Clinical, molecular, and genotype-phenotype correlation studies from 25 cases of oral-facial-digital syndrome type 1: A French and Belgian Collaborative Study

Journal of Medical Genetics (Impact Factor: 6.34). 02/2006; 43(1):54-61. DOI: 10.1136/jmg.2004.027672
Source: PubMed


Oral-facial-digital syndrome type 1 (OFD1) is characterised by an X linked dominant mode of inheritance with lethality in males. Clinical features include facial dysmorphism with oral, tooth, and distal abnormalities, polycystic kidney disease, and central nervous system malformations. Large interfamilial and intrafamilial clinical variability has been widely reported, and 18 distinct mutations have been previously reported within OFD1. A French and Belgian collaborative study collected 25 cases from 16 families. OFD1 was analysed using direct sequencing and phenotype-genotype correlation was performed using chi2 test. X inactivation studies were performed on blood lymphocytes. In 11 families, 11 novel mutations, including nine frameshift, one nonsense, and one missense mutation were identified, which spanned nine different exons. A combination of our results with previously reported cases showed that the majority of mutations (65.5%) was located in exons 3, 8, 9, 13, and 16. There was phenotype-genotype correlation between (a) polycystic kidney disease and splice mutations; (b) mental retardation and mutations located in exons 3, 8, 9, 13, and 16; and (c) tooth abnormalities and mutations located in coiled coil domains. Comparing the phenotype of the families with a pathogenic mutation to families with absence of OFD1 mutation, polycystic kidneys and short stature were significantly more frequent in the group with no OFD1 mutation, whereas lingual hamartomas were significantly more frequent in the group with OFD1 mutation. Finally, an X inactivation study showed non-random X inactivation in a third of the samples. Differential X inactivation between mothers and daughters in two families with high intrafamilial variability was of particular interest. Slight phenotype-genotype correlations were established, and X inactivation study showed that skewed X inactivation could be partially involved in the pathogenesis of intrafamilial clinical variability.

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Available from: Didier Devys, Mar 25, 2015
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    • "Mutation analysis was performed as described [7,8]. Negative cases were subjected to semiquantitative fluorescent multiplex method (QFMPSF), and relative quantification by real-time PCR (qPCR) to identify genomic rearrangements as described [28]. "
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    ABSTRACT: Background Oral-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. Methods A 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. Results Seventeen 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. Conclusions Our 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.
    Full-text · Article · May 2014 · Orphanet Journal of Rare Diseases
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    • "Importantly, mutations of the OFD1 gene in humans can also result in defects of the craniofacial midline. A mid-sagittal section of a medical computed tomography scan of a patient with an OFD1 mutation (c.412G > A, p.G138S) demonstrated abnormalities of the sphenoid bone with defective ossification below the pituitary gland [26]. Clinical examination of the same patient revealed mid-facial anomalies, including a midline upper cleft lip (Figure 3g,h). "
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    ABSTRACT: Background The pituitary gland is formed by the juxtaposition of two tissues: neuroectoderm arising from the basal diencephalon, and oral epithelium, which invaginates towards the central nervous system from the roof of the mouth. The oral invagination that reaches the brain from the mouth is referred to as Rathke’s pouch, with the tip forming the adenohypophysis and the stalk disappearing after the earliest stages of development. In tetrapods, formation of the cranial base establishes a definitive barrier between the pituitary and oral cavity; however, numerous extinct and extant vertebrate species retain an open buccohypophyseal canal in adulthood, a vestige of the stalk of Rathke’s pouch. Little is currently known about the formation and function of this structure. Here we have investigated molecular mechanisms driving the formation of the buccohypophyseal canal and their evolutionary significance. Results We show that Rathke’s pouch is located at a boundary region delineated by endoderm, neural crest-derived oral mesenchyme and the anterior limit of the notochord, using CD1, R26R-Sox17-Cre and R26R-Wnt1-Cre mouse lines. As revealed by synchrotron X-ray microtomography after iodine staining in mouse embryos, the pouch has a lobulated three-dimensional structure that embraces the descending diencephalon during pituitary formation. Polarisfl/fl; Wnt1-Cre, Ofd1-/- and Kif3a-/- primary cilia mouse mutants have abnormal sonic hedgehog (Shh) signaling and all present with malformations of the anterior pituitary gland and midline structures of the anterior cranial base. Changes in the expressions of Shh downstream genes are confirmed in Gas1-/- mice. From an evolutionary perspective, persistence of the buccohypophyseal canal is a basal character for all vertebrates and its maintenance in several groups is related to a specific morphology of the midline that can be related to modulation in Shh signaling. Conclusion These results provide insight into a poorly understood ancestral vertebrate structure. It appears that the opening of the buccohypophyseal canal depends upon Shh signaling and that modulation in this pathway most probably accounts for its persistence in phylogeny.
    Full-text · Article · Mar 2013 · BMC Biology
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    • "However, classification into the subtypes is not always easy or clear, and additional subgroups have been proposed [5–7]. Only OFD syndrome type 1, which represents only a small portion of all OFD syndromes, has an established genetic defect so far [8,9]. This subtype is characterized by an X-linked dominant mode of inheritance with mutations in the OFD1 gene. "
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    ABSTRACT: The oral-facial-digital (OFD) syndrome is a heterogeneous group of abnormalities that share anomalies of the oral cavity, face and digits of hands and feet. On the basis of other anomalies of brain, kidneys, limbs, eyes and other organs, at least 13 subgroups have been described. We here describe four unrelated patients with this syndrome, who have the typical facial, oral and digital anomalies and also anomalies of other organs and systems. Facial features, digital malformations, as well as the existence of additional malformations all of which can be classified into different subgroups. The report points out the difficulty in delineation of the subtypes of OFD syndrome because of the overlapping features between OFD subgroups.
    Full-text · Article · Jun 2012 · Balkan Journal of Medical Genetics
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