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Oral-facial-digital syndromes (OFDS) gather rare genetic disorders characterised by facial, oral and digital abnormalities associated with a wide range of additional features (polycystic kidney disease, cerebral malformations and several others) to delineate a growing list of OFDS subtypes. The most frequent, OFD type I, is caused by a heterozygous mutation in the OFD1 gene encoding a centrosomal protein. The wide clinical heterogeneity of OFDS suggests the involvement of other ciliary genes. For 15 years, we have aimed to identify the molecular bases of OFDS. This effort has been greatly helped by the recent development of whole-exome sequencing (WES). Here, we present all our published and unpublished results for WES in 24 cases with OFDS. We identified causal variants in five new genes ( C2CD3 , TMEM107 , INTU , KIAA0753 and IFT57 ) and related the clinical spectrum of four genes in other ciliopathies ( C5orf42 , TMEM138 , TMEM231 and WDPCP ) to OFDS. Mutations were also detected in two genes previously implicated in OFDS. Functional studies revealed the involvement of centriole elongation, transition zone and intraflagellar transport defects in OFDS, thus characterising three ciliary protein modules: the complex KIAA0753-FOPNL-OFD1, a regulator of centriole elongation; the Meckel-Gruber syndrome module, a major component of the transition zone; and the CPLANE complex necessary for IFT-A assembly. OFDS now appear to be a distinct subgroup of ciliopathies with wide heterogeneity, which makes the initial classification obsolete. A clinical classification restricted to the three frequent/well-delineated subtypes could be proposed, and for patients who do not fit one of these three main subtypes, a further classification could be based on the genotype., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Non-progressive congenital ataxias (NPCA) with or without intellectual disability (ID) are clinically and genetically heterogeneous conditions. As a consequence, the identification of the genes responsible for these phenotypes remained limited., Objective: Identification of a new gene responsible for NPCA and ID. Methods Following the discovery of three familial or sporadic cases with an intragenic calmodulin-binding transcription activator 1 (CAMTA1) rearrangement identified by an array-CGH and recruited from a national collaboration, the authors defined the clinical and molecular characteristics of such rearrangements, and searched for patients with point mutations by direct sequencing., Results: Intragenic copy number variations of CAMTA1 were all located in the CG-1 domain of the gene. It segregated with autosomal dominant ID with non-progressive congenital cerebellar ataxia (NPCA) in two unrelated families, and was de novo deletion located in the same domain in a child presenting with NPCA. In the patients with ID, the deletion led to a frameshift, producing a truncated protein, while this was not the case for the patient with isolated childhood ataxia. Brain MRI of the patients revealed a pattern of progressive atrophy of cerebellum medium lobes and superior vermis, parietal lobes and hippocampi. DNA sequencing of the CG-1 domain in 197 patients with sporadic or familial non-syndromic intellectual deficiency, extended to full DNA sequencing in 50 patients with ID and 47 additional patients with childhood ataxia, identified no pathogenic mutation., Conclusion: The authors have evidence that loss-of-function of CAMTA1, a brain-specific calcium responsive transcription factor, is responsible for NPCA with or without ID. Accession numbers CAMTA1 reference sequence used was ENST00000303635. Protein sequence was ENSP00000306522.