Two novel homozygous RAB3GAP1 mutations cause Warburg micro syndrome.
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ABSTRACT:
SUBMITTER: Imagawa E
PROVIDER: S-EPMC4785564 | biostudies-literature | 2015
REPOSITORIES: biostudies-literature
Publications
Two novel homozygous RAB3GAP1 mutations cause Warburg micro syndrome.
Imagawa Eri E Fukai Ryoko R Behnam Mahdiyeh M Goyal Manisha M Nouri Narges N Nakashima Mitsuko M Tsurusaki Yoshinori Y Saitsu Hirotomo H Salehi Mansour M Kapoor Seema S Tanaka Fumiaki F Miyake Noriko N Matsumoto Naomichi N
Human genome variation 20150917
Warburg micro syndrome is an autosomal recessive disease where patients present with optic, neurologic and genital symptoms. Until now, four disease genes for Warburg micro syndrome, RAB3GAP1, RAB3GAP2, RAB18 and TBC1D20, have been identified. Here, we report two novel homozygous RAB3GAP1 mutations (c.22G>T, p.Glu8* and c.1353delA, p.Pro452Hisfs*5) in two consanguineous families by whole-exome sequencing. ...[more]
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Project description:This report details two novel RAB3GAP1 mutations causing Warburg Micro syndrome, a rare autosomal recessive disorder characterized by multiple organ abnormalities involving the ocular, nervous, and endocrine systems. Two Italian sisters were referred to our department for the assessment of congenital bilateral cataracts. They also presented with microphthalmia, postnatal microcephaly, severe developmental delay, and hypotony. Perinatal investigations were negative for any toxins or infectious diseases during pregnancy, including toxoplasmosis, rubella, cytomegalovirus, and herpes virus. Genetic tests were performed on samples from probands and their parents, targeting a total of 114 genes. After sequence analysis of RAB3GAP1, two heterozygous changes were identified in both sisters: C.519G>A, p.(Trp173Ter) and c.2486T>A, p.(Leu829Ter). The identified mutations have not previously been described in the literature, but they affect critical regions of the gene, suggesting a legitimate causal relationship between the genetic alterations and the clinical features of the patients.
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Project description: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.
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Project description:In this study, we detected a novel pathogenic variant and a previously reported variant in RAB3GAP1 by whole-exome sequencing (NM_001172435.2: c.1552C>T, p.Gln518*; c.1471C>T, p.Arg491*). The first patient is a 3-year-old girl who presented with bilateral congenital cataracts, developmental delay, abnormal craniofacial features, drug-resistant constipation, and corpus callosum hypoplasia. The proband of the second family is a 13-year-old boy who suffers from developmental delay, quadriplegia, intellectual disability, abnormal craniofacial features, and corpus callosum hypoplasia.
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Project description:Background and purposeWarburg Micro syndrome (WARBM) is a rare autosomal recessive genetic disease characterized by ocular, neurologic, and endocrine anomalies. WARBM is a phenotypically and genetically heterogeneous syndrome caused by mutations in RAB3GAP1, RAB3GAP2, RAB18, and TBC1D20. Here we present the clinical and genetic characterization of a consanguineous Tunisian family with a WARBM phenotype presenting two pathogenic variations, one of which is on RAB3GAP1.MethodsWe applied whole-exome sequencing (WES) to two affected young males presenting a WARBM-compatible phenotype.ResultsWe reveal a new variation in RAB3GAP1 (NM_012233.3: c.297del, p.Gln99fs) and another variation in ABCD1 (NM_000033: c.896A>G, p.His299Arg). Each of these mutations, which in silico predictions concluded as being pathogenic variations, affects a critical protein region. Both affected males presented a WARBM-compatible phenotype, with severe intellectual disability, severe developmental delay, postnatal growth delay, postnatal microcephaly, congenital bilateral cataracts, general hypotonia, and a thin corpus callosum without a splenium. However, intrafamilial clinical heterogeneity was present, since only the oldest child had large ears, microphthalmia, foot deformities, and a genital anomaly, and only the youngest child had microcornea. Despite the mutation identified in ABCD1, our patients did not have any X-linked symptoms of adrenoleukodystrophy disorder that are usually caused by ABCD1 mutations, which prompted our interest in clinical monitoring.ConclusionsWES analysis of a consanguineous Tunisian family with WARBM revealed a novel variation in RAB3GAP1 (NM_012233.3: c.297del, p.Gln99fs) that is most likely pathogenic and allowed us to confirm the diagnosis of WARBM.
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