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Mutation Spectrum in RAB 3 GAP 1 , RAB 3 GAP 2 , and RAB 18 and Genotype–Phenotype Correlations in W arburg M icro Syndrome and M artsolf Syndrome
Author(s) -
Handley Mark T.,
MorrisRosendahl Deborah J.,
Brown Stephen,
Macdonald Fiona,
Hardy Carol,
Bem Danai,
Carpanini Sarah M.,
Borck Guntram,
Martorell Loreto,
Izzi Claudia,
Faravelli Francesca,
Accorsi Patrizia,
Pinelli Lorenzo,
BaselVanagaite Lina,
Peretz Gabriela,
AbdelSalam Ghada M.H.,
Zaki Maha S.,
Jansen Anna,
Mowat David,
Glass Ian,
Stewart Helen,
Mancini Grazia,
Lederer Damien,
Roscioli Tony,
Giuliano Fabienne,
Plomp Astrid S.,
Rolfs Arndt,
Graham John M.,
Seemanova Eva,
Poo Pilar,
GarcíaCazorla Àngels,
Edery Patrick,
Jackson Ian J.,
Maher Eamonn R.,
Aligianis Irene A.
Publication year - 2013
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22296
Subject(s) - biology , rab , genetics , phenotype , gene , mutation , germline , germline mutation , genetic heterogeneity , gtpase
ABSTRACT W arburg M icro syndrome and M artsolf syndrome ( MS ) are heterogeneous autosomal‐recessive developmental disorders characterized by brain, eye, and endocrine abnormalities. Causative biallelic germline mutations have been identified in RAB 3 GAP 1 , RAB 3 GAP 2 , or RAB 18 , 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 M icro and nine M artsolf families were investigated, identifying mutations in RAB 3 GAP 1 in 41% of cases, mutations in RAB 3 GAP 2 in 7% of cases, and mutations in RAB 18 in 5% of cases. These are listed in L eiden O pen source V ariation D atabases, which was created by us for all three genes. Genotype–phenotype correlations for these genes have now established that the clinical phenotypes in M icro 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 M icro syndrome and milder mutations causing MS . RAB18 has not yet been linked to the RAB 3 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.