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BackgroundSegmentation defects of the vertebrae (SDV) are non-specific features found in various syndromes. The molecular bases of SDV are not fully elucidated due to the wide range of phenotypes and classification issues. The genes involved are in the Notch signalling pathway, which is a key system in somitogenesis. Here we report on mutations identified in a diagnosis cohort of SDV. We focused on spondylocostal dysostosis (SCD) and the phenotype of these patients in order to establish a diagnostic strategy when confronted with SDV.Patients and methodsWe used DNA samples from a cohort of 73 patients and performed targeted sequencing of the five known SCD-causing genes (DLL3, MESP2, LFNG, HES7 and TBX6) in the first 48 patients and whole-exome sequencing (WES) in 28 relevant patients.ResultsTen diagnoses, including four biallelic variants in TBX6, two biallelic variants in LFNG and DLL3, and one in MESP2 and HES7, were made with the gene panel, and two diagnoses, including biallelic variants in FLNB and one variant in MEOX1, were made by WES. The diagnostic yield of the gene panel was 10/73 (13.7%) in the global cohort but 8/10 (80%) in the subgroup meeting the SCD criteria; the diagnostic yield of WES was 2/28 (8%).ConclusionAfter negative array CGH, targeted sequencing of the five known SCD genes should only be performed in patients who meet the diagnostic criteria of SCD. The low proportion of candidate genes identified by WES in our cohort suggests the need to consider more complex genetic architectures in cases of SDV.

Townes‐Brocks syndrome is an autosomal dominantly inherited disorder, which comprises multiple birth defects including renal, ear, anal, and limb malformations. TBS has been shown to result from mutations in SALL1, a human gene related to the developmental regulator SAL of Drosophila melanogaster. The SALL1 gene product is a zinc finger protein thought to act as a transcription factor. It contains four highly conserved, evenly distributed C2H2 double zinc finger domains. A single C2H2 motif is attached to the second domain, and at the amino terminus SALL1 contains a C2HC motif. Most mutations causing TBS are clustered in the N‐terminal third of the SALL1 coding region and result in the production of truncated proteins containing only one or none of the C2H2 domains and the N‐terminal transcriptional repressor domain of SALL1. Twenty‐three SALL1 mutations were reported prior to this work, 22 of which are located in exon 2, 5′ of the second double zinc finger‐encoding region. Here we present 12 novel mutations in SALL1 associated with Townes‐Brocks syndrome in 13 unrelated families. These include three nonsense mutations, three short insertions and six short deletions. Thus the number of SALL1 mutations increases to 35. Rare phenotypical features among mutation positive patients include hypothyroidism, vaginal aplasia with bifid uterus, cryptorchidism, bifid scrotum without hypospadia scrotalis, unilateral chorioretinal coloboma with loss of vision, dorsal hypoplasia of the corpus callosum, and umbilical hernia. © 2005 Wiley‐Liss, Inc.

John Wallingford and colleagues combine proteomics, in vivo imaging and genetic analyses to identify a new ciliopathy-associated protein module, which they call CPLANE. They show that CPLANE proteins, which include Fuzzy, Inturned and Wdpcp, interact with Jbts17 at basal bodies, where they act to recruit a specific subset of intraflagellar transport proteins. Cilia use microtubule-based intraflagellar transport (IFT) to organize intercellular signaling. Ciliopathies are a spectrum of human diseases resulting from defects in cilia structure or function. The mechanisms regulating the assembly of ciliary multiprotein complexes and the transport of these complexes to the base of cilia remain largely unknown. Combining proteomics, in vivo imaging and genetic analysis of proteins linked to planar cell polarity (Inturned, Fuzzy and Wdpcp), we identified and characterized a new genetic module, which we term CPLANE (ciliogenesis and planar polarity effector), and an extensive associated protein network. CPLANE proteins physically and functionally interact with the poorly understood ciliopathy-associated protein Jbts17 at basal bodies, where they act to recruit a specific subset of IFT-A proteins. In the absence of CPLANE, defective IFT-A particles enter the axoneme and IFT-B trafficking is severely perturbed. Accordingly, mutation of CPLANE genes elicits specific ciliopathy phenotypes in mouse models and is associated with ciliopathies in human patients.

While the XYY and XXYY syndromes have been several time described in patients, the combination of both syndromes in an individual is a rare event and may result in a severe phenotype. In the present observation, a boy with congenital scoliosis due to segmented thoracic hemivertebra associated with radioulnar synostosis and congenital heart disease is described. Chromosome G-banding and FISH analysis demonstrated a de novo mosaic karyotype 48, XXYY/47, XYY in this patient. To the best of our knowledge, this is the first report of a combination of XYY and XXYY syndromes.

Treacher Collins/Franceschetti syndrome (TCS; OMIM 154500) is a disorder of craniofacial development belonging to the heterogeneous group of mandibulofacial dysostoses. TCS is classically characterized by bilateral mandibular and malar hypoplasia, downward-slanting palpebral fissures, and microtia. To date, three genes have been identified in TCS:,TCOF1, POLR1D, and POLR1C. We report a clinical and extensive molecular study, including TCOF1, POLR1D, POLR1C, and EFTUD2 genes, in a series of 146 patients with TCS. Phenotype–genotype correlations were investigated for 19 clinical features, between TCOF1 and POLR1D, and the type of mutation or its localization in the TCOF1 gene. We identified 92/146 patients (63%) with a molecular anomaly within TCOF1, 9/146 (6%) within POLR1D, and none within POLR1C. Among the atypical negative patients (with intellectual disability and/or microcephaly), we identified four patients carrying a mutation in EFTUD2 and two patients with 5q32 deletion encompassing TCOF1 and CAMK2A in particular. Congenital cardiac defects occurred more frequently among patients with TCOF1 mutation (7/92, 8%) than reported in the literature. Even though TCOF1 and POLR1D were associated with extreme clinical variability, we found no phenotype–genotype correlation. In cases with a typical phenotype of TCS, 6/146 (4%) remained with an unidentified molecular defect.

Oral-facial-digital syndromes (OFDS) gather rare genetic disorders characterized 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 OFD 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 OFDS cases. We identified causal variants in five new genes (C2CD3, TMEM107, INTU, KIAA0753, IFT57) and related the clinical spectrum of four genes in other ciliopathies (C5orf42, TMEM138, TMEM231, 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 characterizing three ciliary protein modules: the complex KIAA0753-FOPNL-OFD1, a regulator of centriole elongation; the MKS 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 3 main subtypes, a further classification could be based on the genotype.

Van der Woude syndrome (VWS), caused by dominant IRF6 mutation, is the most common cleft syndrome. In 15% of the patients, lip pits are absent and the phenotype mimics isolated clefts. Therefore, we hypothesized that some of the families classified as having non-syndromic inherited cleft lip and palate could have an IRF6 mutation. We screened in total 170 patients with cleft lip with or without cleft palate (CL/P): 75 were syndromic and 95 were a priori part of multiplex non-syndromic families. A mutation was identified in 62.7 and 3.3% of the patients, respectively. In one of the 95 a priori non-syndromic families with an autosomal dominant inheritance (family B), new insights into the family history revealed the presence, at birth, of lower lip pits in two members and the diagnosis was revised as VWS. A novel lower lip sign was observed in one individual in this family. Interestingly, a similar lower lip sign was also observed in one individual from a 2nd family (family A). This consists of 2 nodules below the lower lip on the external side. In a 3rd multiplex family (family C), a de novo mutation was identified in an a priori non-syndromic CL/P patient. Re-examination after mutation screening revealed the presence of a tiny pit-looking lesion on the inner side of the lower lip leading to a revised diagnosis of VWS. On the basis of this data, we conclude that IRF6 should be screened when any doubt rises about the normality of the lower lip and also if a non-syndromic cleft lip patient (with or without cleft palate) has a family history suggestive of autosomal dominant inheritance. Copyright © 2010 S. Karger AG, Basel [PUBLICATION ABSTRACT]

The occurrence of mosaic ring chromosome 13 is rare. The mechanism of ring chromosome formation is usually associated with loss of genetic material. We report 2 cases of mosaic ring chromosome 13, resulting in deletion of 13qter. The first patient, a 15 year-old boy, presented a delayed psychomotor development, mental retardation, dysmorphic features and bleeding disorders associated with a de novo terminal 13q34 deletion. The second case was a foetus of 31 weeks with prenatal diagnosis of severe malformation such as holoprosencephaly, congenital cardiac defects, gastro-intestinal abnormalities with intrauterine growth retardation, the molecular analysis showed a de novo deletion encompassing the region 13q31.3-q34.