TY - JOUR
T1 - Mutation spectrum in RAB3GAP1, RAB3GAP2, and RAB18 and genotype-phenotype correlations in warburg micro syndrome and Martsolf syndrome
AU - Handley, Mark T.
AU - Morris-Rosendahl, Deborah J.
AU - Brown, Stephen
AU - Macdonald, Fiona
AU - Hardy, Carol
AU - Bem, Danai
AU - Carpanini, Sarah M.
AU - Borck, Guntram
AU - Martorell, Loreto
AU - Izzi, Claudia
AU - Faravelli, Francesca
AU - Accorsi, Patrizia
AU - Pinelli, Lorenzo
AU - Basel-Vanagaite, Lina
AU - Peretz, Gabriela
AU - Abdel-Salam, Ghada M. H.
AU - Zaki, Maha S.
AU - Jansen, Anna
AU - Mowat, David
AU - Glass, Ian
AU - Stewart, Helen
AU - Mancini, Grazia
AU - Lederer, Damien
AU - Roscioli, Tony
AU - Giuliano, Fabienne
AU - Plomp, Astrid S.
AU - Rolfs, Arndt
AU - Graham, John M.
AU - Seemanova, Eva
AU - Poo, Pilar
AU - García-Cazorla, Angels
AU - Edery, Patrick
AU - Jackson, Ian J.
AU - Maher, Eamonn R.
AU - Aligianis, Irene A.
PY - 2013
Y1 - 2013
N2 - Warburg Micro syndrome and Martsolf syndrome (MS) are heterogeneous autosomal-recessive developmental disorders characterized by brain, eye, and endocrine abnormalities. Causative biallelic germline mutations have been identified in RAB3GAP1, RAB3GAP2, or RAB18, each of which encode proteins involved in membrane trafficking. This report provides an up to date overview of all known disease variants identified in 29 previously published families and 52 new families. One-hundred and forty-four Micro and nine Martsolf families were investigated, identifying mutations in RAB3GAP1 in 41% of cases, mutations in RAB3GAP2 in 7% of cases, and mutations in RAB18 in 5% of cases. These are listed in Leiden Open source Variation Databases, which was created by us for all three genes. Genotype-phenotype correlations for these genes have now established that the clinical phenotypes in Micro syndrome and MS represent a phenotypic continuum related to the nature and severity of the mutations present in the disease genes, with more deleterious mutations causing Micro syndrome and milder mutations causing MS. RAB18 has not yet been linked to the RAB3 pathways, but mutations in all three genes cause an indistinguishable phenotype, making it likely that there is some overlap. There is considerable genetic heterogeneity for these disorders and further gene identification will help delineate these pathways
AB - Warburg Micro syndrome and Martsolf syndrome (MS) are heterogeneous autosomal-recessive developmental disorders characterized by brain, eye, and endocrine abnormalities. Causative biallelic germline mutations have been identified in RAB3GAP1, RAB3GAP2, or RAB18, each of which encode proteins involved in membrane trafficking. This report provides an up to date overview of all known disease variants identified in 29 previously published families and 52 new families. One-hundred and forty-four Micro and nine Martsolf families were investigated, identifying mutations in RAB3GAP1 in 41% of cases, mutations in RAB3GAP2 in 7% of cases, and mutations in RAB18 in 5% of cases. These are listed in Leiden Open source Variation Databases, which was created by us for all three genes. Genotype-phenotype correlations for these genes have now established that the clinical phenotypes in Micro syndrome and MS represent a phenotypic continuum related to the nature and severity of the mutations present in the disease genes, with more deleterious mutations causing Micro syndrome and milder mutations causing MS. RAB18 has not yet been linked to the RAB3 pathways, but mutations in all three genes cause an indistinguishable phenotype, making it likely that there is some overlap. There is considerable genetic heterogeneity for these disorders and further gene identification will help delineate these pathways
U2 - https://doi.org/10.1002/humu.22296
DO - https://doi.org/10.1002/humu.22296
M3 - Article
C2 - 23420520
SN - 1059-7794
VL - 34
SP - 686
EP - 696
JO - Human mutation
JF - Human mutation
IS - 5
ER -