Large homozygous RAB3GAP1 gene microdeletion causes Warburg Micro Syndrome 1

Abstract

Warburg micro syndrome (WARBM) is a genetic heterogeneous disease characterized by microcephaly, intellectual disability, brain, ocular, and endocrine anomalies. WARBM1-4 can be caused by biallelic mutations of the RAB3GAP1 (RAB3 GTPase-activating protein 1), RAB3GAP2, RAB18 (RAS-associated protein RAB18), or TBC1D20 (TBC1 domain protein, member 20) gene, respectively. Here, we delineate the so far largest intragenic homozygous RAB3GAP1 microdeletion. Despite the size of the RAB3GAP1 gene deletion, the patient phenotype is mainly consistent with that of other WARBM1 patients, supporting strongly the theory that WARBM1 is caused by a loss of RAB3GAP1 function. We further highlight osteopenia as a feature of WARBM1.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-014-0113-9) contains supplementary material, which is available to authorized users.

Warburg micro syndrome in siblings from India

“…Children have profound mental retardation with lower limb hypertonia and upper limbs and trunk hypotonia. [ 5 6 7 8 ] MRI findings of pathognomic of this condition are hypoplasia/agenesis of corpus callosum. Other MRI features seen are gyral abnormalities, subcortical atrophy, reduced myelination, plagiocephaly, hippocampic malformation, and pachygyria.…”

“…These two syndromes represent a phenotypic continuity due to the severity of the mutations present in RAB3GAP1 and RAB3-GAP2. [ 8 ] In view of the severity of disease, Martsolf syndrome is unlikely.…”

Micro and Martsolf syndromes in 34 new patients: Refining the phenotypic spectrum and further molecular insights

“…1,4 Kyphosis and scoliosis were reported thereafter in few patients. 16,18,21 In the current study, kyphosis and scoliosis were found in four patients each. Chest anomalies are very rare, pectus excavatum and pectus carinatum were both described in one patient with Micro syndrome each.…”

“…Interestingly, one of our patients had a homozygous deletion of the whole RAB3GAP1 gene which has not been reported before. To our knowledge, the largest deletion described before within the RAB3GAP1 gene was a deletion encompassing exons 4‐15 18 . Contrarily, one missense (c.2522C>T, p.Ala841Val) and one nonsense (c.589C>T, p.Arg197*) mutations in RAB3GAP2 have been identified in two patients with Micro syndrome.…”

Warburg micro syndrome type 1 associated with peripheral neuropathy and cardiomyopathy

“…Interestingly, in this pair of patients a mild growth hormone deficiency was detected, and X-ray examination revealed severe osteopenia, which have been not detected to date in WARBM [16]. For molecular diagnostic purposes, the lack or presence of some atypical symptoms should not preclude the molecular analysis of the RAB genes.…”