At the onset of NICCD, we found that the “Clinical diagnosed Group” had higher levels of intermediate products of the urea cycle, free carnitine, and short-chain and long-chain acylcarnitines than those in the “Newborn-screen Group,” but the levels of ketogenic/glucogenic amino acids and several medium-chain acylcarnitines were lower. Furthermore, concentrations of direct bilirubin, total bile acid, lactate, prothrombin time, and several liver enzymes were significantly higher while total protein, amylase, and hemoglobin were lower in the “Clinical diagnosed Group” than in the “Newborn-screen Group.” Dynamic change analysis showed that direct bilirubin, albumin, arginine, and citrulline were the earliest metabolic derangements to reach peak levels in NICCD groups, followed by acylcarnitine profiles, and finally with the elevation of liver enzymes. All abnormal characteristic metabolic indicators in the “Newborn-screen Group” came back to normal levels at earlier ages than the “Clinical diagnosed Group.” c.852_855del (41.2%), IVS16ins3kb (17.6%), c.615 + 5G>A (9.6%), 1638_1660dup (4.4%), and c.1177 + 1G>A (3.7%) accounted for 76.5% of all the mutated SLC25A13 alleles in our population.Conclusion: Argininosuccinate synthesis, gluconeogenesis, ketogenesis, fatty acid oxidation, liver function, and cholestasis were more severely affected in the “Clinical diagnosed Group.” The “Newborn-screen Group” had a better prognosis which highlighted the importance of newborn screening of NICCD.

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Section: Discussionsupporting

confidence: 87%

Dynamic changes of metabolic characteristics in neonatal intrahepatic cholestasis caused by citrin deficiency

Zhang

Zhu²,

Miao³

et al. 2022

Front. Mol. Biosci.

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“…The accumulation of more NGS data leads to increased numbers of variants of unknown significance, and many of those variants are very rare and sometimes unique to each individual [ 12 ]. Recently, carrier frequencies of 11 recessive newborn screening diseases were estimated using Japanese whole genome reference panels, and the actual carrier frequencies of some diseases were found to depart from the calculated carrier frequencies based on the disease incidence rates [ 13 ]. This departure may be due to inaccurate estimation of the functional effect of variants or to inaccurate diagnosis [ 13 ].…”

Section: Discussionmentioning

confidence: 99%

“…Recently, carrier frequencies of 11 recessive newborn screening diseases were estimated using Japanese whole genome reference panels, and the actual carrier frequencies of some diseases were found to depart from the calculated carrier frequencies based on the disease incidence rates [ 13 ]. This departure may be due to inaccurate estimation of the functional effect of variants or to inaccurate diagnosis [ 13 ]. Accumulation of genotype data with accurate phenotyping, including those of “healthy” or “asymptomatic” individuals in various ethnic populations, will improve the genetic diagnosis for GS patients.…”

Section: Discussionmentioning

confidence: 99%

“… a The allele frequencies of the variants in the Japanese population were from those of the Japanese Multi Omics Reference Panel (3.5KJPNv2), Tohoku University ( https://jmorp.megabank.tohoku.ac.jp ) [ 13 ]. b The allele frequencies of the variants in the Japanese GS patients were from the study by Fujimura et al [ 11 ].…”

Section: Figmentioning

confidence: 99%

Section: Figmentioning

confidence: 99%

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A Family with Gitelman Syndrome with Asymptomatic Phenotypes while Carrying Reported SLC12A3 Mutations

Ishikawa

Tada

Tanaka

et al. 2020

Case Rep Nephrol Dial

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Gitelman syndrome (GS) is an autosomal recessive disorder characterized by alkalosis, hypokalemia, and hypomagnesemia. Although hundreds of genetic variants associated with GS have been reported, many of them are categorized as of uncertain significance in ClinVar. Here, we describe a pediatric GS patient from a three-generation family whose mother and maternal grandmother were asymptomatic. The proband was a 16-year-old Japanese girl with muscle weakness and continuous hypokalemic metabolic alkalosis. The patient, her mother, and her maternal grandmother were compound heterozygous for, and each expressing a different combination of, previously reported SLC12A3 variants in GS patients. The mother and the

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Challenges for the implementation of next generation sequencing-based expanded carrier screening: Lessons learned from the ciliopathies

et al. 2022

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Next generation sequencing (NGS) can detect carrier status for rare recessive disorders, informing couples about their reproductive risk. The recent ACMG recommendations support offering NGS-based carrier screening (NGS-CS) in an ethnic and population-neutral manner for all genes that have a carrier frequency >1/200 (based on GnomAD). To evaluate current challenges for NGS-CS, we focused on the ciliopathies, a well-studied group of rare recessive disorders. We analyzed 118 ciliopathy genes by whole exome sequencing in ~400 healthy local individuals and ~1000 individuals from the UK1958-birth cohort. We found 20% of healthy individuals (1% of couples) to be carriers of reportable variants in a ciliopathy gene, while 50% (4% of couples) carry variants of uncertain significance (VUS). This large proportion of VUS is partly explained by the limited utility of the ACMG/AMP variant-interpretation criteria in healthy individuals, where phenotypic match or segregation criteria cannot be used. Most missense variants are thus classified as VUS and not reported, which reduces the negative predictive value of the screening test. We show how gene-specific variation patterns and structural protein information can help prioritize variants most likely to be disease-causing, for (future) functional assays. Even when considering only strictly pathogenic variants, the observed carrier frequency is substantially higher than expected based on estimated disease prevalence, challenging the 1/200 carrier frequency cut-off proposed for choice of genes to screen. Given the challenges linked to variant interpretation in healthy individuals and the uncertainties about true carrier frequencies, genetic counseling must clearly disclose these limitations of NGS-CS.

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Estimating carrier frequencies of newborn screening disorders using a whole-genome reference panel of 3552 Japanese individuals

Cited by 8 publications

References 94 publications

Dynamic changes of metabolic characteristics in neonatal intrahepatic cholestasis caused by citrin deficiency

Dynamic changes of metabolic characteristics in neonatal intrahepatic cholestasis caused by citrin deficiency

A Family with Gitelman Syndrome with Asymptomatic Phenotypes while Carrying Reported SLC12A3 Mutations

Challenges for the implementation of next generation sequencing-based expanded carrier screening: Lessons learned from the ciliopathies

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