Warburg micro syndrome type 1 associated with peripheral neuropathy and cardiomyopathy

Kabzińska, Dagmara; Mierzewska, Hanna; Senderek, Jan; Kochański, Andrzej

doi:10.5114/fn.2016.62537

Cited by 9 publications

(5 citation statements)

References 13 publications

(18 reference statements)

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“…WARBM is a heterogeneous group of autosomal recessive disorders that can be resulted from loss-of-function mutations in RAB3GAP1/2 , RAB18 , and TBC1D20 [ 43 , 44 ] . These genes encode the ‘RAB proteins’ that mainly function as molecular switches [ 45 ]; they can also regulate membrane trafficking in a spatially and temporally restricted manner [ 46 ].…”

Section: Discussionmentioning

confidence: 99%

Novel manifestations of Warburg micro syndrome type 1 caused by a new splicing variant of RAB3GAP1: a case report

et al. 2021

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Background The present study aimed to determine the underlying genetic factors causing the possible Warburg micro syndrome (WARBM) phenotype in two Iranian patients. Case presentation A 5-year-old female and a 4.5-year-old male were referred due to microcephaly, global developmental delay, and dysmorphic features. After doing neuroimaging and clinical examinations, due to the heterogeneity of neurodevelopmental disorders, we subjected 7 family members to whole-exome sequencing. Three candidate variants were confirmed by Sanger sequencing and allele frequency of each variant was also determined in 300 healthy ethnically matched people using the tetra-primer amplification refractory mutation system-PCR and PCR-restriction fragment length polymorphism. To show the splicing effects, reverse transcription-PCR (RT-PCR) and RT-qPCR were performed, followed by Sanger sequencing. A novel homozygous variant—NM_012233.2: c.151-5 T > G; p.(Gly51IlefsTer15)—in the RAB3GAP1 gene was identified as the most likely disease-causing variant. RT-PCR/RT-qPCR showed that this variant can activate a cryptic site of splicing in intron 3, changing the splicing and gene expression processes. We also identified some novel manifestations in association with WARBM type 1 to touch upon abnormal philtrum, prominent antitragus, downturned corners of the mouth, malaligned teeth, scrotal hypoplasia, low anterior hairline, hypertrichosis of upper back, spastic diplegia to quadriplegia, and cerebral white matter signal changes. Conclusions Due to the common phenotypes between WARBMs and Martsolf syndrome (MIM: 212720), we suggest using the “RABopathies” term that can in turn cover a broad range of manifestations. This study can per se increase the genotype-phenotype spectrum of WARBM type 1.

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Section: Discussionmentioning

confidence: 99%

Novel manifestations of Warburg micro syndrome type 1 caused by a new splicing variant of RAB3GAP1: a case report

et al. 2021

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“…Joint hypermobility and skin hyperextensibility were first described in a Turkish boy with a splice donor mutation (748+ G>A) (Yüksel et al, 2007). Planovalgus feet were to be noted in some patients (Kabzińska et al, 2016). Long slenderic fingers (6/7), small joint laxity (5/7), small feet (5/7), and overlapping toes (4/7) were the most common skeletal findings of index patients.…”

Section: Discussionmentioning

confidence: 99%

From cataract to syndrome diagnosis: Revaluation of Warburg‐Micro syndrome Type 1 patients

Albayrak

Elçioğlu

Yeter

et al. 2021

American J of Med Genetics Pt A

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Warburg-Micro syndrome (WARBM) is a rare autosomal recessively inherited neuro-ophthalmologic syndrome. Although WARBM shows genetic heterogeneity, the pathogenic variants in RAB3GAP1 were the most common cause of WARBM. In this study, we aimed to evaluate the detailed clinical and dysmorphic features of seven WARBM1 patients and overview the variant spectrum of RAB3GAP1 in comparison with the literature who were referred due to congenital cataracts. A previously reported homozygous variant (c.2187_2188delGAinsCT) was identified in three of these patients, while the other four had three novel variants (c.251_258delAGAA, c.2606+1G>A, and c.2861_2862dupGC). Congenital cataract and corpus callosum hypo/agenesia are pathognomonic for WARBM, which could be distinguished from other similar syndromes with additional typical dysmorphic facial features. Although there is no known phenotype and genotype correlation in any type of WARBM, RAB3GAP1 gene analysis should be previously requested as the first step of genetic diagnosis in clinically suspicious patients when it is not possible to request a multi-gene panel.

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“…However, one of the patients described by Morris‐Rosendahl and co‐authors had cardiac ventricle septal defect 17 . In addition, Kabzińska et al reported a patient with Micro syndrome and cardiomyopathy and claimed that it might be a rare additional symptom coexisting with the syndrome 23 . Other rare and unusual manifestations described in patients with Micro syndrome include peripheral neuropathy (six patients), hearing impairment (three patients), distal extra crease on the fourth finger (one patient), incomplete fourth finger fold (one patient), trigonocephaly (one patient), cleft palate (one patient), skin hyperextensibility and joint hypermobility (one patient) 4,8,17,20,24,25 although, none of them were manifested in our series.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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Micro and Martsolf syndromes are rare clinically and genetically overlapping disorders caused by mutations in RAB3GAP1, RAB3GAP2, RAB18 and TBC1D20 genes. We describe 34 new patients, 27 with Micro and seven with Martsolf. Patients presented with the characteristic clinical manifestations of the two syndromes, including postnatal microcephaly, congenital cataracts, microphthalmia, optic atrophy, spasticity and intellectual disability. Brain imaging showed in the majority of cases polymicrogyria, thin corpus callosum, cortical atrophy, and white matter dysmyelination. Unusual additional findings were pectus excavatum (four patients), pectus carinatum (three patients), congenital heart disease (three patients) and bilateral calcification in basal ganglia (one patient). Mutational analysis of RAB3GAP1 and RAB3GAP2 revealed 21 mutations, including 14 novel variants. RAB3GAP1 mutations were identified in 22 patients with Micro, including a deletion of the entire gene in one patient. On the other hand, RAB3GAP2 mutations were identified in two patients with Micro and all Martsolf patients. Moreover, exome sequencing unraveled a TBC1D20 mutation in an additional family with Micro syndrome. Our results expand the phenotypic and mutational spectrum associated with Micro and Martsolf syndromes. Due to the overlapped severities and genetic basis of both syndromes, we suggest to be comprehended as one entity "Micro/Martsolf spectrum" or "RAB18 deficiency."

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Warburg micro syndrome type 1 associated with peripheral neuropathy and cardiomyopathy

Abstract: A b s t r a c t

Cited by 9 publications

References 13 publications

Novel manifestations of Warburg micro syndrome type 1 caused by a new splicing variant of RAB3GAP1: a case report

Novel manifestations of Warburg micro syndrome type 1 caused by a new splicing variant of RAB3GAP1: a case report

From cataract to syndrome diagnosis: Revaluation of Warburg‐Micro syndrome Type 1 patients

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

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