Spectrum analysis of inborn errors of metabolism for expanded newborn screening in a northwestern Chinese population

Zhang, Ruixue; Qiang, Rong; Song, ChengRong; Ma, Xiaoping; Zhang, Yan; Li, Fengxia; Wang, Rui; Yu, Wenbin; Feng, Mengyu; Yang, Long-Hao; Wang, Xiaobin; Cai, Na

doi:10.1038/s41598-021-81897-y

Cited by 33 publications

(31 citation statements)

References 35 publications

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“…The incidence of GA1 in the selected southern Chinese population was about 1 in 47,044 births, which is comparable to other studied populations [15,16]. Comparing with the incidence reported in different regions of China, the local incidence is higher that reported in Zhejiang province (1:64,708) and Jiangsu province (1:89,335) in southern China [17,18], and Xi'an city (1:73,076) in northern China [19].…”

Section: Discussionsupporting

confidence: 67%

Glutaric Acidemia type 1 with Atypical Acylcarnitine Profile During Newborn Screening

Lin¹,

Wang²,

Cai³

et al. 2021

Preprint

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Background and aims Glutaric acidemia type 1 (GA1) is a treatable disorder of cerebral organic acid metabolism caused by a defective glutaryl-CoA dehydrogenase (GCDH) gene. There is scarcity of reports of GA1 diagnoses following newborn screening (NBS) in the Chinese population. We assessed the acylcarnitine profiles and genetic characteristics of patients with GA1 identified via NBS.Materials and methods From January 2014 to September 2020, a total of 517,484 newborns screened by tandem mass spectrometry were recruited for this study. Newborns with elevated isovalerylcarnitine (C5DC) levels were recalled, those who tested positive on second screen were referred for confirmatory tests.Results Of 517,484 screened newborns, thirteen patients were diagnosed with GA1, including eleven neonatal GA1 and two maternal GA1 patients. The incidence of GA1 in the Quanzhou region was estimated to be 1 in 47,044 newborns. The initial NBS results showed that all but one of the patients had moderately or markedly increased C5DC levels. The neonatal GA1 patient with low free carnitine (C0) level suggestive of primary carnitine deficiency (PCD) while just the contrary to a typical GA1. Nine neonatal GA1 patients underwent urinary organic acid analyses: eight had elevated GA levels and one was reported in the normal range. Ten distinct GCDH variants were identified, eight were previously reported and two were newly identified. In silico prediction tools and protein modelling analysis suggested that the newly identified variants were potentially pathogenic. The most common variant was c.1244-2A > C, which had an allelic frequency of 54.55% (12/22), followed by c.1261G > A (p.Ala421Thr) (9.09%, 2/22). Conclusions GA1 patients may show only with low C0 levels at the initial screening and recall stages that may be overlooked. Maternal GA1 patients can also be detected during NBS duo to the low C0 levels in their infants. Therefore, PCD should be included in the differential diagnosis for GA1, and multigene panel testing should be performed in newborns with low C0 levels.

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Section: Discussionsupporting

confidence: 67%

Glutaric Acidemia type 1 with Atypical Acylcarnitine Profile During Newborn Screening

Lin¹,

Wang²,

Cai³

et al. 2021

Preprint

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“…The incidence of GA1 in the selected southern Chinese population was approximately 1 in 47,044 births, similar to other studied populations [ 13 , 14 ]. Compared with the incidence reported in other Chinese regions, the local incidence is higher than that reported in the Zhejiang (1:64,708) and Jiangsu (1:89,335) provinces of southern China [ 15 , 16 ] and Xi’an City (1:73,076) in northern China [ 17 ].…”

Section: Discussionmentioning

confidence: 76%

Biochemical and molecular features of Chinese patients with glutaric acidemia type 1 detected through newborn screening

Lin¹,

Wang²,

Cai³

et al. 2021

Orphanet J Rare Dis

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Background Glutaric acidemia type 1 (GA1) is a treatable disorder affecting cerebral organic acid metabolism caused by a defective glutaryl-CoA dehydrogenase (GCDH) gene. GA1 diagnosis reports following newborn screening (NBS) are scarce in the Chinese population. This study aimed to assess the acylcarnitine profiles and genetic characteristics of patients with GA1 identified through NBS. Results From January 2014 to September 2020, 517,484 newborns were screened by tandem mass spectrometry, 102 newborns with elevated glutarylcarnitine (C5DC) levels were called back. Thirteen patients were diagnosed with GA1, including 11 neonatal GA1 and two maternal GA1 patients. The incidence of GA1 in the Quanzhou region was estimated at 1 in 47,044 newborns. The initial NBS results showed that all but one of the patients had moderate to markedly increased C5DC levels. Notably, one neonatal patient with low free carnitine (C0) level suggest primary carnitine deficiency (PCD) but was ultimately diagnosed as GA1. Nine neonatal GA1 patients underwent urinary organic acid analyses: eight had elevated GA and 3HGA levels, and one was reported to be within the normal range. Ten distinct GCDH variants were identified. Eight were previously reported, and two were newly identified. In silico prediction tools and protein modeling analyses suggested that the newly identified variants were potentially pathogenic. The most common variant was c.1244-2 A>C, which had an allelic frequency of 54.55% (12/22), followed by c.1261G>A (p.Ala421Thr) at 9.09% (2/22). Conclusions Neonatal GA1 patients with increased C5DC levels can be identified through NBS. Maternal GA1 patients can also be detected using NBS due to the low C0 levels in their infants. Few neonatal GA1 patients may have atypical acylcarnitine profiles that are easy to miss during NBS; therefore, multigene panel testing should be performed in newborns with low C0 levels. This study indicates that the GCDH variant spectra were heterogeneous in this southern Chinese cohort.

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“…NBS for PCD has been successfully implemented in most parts of China, patients usually had better prognosis following early L-carnitine therapy. The incidence of PCD varies greatly throughout China, ranging from 1:8,938 to 1:48,717 [13][14][15].…”

Section: Discussionmentioning

confidence: 99%

“…By contrast, our data revealed that c.760C>T (p.R254*) was the most common variant in this cohort of patients, and its allele frequency was almost equal to the sum of the other two variants. c.760C>T (p.R254*) is a loss-of-function variant that can cause severe clinical symptoms, it was common in southern China but was rarely detected in northern China[14,22,[24][25][26], indicating this variant presented different geographic distribution. Whereas c.1400C>G (p.S467C) with residual function may result in a milder phenotype, it was common in both southern and northern China[14,22,24, 26], suggesting this variant was common in the general Chinese population.Regarding the relationship between genotype and biochemical phenotype, signi cant difference was observed in C0 levels between patients with N/N and M/M genotypes, and most patients with N/N genotype had low C0 levels compared to the N/M group, indicating patients with null variants were associated with low C0 levels.…”

mentioning

confidence: 99%

Biochemical And Genetic Characteristics of Patients With Primary Carnitine Deficiency Identified Through Newborn Screening

Lin

Chen

et al. 2021

Preprint

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Background: Primary carnitine deficiency (PCD) is an autosomal recessive disorder of the carnitine transportation that leads to impaired fatty acid oxidation. Large-scale studies on newborn screening (NBS) for PCD are limited. This study aimed to investigate the biochemical and genetic characteristics of patients with PCD detected by NBS.Results: A total of 548,247 newborns were screened for PCD between January 2014 and June 2021, 1714 newborns had low free carnitine (C0) levels were called back and forty-nine patients were diagnosed with PCD. The latest incidence rate in Quanzhou, China was estimated to be 1 in 11,189 newborns. NBS results showed that all patients had varying degrees of decreased C0 levels, while seven patients exhibited normal C0 levels during recall review. All patients harbored biallelic pathogenic variants in the SLC22A5 gene. Nineteen distinct SLC22A5 variants were detected in the 49 patients, most of the detected variants were clustered in exons 1, 4, and 7. The top eight variants together had an allele frequency of 86.73%. The most common variant was c.760C>T (p.R254*) with an allele frequency of 31.63%, followed by c.51C>G (p.F17L) (17.35%) and c.1400C>G (p.S467C) (16.33%). The C0 level of patients with N/N genotype was significantly lower than that of M/M group. The C0 level of patients with genotypes of R254*/R254* and R254*/F17L were far lower than patients with genotype of R254*/S467C.Conclusions: This study presented more than 500,000 NBS data with the latest incidence of 1:11,189 in Quanzhou area. The SLC22A5 variant spectrum in the selected southern Chinese population was updated. Patients with null variants were associated with low C0 levels. It is necessary to combine genetic testing to improve screening efficiency due to PCD patients may have normal C0 levels during NBS and recall review.

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Spectrum analysis of inborn errors of metabolism for expanded newborn screening in a northwestern Chinese population

Cited by 33 publications

References 35 publications

Glutaric Acidemia type 1 with Atypical Acylcarnitine Profile During Newborn Screening

Glutaric Acidemia type 1 with Atypical Acylcarnitine Profile During Newborn Screening

Biochemical and molecular features of Chinese patients with glutaric acidemia type 1 detected through newborn screening

Biochemical And Genetic Characteristics of Patients With Primary Carnitine Deficiency Identified Through Newborn Screening

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