caa a22 4500 445861339 CHVBK 20180317145444.0 cr unu---uuuuu 170323e20110101xx s 000 0 eng 10.1007/s00439-010-0896-2 doi (NATIONALLICENCE)springer-10.1007/s00439-010-0896-2 A homozygous RAB3GAP2 mutation causes Warburg Micro syndrome [Elektronische Daten] [Guntram Borck, Heidrun Wunram, Angela Steiert, Alexander Volk, Friederike Körber, Sigrid Roters, Peter Herkenrath, Bernd Wollnik, Deborah Morris-Rosendahl, Christian Kubisch] Warburg Micro syndrome and Martsolf syndrome are clinically overlapping autosomal recessive conditions characterized by congenital cataracts, microphthalmia, postnatal microcephaly, and developmental delay. The neurodevelopmental and ophthalmological phenotype is more severe in Warburg Micro syndrome in which cerebral malformations and severe motor and mental retardation are common. While biallelic loss-of-function mutations in RAB3GAP1 are present in the majority of patients with Warburg Micro syndrome; a hypomorphic homozygous splicing mutation of RAB3GAP2 has been reported in a single family with Martsolf syndrome. Here, we report a novel homozygous RAB3GAP2 small in-frame deletion, c.499_507delTTCTACACT (p.Phe167_Thr169del) that causes Warburg Micro syndrome in a girl from a consanguineous Turkish family presenting with congenital cataracts, microphthalmia, absent visually evoked potentials, microcephaly, polymicrogyria, hypoplasia of the corpus callosum, and severe developmental delay. No RAB3GAP2 mutations were detected in ten additional unrelated patients with RAB3GAP1-negative Warburg Micro syndrome, consistent with further genetic heterogeneity. In conclusion, we provide evidence that RAB3GAP2 mutations are not specific to Martsolf syndrome. Rather, our findings suggest that loss-of-function mutations of RAB3GAP1 as well as functionally severe RAB3GAP2 mutations cause Warburg Micro syndrome while hypomorphic RAB3GAP2 mutations can result in the milder Martsolf phenotype. Thus, a phenotypic severity gradient may exist in the RAB3GAP-associated disease continuum (the "Warburg-Martsolf syndrome”) which is presumably determined by the mutant gene and the nature of the mutation. Springer-Verlag, 2010 Borck Guntram Institute of Human Genetics, University of Cologne, Kerpener Str. 34, 50931, Cologne, Germany aut Wunram Heidrun Department of Pediatrics, University of Cologne, Cologne, Germany aut Steiert Angela Institute for Human Genetics, University Clinic Freiburg, Freiburg, Germany aut Volk Alexander Institute of Human Genetics, University of Cologne, Kerpener Str. 34, 50931, Cologne, Germany aut Körber Friederike Department of Pediatric Radiology, University of Cologne, Cologne, Germany aut Roters Sigrid Department of Ophthalmology, University of Cologne, Cologne, Germany aut Herkenrath Peter Department of Pediatrics, University of Cologne, Cologne, Germany aut Wollnik Bernd Institute of Human Genetics, University of Cologne, Kerpener Str. 34, 50931, Cologne, Germany aut Morris-Rosendahl Deborah Institute for Human Genetics, University Clinic Freiburg, Freiburg, Germany aut Kubisch Christian Institute of Human Genetics, University of Cologne, Kerpener Str. 34, 50931, Cologne, Germany aut Human Genetics Springer-Verlag 129/1(2011-01-01), 45-50 0340-6717 129:1<45 2011 129 439 https://doi.org/10.1007/s00439-010-0896-2 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s00439-010-0896-2 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Borck Guntram Institute of Human Genetics, University of Cologne, Kerpener Str. 34, 50931, Cologne, Germany aut NATIONALLICENCE 700 1- Wunram Heidrun Department of Pediatrics, University of Cologne, Cologne, Germany aut NATIONALLICENCE 700 1- Steiert Angela Institute for Human Genetics, University Clinic Freiburg, Freiburg, Germany aut NATIONALLICENCE 700 1- Volk Alexander Institute of Human Genetics, University of Cologne, Kerpener Str. 34, 50931, Cologne, Germany aut NATIONALLICENCE 700 1- Körber Friederike Department of Pediatric Radiology, University of Cologne, Cologne, Germany aut NATIONALLICENCE 700 1- Roters Sigrid Department of Ophthalmology, University of Cologne, Cologne, Germany aut NATIONALLICENCE 700 1- Herkenrath Peter Department of Pediatrics, University of Cologne, Cologne, Germany aut NATIONALLICENCE 700 1- Wollnik Bernd Institute of Human Genetics, University of Cologne, Kerpener Str. 34, 50931, Cologne, Germany aut NATIONALLICENCE 700 1- Morris-Rosendahl Deborah Institute for Human Genetics, University Clinic Freiburg, Freiburg, Germany aut NATIONALLICENCE 700 1- Kubisch Christian Institute of Human Genetics, University of Cologne, Kerpener Str. 34, 50931, Cologne, Germany aut NATIONALLICENCE 773 0- Human Genetics Springer-Verlag 129/1(2011-01-01), 45-50 0340-6717 129:1<45 2011 129 439 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer