Identification of deep intronic variants of PAH in phenylketonuria using full-length gene sequencing

Background Phenylketonuria (PKU) is an autosomal recessive congenital metabolic disorder caused by PAH variants. Previously, approximately 5% of PKU patients remained undiagnosed after Sanger sequencing and multiplex ligation-dependent probe amplification. To date, increasing numbers of pathogenic d...
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Autor*in:	Zhang, Chuan [verfasserIn] Yan, Yousheng Zhou, Bingbo Wang, Yupei Tian, Xinyuan Hao, Shengju Ma, Panpan Zheng, Lei Zhang, Qinghua Hui, Ling Wang, Yan Cao, Zongfu Ma, Xu

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2023

Schlagwörter:	PKU Deep intronic variant RNA splicing Minigene

Anmerkung:	© The Author(s) 2023

Übergeordnetes Werk:	Enthalten in: Orphanet journal of rare diseases - London : BioMed Central, 2006, 18(2023), 1 vom: 26. Mai
Übergeordnetes Werk:	volume:18 ; year:2023 ; number:1 ; day:26 ; month:05

Links:	Volltext

DOI / URN:	10.1186/s13023-023-02742-1

Katalog-ID:	SPR051659700

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520			\|a Background Phenylketonuria (PKU) is an autosomal recessive congenital metabolic disorder caused by PAH variants. Previously, approximately 5% of PKU patients remained undiagnosed after Sanger sequencing and multiplex ligation-dependent probe amplification. To date, increasing numbers of pathogenic deep intronic variants have been reported in more than 100 disease-associated genes. Methods In this study, we performed full-length sequencing of PAH to investigate the deep intronic variants in PAH of PKU patients without definite genetic diagnosis. Results We identified five deep intronic variants (c.1199+502A>T, c.1065+241C>A, c.706+368T>C, c.706+531>C, and c.706+608A>C). Of these, the c.1199+502A>T variant was found at high frequency and may be a hotspot PAH variant in Chinese PKU. c.706+531T>C and c.706+608A>C are two novel variants that extend the deep intronic variant spectrum of PAH. Conclusion Deep intronic variant pathogenicity analysis can further improve the genetic diagnosis of PKU patients. In silico prediction and minigene analysis are powerful approaches for studying the functions and effects of deep intronic variants. Targeted sequencing after full-length gene amplification is an economical and effective tool for the detection of deep intron variation in genes with small fragments.
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allfields	10.1186/s13023-023-02742-1 doi (DE-627)SPR051659700 (SPR)s13023-023-02742-1-e DE-627 ger DE-627 rakwb eng Zhang, Chuan verfasserin aut Identification of deep intronic variants of PAH in phenylketonuria using full-length gene sequencing 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2023 Background Phenylketonuria (PKU) is an autosomal recessive congenital metabolic disorder caused by PAH variants. Previously, approximately 5% of PKU patients remained undiagnosed after Sanger sequencing and multiplex ligation-dependent probe amplification. To date, increasing numbers of pathogenic deep intronic variants have been reported in more than 100 disease-associated genes. Methods In this study, we performed full-length sequencing of PAH to investigate the deep intronic variants in PAH of PKU patients without definite genetic diagnosis. Results We identified five deep intronic variants (c.1199+502A>T, c.1065+241C>A, c.706+368T>C, c.706+531>C, and c.706+608A>C). Of these, the c.1199+502A>T variant was found at high frequency and may be a hotspot PAH variant in Chinese PKU. c.706+531T>C and c.706+608A>C are two novel variants that extend the deep intronic variant spectrum of PAH. Conclusion Deep intronic variant pathogenicity analysis can further improve the genetic diagnosis of PKU patients. In silico prediction and minigene analysis are powerful approaches for studying the functions and effects of deep intronic variants. Targeted sequencing after full-length gene amplification is an economical and effective tool for the detection of deep intron variation in genes with small fragments. PKU (dpeaa)DE-He213 Deep intronic variant (dpeaa)DE-He213 RNA splicing (dpeaa)DE-He213 Minigene (dpeaa)DE-He213 Yan, Yousheng aut Zhou, Bingbo aut Wang, Yupei aut Tian, Xinyuan aut Hao, Shengju aut Ma, Panpan aut Zheng, Lei aut Zhang, Qinghua aut Hui, Ling aut Wang, Yan aut Cao, Zongfu (orcid)0000-0002-9707-8765 aut Ma, Xu aut Enthalten in Orphanet journal of rare diseases London : BioMed Central, 2006 18(2023), 1 vom: 26. Mai (DE-627)50900637X (DE-600)2225857-7 1750-1172 nnns volume:18 year:2023 number:1 day:26 month:05 https://dx.doi.org/10.1186/s13023-023-02742-1 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 18 2023 1 26 05
spelling	10.1186/s13023-023-02742-1 doi (DE-627)SPR051659700 (SPR)s13023-023-02742-1-e DE-627 ger DE-627 rakwb eng Zhang, Chuan verfasserin aut Identification of deep intronic variants of PAH in phenylketonuria using full-length gene sequencing 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2023 Background Phenylketonuria (PKU) is an autosomal recessive congenital metabolic disorder caused by PAH variants. Previously, approximately 5% of PKU patients remained undiagnosed after Sanger sequencing and multiplex ligation-dependent probe amplification. To date, increasing numbers of pathogenic deep intronic variants have been reported in more than 100 disease-associated genes. Methods In this study, we performed full-length sequencing of PAH to investigate the deep intronic variants in PAH of PKU patients without definite genetic diagnosis. Results We identified five deep intronic variants (c.1199+502A>T, c.1065+241C>A, c.706+368T>C, c.706+531>C, and c.706+608A>C). Of these, the c.1199+502A>T variant was found at high frequency and may be a hotspot PAH variant in Chinese PKU. c.706+531T>C and c.706+608A>C are two novel variants that extend the deep intronic variant spectrum of PAH. Conclusion Deep intronic variant pathogenicity analysis can further improve the genetic diagnosis of PKU patients. In silico prediction and minigene analysis are powerful approaches for studying the functions and effects of deep intronic variants. Targeted sequencing after full-length gene amplification is an economical and effective tool for the detection of deep intron variation in genes with small fragments. PKU (dpeaa)DE-He213 Deep intronic variant (dpeaa)DE-He213 RNA splicing (dpeaa)DE-He213 Minigene (dpeaa)DE-He213 Yan, Yousheng aut Zhou, Bingbo aut Wang, Yupei aut Tian, Xinyuan aut Hao, Shengju aut Ma, Panpan aut Zheng, Lei aut Zhang, Qinghua aut Hui, Ling aut Wang, Yan aut Cao, Zongfu (orcid)0000-0002-9707-8765 aut Ma, Xu aut Enthalten in Orphanet journal of rare diseases London : BioMed Central, 2006 18(2023), 1 vom: 26. Mai (DE-627)50900637X (DE-600)2225857-7 1750-1172 nnns volume:18 year:2023 number:1 day:26 month:05 https://dx.doi.org/10.1186/s13023-023-02742-1 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 18 2023 1 26 05
allfields_unstemmed	10.1186/s13023-023-02742-1 doi (DE-627)SPR051659700 (SPR)s13023-023-02742-1-e DE-627 ger DE-627 rakwb eng Zhang, Chuan verfasserin aut Identification of deep intronic variants of PAH in phenylketonuria using full-length gene sequencing 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2023 Background Phenylketonuria (PKU) is an autosomal recessive congenital metabolic disorder caused by PAH variants. Previously, approximately 5% of PKU patients remained undiagnosed after Sanger sequencing and multiplex ligation-dependent probe amplification. To date, increasing numbers of pathogenic deep intronic variants have been reported in more than 100 disease-associated genes. Methods In this study, we performed full-length sequencing of PAH to investigate the deep intronic variants in PAH of PKU patients without definite genetic diagnosis. Results We identified five deep intronic variants (c.1199+502A>T, c.1065+241C>A, c.706+368T>C, c.706+531>C, and c.706+608A>C). Of these, the c.1199+502A>T variant was found at high frequency and may be a hotspot PAH variant in Chinese PKU. c.706+531T>C and c.706+608A>C are two novel variants that extend the deep intronic variant spectrum of PAH. Conclusion Deep intronic variant pathogenicity analysis can further improve the genetic diagnosis of PKU patients. In silico prediction and minigene analysis are powerful approaches for studying the functions and effects of deep intronic variants. Targeted sequencing after full-length gene amplification is an economical and effective tool for the detection of deep intron variation in genes with small fragments. PKU (dpeaa)DE-He213 Deep intronic variant (dpeaa)DE-He213 RNA splicing (dpeaa)DE-He213 Minigene (dpeaa)DE-He213 Yan, Yousheng aut Zhou, Bingbo aut Wang, Yupei aut Tian, Xinyuan aut Hao, Shengju aut Ma, Panpan aut Zheng, Lei aut Zhang, Qinghua aut Hui, Ling aut Wang, Yan aut Cao, Zongfu (orcid)0000-0002-9707-8765 aut Ma, Xu aut Enthalten in Orphanet journal of rare diseases London : BioMed Central, 2006 18(2023), 1 vom: 26. Mai (DE-627)50900637X (DE-600)2225857-7 1750-1172 nnns volume:18 year:2023 number:1 day:26 month:05 https://dx.doi.org/10.1186/s13023-023-02742-1 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 18 2023 1 26 05
allfieldsGer	10.1186/s13023-023-02742-1 doi (DE-627)SPR051659700 (SPR)s13023-023-02742-1-e DE-627 ger DE-627 rakwb eng Zhang, Chuan verfasserin aut Identification of deep intronic variants of PAH in phenylketonuria using full-length gene sequencing 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2023 Background Phenylketonuria (PKU) is an autosomal recessive congenital metabolic disorder caused by PAH variants. Previously, approximately 5% of PKU patients remained undiagnosed after Sanger sequencing and multiplex ligation-dependent probe amplification. To date, increasing numbers of pathogenic deep intronic variants have been reported in more than 100 disease-associated genes. Methods In this study, we performed full-length sequencing of PAH to investigate the deep intronic variants in PAH of PKU patients without definite genetic diagnosis. Results We identified five deep intronic variants (c.1199+502A>T, c.1065+241C>A, c.706+368T>C, c.706+531>C, and c.706+608A>C). Of these, the c.1199+502A>T variant was found at high frequency and may be a hotspot PAH variant in Chinese PKU. c.706+531T>C and c.706+608A>C are two novel variants that extend the deep intronic variant spectrum of PAH. Conclusion Deep intronic variant pathogenicity analysis can further improve the genetic diagnosis of PKU patients. In silico prediction and minigene analysis are powerful approaches for studying the functions and effects of deep intronic variants. Targeted sequencing after full-length gene amplification is an economical and effective tool for the detection of deep intron variation in genes with small fragments. PKU (dpeaa)DE-He213 Deep intronic variant (dpeaa)DE-He213 RNA splicing (dpeaa)DE-He213 Minigene (dpeaa)DE-He213 Yan, Yousheng aut Zhou, Bingbo aut Wang, Yupei aut Tian, Xinyuan aut Hao, Shengju aut Ma, Panpan aut Zheng, Lei aut Zhang, Qinghua aut Hui, Ling aut Wang, Yan aut Cao, Zongfu (orcid)0000-0002-9707-8765 aut Ma, Xu aut Enthalten in Orphanet journal of rare diseases London : BioMed Central, 2006 18(2023), 1 vom: 26. Mai (DE-627)50900637X (DE-600)2225857-7 1750-1172 nnns volume:18 year:2023 number:1 day:26 month:05 https://dx.doi.org/10.1186/s13023-023-02742-1 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 18 2023 1 26 05
allfieldsSound	10.1186/s13023-023-02742-1 doi (DE-627)SPR051659700 (SPR)s13023-023-02742-1-e DE-627 ger DE-627 rakwb eng Zhang, Chuan verfasserin aut Identification of deep intronic variants of PAH in phenylketonuria using full-length gene sequencing 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2023 Background Phenylketonuria (PKU) is an autosomal recessive congenital metabolic disorder caused by PAH variants. Previously, approximately 5% of PKU patients remained undiagnosed after Sanger sequencing and multiplex ligation-dependent probe amplification. To date, increasing numbers of pathogenic deep intronic variants have been reported in more than 100 disease-associated genes. Methods In this study, we performed full-length sequencing of PAH to investigate the deep intronic variants in PAH of PKU patients without definite genetic diagnosis. Results We identified five deep intronic variants (c.1199+502A>T, c.1065+241C>A, c.706+368T>C, c.706+531>C, and c.706+608A>C). Of these, the c.1199+502A>T variant was found at high frequency and may be a hotspot PAH variant in Chinese PKU. c.706+531T>C and c.706+608A>C are two novel variants that extend the deep intronic variant spectrum of PAH. Conclusion Deep intronic variant pathogenicity analysis can further improve the genetic diagnosis of PKU patients. In silico prediction and minigene analysis are powerful approaches for studying the functions and effects of deep intronic variants. Targeted sequencing after full-length gene amplification is an economical and effective tool for the detection of deep intron variation in genes with small fragments. PKU (dpeaa)DE-He213 Deep intronic variant (dpeaa)DE-He213 RNA splicing (dpeaa)DE-He213 Minigene (dpeaa)DE-He213 Yan, Yousheng aut Zhou, Bingbo aut Wang, Yupei aut Tian, Xinyuan aut Hao, Shengju aut Ma, Panpan aut Zheng, Lei aut Zhang, Qinghua aut Hui, Ling aut Wang, Yan aut Cao, Zongfu (orcid)0000-0002-9707-8765 aut Ma, Xu aut Enthalten in Orphanet journal of rare diseases London : BioMed Central, 2006 18(2023), 1 vom: 26. Mai (DE-627)50900637X (DE-600)2225857-7 1750-1172 nnns volume:18 year:2023 number:1 day:26 month:05 https://dx.doi.org/10.1186/s13023-023-02742-1 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 18 2023 1 26 05
language	English
source	Enthalten in Orphanet journal of rare diseases 18(2023), 1 vom: 26. Mai volume:18 year:2023 number:1 day:26 month:05
sourceStr	Enthalten in Orphanet journal of rare diseases 18(2023), 1 vom: 26. Mai volume:18 year:2023 number:1 day:26 month:05
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authorswithroles_txt_mv	Zhang, Chuan @@aut@@ Yan, Yousheng @@aut@@ Zhou, Bingbo @@aut@@ Wang, Yupei @@aut@@ Tian, Xinyuan @@aut@@ Hao, Shengju @@aut@@ Ma, Panpan @@aut@@ Zheng, Lei @@aut@@ Zhang, Qinghua @@aut@@ Hui, Ling @@aut@@ Wang, Yan @@aut@@ Cao, Zongfu @@aut@@ Ma, Xu @@aut@@
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Previously, approximately 5% of PKU patients remained undiagnosed after Sanger sequencing and multiplex ligation-dependent probe amplification. To date, increasing numbers of pathogenic deep intronic variants have been reported in more than 100 disease-associated genes. Methods In this study, we performed full-length sequencing of PAH to investigate the deep intronic variants in PAH of PKU patients without definite genetic diagnosis. Results We identified five deep intronic variants (c.1199+502A>T, c.1065+241C>A, c.706+368T>C, c.706+531>C, and c.706+608A>C). Of these, the c.1199+502A>T variant was found at high frequency and may be a hotspot PAH variant in Chinese PKU. c.706+531T>C and c.706+608A>C are two novel variants that extend the deep intronic variant spectrum of PAH. Conclusion Deep intronic variant pathogenicity analysis can further improve the genetic diagnosis of PKU patients. 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author	Zhang, Chuan
spellingShingle	Zhang, Chuan misc PKU misc Deep intronic variant misc RNA splicing misc Minigene Identification of deep intronic variants of PAH in phenylketonuria using full-length gene sequencing
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topic_title	Identification of deep intronic variants of PAH in phenylketonuria using full-length gene sequencing PKU (dpeaa)DE-He213 Deep intronic variant (dpeaa)DE-He213 RNA splicing (dpeaa)DE-He213 Minigene (dpeaa)DE-He213
topic	misc PKU misc Deep intronic variant misc RNA splicing misc Minigene
topic_unstemmed	misc PKU misc Deep intronic variant misc RNA splicing misc Minigene
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title	Identification of deep intronic variants of PAH in phenylketonuria using full-length gene sequencing
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title_full	Identification of deep intronic variants of PAH in phenylketonuria using full-length gene sequencing
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author_browse	Zhang, Chuan Yan, Yousheng Zhou, Bingbo Wang, Yupei Tian, Xinyuan Hao, Shengju Ma, Panpan Zheng, Lei Zhang, Qinghua Hui, Ling Wang, Yan Cao, Zongfu Ma, Xu
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title_sort	identification of deep intronic variants of pah in phenylketonuria using full-length gene sequencing
title_auth	Identification of deep intronic variants of PAH in phenylketonuria using full-length gene sequencing
abstract	Background Phenylketonuria (PKU) is an autosomal recessive congenital metabolic disorder caused by PAH variants. Previously, approximately 5% of PKU patients remained undiagnosed after Sanger sequencing and multiplex ligation-dependent probe amplification. To date, increasing numbers of pathogenic deep intronic variants have been reported in more than 100 disease-associated genes. Methods In this study, we performed full-length sequencing of PAH to investigate the deep intronic variants in PAH of PKU patients without definite genetic diagnosis. Results We identified five deep intronic variants (c.1199+502A>T, c.1065+241C>A, c.706+368T>C, c.706+531>C, and c.706+608A>C). Of these, the c.1199+502A>T variant was found at high frequency and may be a hotspot PAH variant in Chinese PKU. c.706+531T>C and c.706+608A>C are two novel variants that extend the deep intronic variant spectrum of PAH. Conclusion Deep intronic variant pathogenicity analysis can further improve the genetic diagnosis of PKU patients. In silico prediction and minigene analysis are powerful approaches for studying the functions and effects of deep intronic variants. Targeted sequencing after full-length gene amplification is an economical and effective tool for the detection of deep intron variation in genes with small fragments. © The Author(s) 2023
abstractGer	Background Phenylketonuria (PKU) is an autosomal recessive congenital metabolic disorder caused by PAH variants. Previously, approximately 5% of PKU patients remained undiagnosed after Sanger sequencing and multiplex ligation-dependent probe amplification. To date, increasing numbers of pathogenic deep intronic variants have been reported in more than 100 disease-associated genes. Methods In this study, we performed full-length sequencing of PAH to investigate the deep intronic variants in PAH of PKU patients without definite genetic diagnosis. Results We identified five deep intronic variants (c.1199+502A>T, c.1065+241C>A, c.706+368T>C, c.706+531>C, and c.706+608A>C). Of these, the c.1199+502A>T variant was found at high frequency and may be a hotspot PAH variant in Chinese PKU. c.706+531T>C and c.706+608A>C are two novel variants that extend the deep intronic variant spectrum of PAH. Conclusion Deep intronic variant pathogenicity analysis can further improve the genetic diagnosis of PKU patients. In silico prediction and minigene analysis are powerful approaches for studying the functions and effects of deep intronic variants. Targeted sequencing after full-length gene amplification is an economical and effective tool for the detection of deep intron variation in genes with small fragments. © The Author(s) 2023
abstract_unstemmed	Background Phenylketonuria (PKU) is an autosomal recessive congenital metabolic disorder caused by PAH variants. Previously, approximately 5% of PKU patients remained undiagnosed after Sanger sequencing and multiplex ligation-dependent probe amplification. To date, increasing numbers of pathogenic deep intronic variants have been reported in more than 100 disease-associated genes. Methods In this study, we performed full-length sequencing of PAH to investigate the deep intronic variants in PAH of PKU patients without definite genetic diagnosis. Results We identified five deep intronic variants (c.1199+502A>T, c.1065+241C>A, c.706+368T>C, c.706+531>C, and c.706+608A>C). Of these, the c.1199+502A>T variant was found at high frequency and may be a hotspot PAH variant in Chinese PKU. c.706+531T>C and c.706+608A>C are two novel variants that extend the deep intronic variant spectrum of PAH. Conclusion Deep intronic variant pathogenicity analysis can further improve the genetic diagnosis of PKU patients. In silico prediction and minigene analysis are powerful approaches for studying the functions and effects of deep intronic variants. Targeted sequencing after full-length gene amplification is an economical and effective tool for the detection of deep intron variation in genes with small fragments. © The Author(s) 2023
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title_short	Identification of deep intronic variants of PAH in phenylketonuria using full-length gene sequencing
url	https://dx.doi.org/10.1186/s13023-023-02742-1
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author2	Yan, Yousheng Zhou, Bingbo Wang, Yupei Tian, Xinyuan Hao, Shengju Ma, Panpan Zheng, Lei Zhang, Qinghua Hui, Ling Wang, Yan Cao, Zongfu Ma, Xu
author2Str	Yan, Yousheng Zhou, Bingbo Wang, Yupei Tian, Xinyuan Hao, Shengju Ma, Panpan Zheng, Lei Zhang, Qinghua Hui, Ling Wang, Yan Cao, Zongfu Ma, Xu
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up_date	2024-07-03T23:07:18.615Z
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Previously, approximately 5% of PKU patients remained undiagnosed after Sanger sequencing and multiplex ligation-dependent probe amplification. To date, increasing numbers of pathogenic deep intronic variants have been reported in more than 100 disease-associated genes. Methods In this study, we performed full-length sequencing of PAH to investigate the deep intronic variants in PAH of PKU patients without definite genetic diagnosis. Results We identified five deep intronic variants (c.1199+502A>T, c.1065+241C>A, c.706+368T>C, c.706+531>C, and c.706+608A>C). Of these, the c.1199+502A>T variant was found at high frequency and may be a hotspot PAH variant in Chinese PKU. c.706+531T>C and c.706+608A>C are two novel variants that extend the deep intronic variant spectrum of PAH. Conclusion Deep intronic variant pathogenicity analysis can further improve the genetic diagnosis of PKU patients. In silico prediction and minigene analysis are powerful approaches for studying the functions and effects of deep intronic variants. 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Identification of deep intronic variants of PAH in phenylketonuria using full-length gene sequencing

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