A pilot study to estimate incidence of guanidinoacetate methyltransferase deficiency in newborns by direct sequencing of the GAMT gene

被引：16

作者：

Mercimek-Mahmutoglu, S. ^{[1
,2
]}

Pop, A. ^{[3
]}

Kanhai, W. ^{[3
]}

Ojeda, M. Fernandez ^{[3
]}

Holwerda, U. ^{[3
]}

Smith, D. ^{[3
]}

Loeber, J. G. ^{[4
]}

Schielen, P. C. J. I. ^{[4
]}

Salomons, G. S. ^{[3
]}

机构：

[1] Univ Toronto, Dept Pediat, Div Clin & Metab Genet, Toronto, ON M5G 1X8, Canada

[2] Hosp Sick Children, Res Inst, Genet & Genome Biol, Toronto, ON M5G 1X8, Canada

[3] Vrije Univ Amsterdam Med Ctr, Dept Clin Chem, Metab Unit, Amsterdam, Netherlands

[4] Natl Inst Publ Hlth & Environm, Ctr Infect Dis Res & Screening, NL-3720 BA Bilthoven, Netherlands

来源：

GENE | 2016年 / 575卷 / 01期

关键词：

GAMT deficiency; Newborn screening; Newborn blood spots; GAA; Creatine; Sanger sequencing; Functional analysis; INBORN ERROR; ARGININE RESTRICTION; CREATINE; DIAGNOSIS; RECOMMENDATIONS; IMPACT;

D O I：

10.1016/j.gene.2015.08.045

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Background: GAMT deficiency is an autosomal recessive disorder of creatine biosynthesis causing developmental delays or intellectual disability in untreated patients as a result of irreversible brain damage occurring prior to diagnosis. Normal neurodevelopmental outcome has been reported in patients treated from neonatal period highlighting the importance of early treatment. Methods: Five hundred anonymized newborns from the National Newborn Screening Program of The Netherlands were included into this pilot study. Direct sequencing of the coding region of the GAMT gene was applied following DNA extraction. The disease causing nature of novel missense variants in the GAMT gene was studied by overexpression studies. GAA and creatine was measured in blood dot spots. Results: We detected two carriers, one with a known common (c.327G>A) and one with a novel mutation (c.297_309dup (p.Arg105Glyfs*) in the GAMT gene. The estimated incidence of GAMT deficiency was 1:250,000. We also detected five novel missense variants. Overexpression of these variants in GAMT deficient fibroblasts did restore GAMT activity and thus all were considered rare, but not disease causing variants including the c.131G>T (p.Arg44Leu) variant. Interestingly, this variant was predicted to be pathogenic by in silico analysis. The variants were included in the Leiden Open Variation Database (LOVD) database (www.LOVD.nl/GAMT). The average GM level was 1.14 mu mol/L +/- 0.45 standard deviations. The average creatine level was 408 mu mol/L +/- 106. The average GAA/creatine ratio was 2.94 +/- 0.136. Conclusion: The estimated incidence of GAMT deficiency is 1:250,000 newborns based on our pilot study. The newborn screening for GAMT deficiency should be implemented to identify patients at the asymptomatic stage to achieve normal neurodevelopmental outcome for this treatable neurometabolic disease. Biochemical investigations including GAA, creatine and GAMT enzyme activity measurements are essential to confirm the diagnosis of GAMT deficiency. According to availability, all missense variants can be assessed functionally, as in silico prediction analysis of missense variants is not sufficient to confirm the pathogenicity of missense variants. Crown Copyright (C) 2015 Published by Elsevier B.V. All rights reserved.

引用

页码：127 / 131

页数：5