Revealing the functions of novel mutations in <i>RAB3GAP1</i> in Martsolf and Warburg micro syndromes

Koparır, Asuman; Karataş, Ömer Faruk; Yilmaz, Seda; Suer, İlknur; Özer, Buğra; Yücetürk, Betül; Özen, Mustafa

doi:10.1002/ajmg.a.61065

Cited by 11 publications

(15 citation statements)

References 39 publications

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“…However, low birth weight is not a sine qua nonfinding in the other reported cases. The c.2187_2188delinsCT variation, which was previously reported in two patients by Koparir et al, was also identified in P3, P4, and P5 (Koparir et al, 2019). Those 9-and 12-year-old patients had postnatal onset growth retardation including the height was below À3 SD, weight below À2.5 SD, and OFC below À5 SD, subsequent to normal birth measurements.…”

Section: Discussionsupporting

confidence: 65%

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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Section: Discussionsupporting

confidence: 65%

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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“…Spastic quadriplegia has been reported in WARBM, whereas in Martsolf syndrome, spasticity is limited to lower limbs [56]. Molecularly, mutations reported in association with WARBM are mostly predicted to result in NMD and/or loss-of-protein-function [57]. On top of that, we also found that some clinical features, e.g.…”

Section: Discussionsupporting

confidence: 52%

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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“…However, the involvement of epigenetic or environmental factors cannot be ruled out. In view of all molecularly defined families with Martsolf, four had mutations in RAB3GAP2 , 3,6,12 two had mutations in RAB3GAP1 , 3,13 and one family had a mutation in TBC1D20 14 . In addition, Gumus reported a family with overlapping features of the two syndromes due to a splice site mutation in RAB3GAP2 gene 11 …”

Section: Discussionmentioning

confidence: 99%

“…Till now, around 100 families from diverse ethnic groups were molecularly confirmed as Micro syndrome where mutations in RAB3GAP1 were the most common cause (frequency 75%) 3,9,10 . As for Martsolf syndrome, RAB3GAP2 mutations have been described in five families, 3,6,11,12 while RAB3GAP1 and TBC1D20 mutations were found in two and one families, respectively 3,13,14 …”

Section: Introductionmentioning

confidence: 99%

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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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Revealing the functions of novel mutations in RAB3GAP1 in Martsolf and Warburg micro syndromes

Cited by 11 publications

References 39 publications

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

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

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

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

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