<scp><i>INTU</i></scp>‐related oral‐facial‐digital syndrome <scp>XVII</scp>: Clinical spectrum of a rare disorder

Yakar, Omer; Tatar, Abdülgani

doi:10.1002/ajmg.a.62527

Cited by 3 publications

(1 citation statement)

References 10 publications

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“…Mutations in INTU are associated with the ciliopathy phenotype in the OFD type VI syndrome spectrum (OMIM 277170) [ 41 ]. Additionally, in another study, INTU was proposed as a possible cause of OFD type II syndrome (OMIM 252100) [ 40 ] and finally, pathogenic variants of INTU have been reported in two patients with OFDS XVII (OMIM 617926) [ 42 ] ( Table 1 ).…”

Section: Cplane and Ciliopathiesmentioning

confidence: 99%

CPLANE Complex and Ciliopathies

Martín-Salazar

Valverde

2022

Biomolecules

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Primary cilia are non-motile organelles associated with the cell cycle, which can be found in most vertebrate cell types. Cilia formation occurs through a process called ciliogenesis, which involves several mechanisms including planar cell polarity (PCP) and the Hedgehog (Hh) signaling pathway. Some gene complexes, such as BBSome or CPLANE (ciliogenesis and planar polarity effector), have been linked to ciliogenesis. CPLANE complex is composed of INTU, FUZ and WDPCP, which bind to JBTS17 and RSG1 for cilia formation. Defects in these genes have been linked to a malfunction of intraflagellar transport and defects in the planar cell polarity, as well as defective activation of the Hedgehog signalling pathway. These faults lead to defective cilium formation, resulting in ciliopathies, including orofacial–digital syndrome (OFDS) and Bardet–Biedl syndrome (BBS). Considering the close relationship, between the CPLANE complex and cilium formation, it can be expected that defects in the genes that encode subunits of the CPLANE complex may be related to other ciliopathies.

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Section: Cplane and Ciliopathiesmentioning

confidence: 99%

CPLANE Complex and Ciliopathies

Martín-Salazar

Valverde

2022

Biomolecules

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Pathogenic RAB34 variants impair primary cilium assembly and cause a novel oral-facial-digital syndrome

Bruel

Ganga

Nosková

et al. 2023

Human Molecular Genetics

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Oral-facial-digital syndromes (OFDS) are a group of clinically and genetically heterogeneous disorders characterized by defects in the development of the face and oral cavity along with digit anomalies. Pathogenic variants in over twenty genes encoding ciliary proteins have been found to cause OFDS through deleterious structural or functional impacts on primary cilia. We identified by exome sequencing bi-allelic missense variants in a novel disease-causing ciliary gene RAB34 in four individuals from three unrelated families. Affected individuals presented a novel form of OFDS (OFDS-RAB34) accompanied by cardiac, cerebral, skeletal, and anorectal defects. RAB34 encodes a member of the Rab GTPase superfamily and was recently identified as a key mediator of ciliary membrane formation. Unlike many genes required for cilium assembly, RAB34 acts selectively in cell types that use the intracellular ciliogenesis pathway, in which nascent cilia begin to form in the cytoplasm. We find that the protein products of these pathogenic variants, which are clustered near the RAB34 C-terminus, exhibit a strong loss of function. Although some variants retain the ability to be recruited to the mother centriole, cells expressing mutant RAB34 exhibit a significant defect in cilium assembly. While many Rab proteins have been previously linked to ciliogenesis, our studies establish RAB34 as the first small GTPase involved in OFDS and reveal the distinct clinical manifestations caused by impairment of intracellular ciliogenesis.

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Clinical features and genetic analysis of a case series of skeletal ciliopathies in a prenatal setting

Peng,

Zhou,

Chen

et al. 2023

BMC Med Genomics

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Background Short-rib polydactyly syndrome (SRPS) refers to a group of lethal skeletal dysplasias that can be difficult to differentiate between subtypes or from other non-lethal skeletal dysplasias such as Ellis-van Creveld syndrome and Jeune syndrome in a prenatal setting. We report the ultrasound and genetic findings of four unrelated fetuses with skeletal dysplasias. Methods Systemic prenatal ultrasound examination was performed in the second or third trimester. Genetic tests including GTG-banding, single nucleotide polymorphism (SNP) array and exome sequencing were performed with amniocytes or aborted fetal tissues. Results The major and common ultrasound anomalies for the four unrelated fetuses included short long bones of the limbs and narrow thorax. No chromosomal abnormalities and pathogenic copy number variations were detected. Exome sequencing revealed three novel variants in the DYNC2H1 gene, namely NM_001080463.2:c.6809G > A p.(Arg2270Gln), NM_001080463.2:3133C > T p.(Gln1045Ter), and NM_001080463.2:c.337C > T p.(Arg113Trp); one novel variant in the IFT172 gene, NM_015662.3:4540-5 T > A; and one novel variant in the WDR19 gene, NM_025132.4:c.2596G > C p.(Gly866Arg). The genotypes of DYNC2H1, IFT172 and WDR19 and the phenotypes of the fetuses give hints for the diagnosis of short-rib thoracic dysplasia (SRTD) with or without polydactyly 3, 10, and 5, respectively. Conclusion Our findings expand the mutation spectrum of DYNC2H1, IFT172 and WDR19 associated with skeletal ciliopathies, and provide useful information for prenatal diagnosis and genetic counseling on rare skeletal disorders.

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INTU‐related oral‐facial‐digital syndrome XVII: Clinical spectrum of a rare disorder

Cited by 3 publications

References 10 publications

CPLANE Complex and Ciliopathies

CPLANE Complex and Ciliopathies

Pathogenic RAB34 variants impair primary cilium assembly and cause a novel oral-facial-digital syndrome

Clinical features and genetic analysis of a case series of skeletal ciliopathies in a prenatal setting

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