TY - JOUR
T1 - Carrier frequency of guanidinoacetate methyltransferase deficiency in the general population by functional characterization of missense variants in the GAMT gene
AU - Desroches, Caro Lyne
AU - Patel, Jaina
AU - Wang, Peixiang
AU - Minassian, Berge
AU - Marshall, Christian R.
AU - Salomons, Gajja S.
AU - Mercimek-Mahmutoglu, Saadet
N1 - Publisher Copyright:
© 2015, Springer-Verlag Berlin Heidelberg.
PY - 2015/12/1
Y1 - 2015/12/1
N2 - 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.
AB - 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.
KW - Carrier frequency
KW - Exome Variant Server
KW - GAMT deficiency
KW - Missense variants
KW - Site-directed mutagenesis
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U2 - 10.1007/s00438-015-1067-x
DO - 10.1007/s00438-015-1067-x
M3 - Article
C2 - 26003046
AN - SCOPUS:84947868038
SN - 1617-4615
VL - 290
SP - 2163
EP - 2171
JO - Molecular Genetics and Genomics
JF - Molecular Genetics and Genomics
IS - 6
ER -