C5orf42 is the major gene responsible for OFD syndrome type VI

Lopez, Estelle; Thauvin‐Robinet, Christel; Reversade, Bruno; Khartoufi, Nadia El; Devisme, Louise; Holder, Muriel; Ansart-Franquet, Hélène; Avila, Magali; Lacombe, Didier; Kleinfinger, Pascale; Kaori, Irahara; Takanashi, Jun‐ichi; Merrer, Martine Le; Martinovic, Jéléna; Noël, Catherine; Shboul, Mohammad; Ho, Lena; Güven, Yeliz; Razavi, F.; Bürglen, Lydie; Gigot, Nadège; Darmency-Stamboul, Véronique; Thévenon, Julien; Aral, Bernard; Kayserili, Hülya; Huet, Frédéric; Lyonnet, Stanislas; Caignec, Cédric Le; Franco, Brunella; Rivière, Jean‐Baptiste; Faivre, Laurence; Attié‐Bitach, Tania

doi:10.1007/s00439-013-1385-1

Cited by 72 publications

(84 citation statements)

References 31 publications

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“…[24][25][26] One of our cases showed polydactyly of all limbs that was postaxial in all instances (in the literature, preaxial and mesoaxial polydactyly is also reported frequently). 24,26,27 In another case reported in the literature (from a consanguineous mating), an occipital meningocele and abnormal electroretinogram (ERG) were described, 25 neither of which were present in our cases.…”

Section: C5orf42 Tmem67 and Ahi1 Are Important Jbs Genes In The Normentioning

confidence: 54%

“…28 There has been some debate in the literature whether C5orf42 may be the major gene for OFD VI. 26,27 None of the six cases in our cohort showed typical signs of OFD VI, whereas no deleterious variants were found in any of the genes tested in the one case in our cohort with the OFD VI phenotype.…”

Section: C5orf42 Tmem67 and Ahi1 Are Important Jbs Genes In The Normentioning

confidence: 58%

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Joubert syndrome: genotyping a Northern European patient cohort

et al. 2015

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Joubert syndrome (JBS) is a rare neurodevelopmental disorder belonging to the group of ciliary diseases. JBS is genetically heterogeneous, with 420 causative genes identified to date. A molecular diagnosis of JBS is essential for prediction of disease progression and genetic counseling. We developed a targeted next-generation sequencing (NGS) approach for parallel sequencing of 22 known JBS genes plus 599 additional ciliary genes. This method was used to genotype a cohort of 51 well-phenotyped Northern European JBS cases (in some of the cases, Sanger sequencing of individual JBS genes had been performed previously). Altogether, 21 of the 51 cases (41%) harbored biallelic pathogenic mutations in known JBS genes, including 14 mutations not previously described. Mutations in C5orf42 (12%), TMEM67 (10%), and AHI1 (8%) were the most prevalent. C5orf42 mutations result in a purely neurological Joubert phenotype, in one case associated with postaxial polydactyly. Our study represents a population-based cohort of JBS patients not enriched for consanguinity, providing insight into the relative importance of the different JBS genes in a Northern European population. Mutations in C5orf42 are relatively frequent (possibly due to a Dutch founder mutation) and mutations in CEP290 are underrepresented compared with international cohorts. Furthermore, we report a case with heterozygous mutations in CC2D2A and B9D1, a gene associated with the more severe Meckel-Gruber syndrome that was recently published as a potential new JBS gene, and discuss the significance of this finding.

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Section: C5orf42 Tmem67 and Ahi1 Are Important Jbs Genes In The Normentioning

confidence: 54%

Section: C5orf42 Tmem67 and Ahi1 Are Important Jbs Genes In The Normentioning

confidence: 58%

Joubert syndrome: genotyping a Northern European patient cohort

et al. 2015

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“…Interestingly, two OFDVI patients were reported to have a homozygous mutation in TMEM216 , a gene implicated in JSRD and Meckel-Gruber syndrome (MKS) [47], and a mutation in the OFD1 transcript has been reported in an OFDVI case [48]. More recently a high frequency of mutations in C5ORF42 has been reported in OFDVI patients [49]. One out of the 71 OFD1 cases that we have analyzed displayed a typical MTS.…”

Section: Discussionmentioning

confidence: 95%

CNS involvement in OFD1 syndrome: a clinical, molecular, and neuroimaging study

Giudice¹,

Macca

Imperati³

et al. 2014

Orphanet J Rare Dis

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BackgroundOral-facial-digital type 1 syndrome (OFD1; OMIM 311200) belongs to the expanding group of disorders ascribed to ciliary dysfunction. With the aim of contributing to the understanding of the role of primary cilia in the central nervous system (CNS), we performed a thorough characterization of CNS involvement observed in this disorder.MethodsA cohort of 117 molecularly diagnosed OFD type I patients was screened for the presence of neurological symptoms and/or cognitive/behavioral abnormalities on the basis of the available information supplied by the collaborating clinicians. Seventy-one cases showing CNS involvement were further investigated through neuroimaging studies and neuropsychological testing.ResultsSeventeen patients were molecularly diagnosed in the course of this study and five of these represent new mutations never reported before. Among patients displaying neurological symptoms and/or cognitive/behavioral abnormalities, we identified brain structural anomalies in 88.7%, cognitive impairment in 68%, and associated neurological disorders and signs in 53% of cases. The most frequently observed brain structural anomalies included agenesis of the corpus callosum and neuronal migration/organisation disorders as well as intracerebral cysts, porencephaly and cerebellar malformations.ConclusionsOur results support recent published findings indicating that CNS involvement in this condition is found in more than 60% of cases. Our findings correlate well with the kind of brain developmental anomalies described in other ciliopathies. Interestingly, we also described specific neuropsychological aspects such as reduced ability in processing verbal information, slow thought process, difficulties in attention and concentration, and notably, long-term memory deficits which may indicate a specific role of OFD1 and/or primary cilia in higher brain functions.

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“…Because both JS and hydrolethalus syndrome are known to be associated with KIF7 and KIAA0586 (13)(14)(15)(16), HYLS1 is the third gene associated with JS and hydrolethalus syndrome. This study also suggested that HYLS1 is the fourth gene associated with OFD VI after C5orf42, TMEM216, and OFD1 (9,17,18). These observations illustrate clinical variability in ciliopathies and the concept that lethal ciliopathies represent the 'extreme phenotypes' of viable disorders, as in case of the lethal Meckel syndrome.…”

Section: Discussionmentioning

confidence: 75%

A novel HYLS1 homozygous mutation in living siblings with Joubert syndrome

et al. 2016

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The p.Asp211Gly homozygous HYLS1 mutation is so far known to cause only hydrolethalus syndrome, a lethal malformation syndrome. We report living sibling patients with a homozygous no-stop mutation in exon 4 of HYLS1, NM_145014.2:c.900A>C (p.Ter300TyrextTer11) in the second decade of life. The proband has Joubert syndrome (JS). The younger brother also has JS and an enlarged posterior fossa that was initially diagnosed as Dandy-Walker malformation. The present mutation is unique as it affects the stop codon. The product protein HYLS1 plays an essential role in the formation of the primary cilium. This report provides insight into the spectrum of disorders involving midline brain defects closely related to cilium dysfunction or ciliopathy.

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C5orf42 is the major gene responsible for OFD syndrome type VI

Cited by 72 publications

References 31 publications

Joubert syndrome: genotyping a Northern European patient cohort

Joubert syndrome: genotyping a Northern European patient cohort

CNS involvement in OFD1 syndrome: a clinical, molecular, and neuroimaging study

A novel HYLS1 homozygous mutation in living siblings with Joubert syndrome

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