NDLI: Carrier frequency of guanidinoacetate methyltransferase deficiency in the general population by functional characterization of missense variants in the GAMT gene

Content Provider	SpringerLink
Author	Desroches, Caro Lyne Patel, Jaina Wang, Peixiang Minassian, Berge Marshall, Christian R. Salomons, Gajja S. Mercimek Mahmutoglu, Saadet
Copyright Year	2015
Abstract	Guanidinoacetate methyltransferase (GAMT) deficiency is a neurodegenerative disease. Although no symptomatic patients on treatment achieved normal neurodevelopment, three asymptomatic newborns were reported with normal neurodevelopmental outcome on neonatal treatment. GAMT deficiency is therefore a candidate for newborn screening programs, but there are no studies for the carrier frequency of this disease in the general population. To determine carrier frequency of GAMT deficiency, we studied the variants in the GAMT gene reported in the Exome Variant Server database and performed functional characterization of missense variants. We used previously cloned GAMT transcript variant 1 (7 missense variants) and cloned a novel GAMT transcript variant 2 (5 missense variants). The latter was used in Exome Variant Server database according to recommendations of the Human Genome Variation Society. There were 4 missense variants (1 previously reported and 3 novel) with low GAMT enzyme activity indicating pathogenicity. Additionally, there was one novel frameshift and one novel nonsense variant likely pathogenic. There was no measurable GAMT enzyme activity in the wild type of GAMT transcript variant 2. We concluded that GAMT transcript variant 2 is not involved in GAMT protein synthesis. For this reason, Human Genome Variation Society should use mutation nomenclature according to the coding region of the GAMT transcript variant 1. The carrier frequency of GAMT deficiency was 0.123 % in the general population. As early diagnosis results in normal neurodevelopmental outcome, GAMT deficiency should be included in newborn screening programs to diagnose individuals at the asymptomatic stage of the disease to prevent permanent neurodevelopmental disability.
Starting Page	2163
Ending Page	2171
Page Count	9
File Format	PDF
ISSN	16174615
Journal	Molecular and General Genetics MGG
Volume Number	290
Issue Number	6
e-ISSN	16174623
Language	English
Publisher	Springer Berlin Heidelberg
Publisher Date	2015-05-24
Publisher Place	Berlin/Heidelberg
Access Restriction	Subscribed
Subject Keyword	GAMT deficiency Site-directed mutagenesis Missense variants Exome Variant Server Carrier frequency Cell Biology Biochemistry Microbial Genetics and Genomics Plant Genetics & Genomics Animal Genetics and Genomics
Content Type	Text
Resource Type	Article
Subject	Genetics Molecular Biology Medicine

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