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... 1). The grandmother’s facial features were typical of OFD1. She did not have cleft palate like her daughter and granddaughter. Instead, alveolar notching with miss- ing teeth were seen. No abnormalities of the hands were seen. At the age of 44 years, she had just undergone a kidney trans- plant because of polycystic kidney disease. The kidney disease had been discovered by chance on routine gynaecological examination one year earlier and dialysis treatment was started almost immediately after that. She was unwilling to participate in genetic DNA studies. The daughter had small hands and feet with brachydactyly of the fifth fingers. The syndactyly of her fourth and fifth fingers of the left hand had been operated on as a child. Renal ultrasonography was performed at the age of 23, when the diagnosis of OFD1 was confirmed. Multiple cysts were seen in the right kidney, but no signs of renal failure in the laboratory examinations was found. The granddaughter, aged 1.5 years, has developed nor- mally. In the extremities, there was only mild clinodactyly of the fifth fingers. The cleft palate was asymmetrical. Alveolar notching, suggesting tooth aplasia, and mucobuccal fibrous bands were seen. No signs of retardation were detected in this family. We found a T>G change in intron 5 of the OFD1 gene in the daughter and the granddaughter. The mutation is located 10 nucleotides before the starting nucleotide of exon 6 (fig 3) where it creates a novel splice acceptor site (and adds three novel amino acids to the 5 ′ end of exon 6) resulting in an alternative splicing of mRNA. This was confirmed by the RNA studies described in the Methods section (fig 4). In family II (fig 1), the mother and her two daughters were clinically examined and their facial features and other signs were typical of OFD1 syndrome (table 2). All three patients studied had midline pseudocleft of the upper lip, but no operations had been performed. The tongues of the mother and the older daughter were bilobulated and the younger daughter had multiple lobules in her tongue. No-one in this family had had problems with kidney function and no ultrasonographic examinations of the kidneys were performed. At the age of 42 years, the mother was diagnosed with hyperthyreosis, which was treated with radioactive iodine. The younger daughter had been operated on at the age of 1 year because of a medially located, supernumerary distal phalanx in the right hallux. The left leg grew 3 cm longer than the right leg and at the age of 13 years an orthopaedic operation was performed. The left breast has grown bigger than the right with mastopathic changes. Her mental development has been mildly delayed and she attended a special school. In the older daughter, vaginal bleeding started at the age of 3 months. After investigations, hormonal medication was given for precocious puberty. Epileptic seizures began at the age of 2 1 ⁄ 2 years. Repeated CT scan of the brain showed a hypothalamic hamartoma, which was thought to be the rea- son for the precocious puberty through excretion of hypothalamic hormones. She had short stature with a final height of 1.45 m ( − 3.5 SD) and small hands and feet. The fourth metatarsals were short, especially in the right foot. She attended a special school for handicapped children because of moderate mental retardation and received medication for psychiatric symptoms for a couple of years. In this family, an insertion of AT between nucleotides 1887 and 1888 in exon 16 was detected in all three family members (fig 3). This creates a frameshift resulting in a premature stop codon (TAG) at amino acid position 666 of the OFD1 gene. In family III, the only patient studied had syndactyly of the fourth and fifth fingers of the left hand that had been operated on at the ages of 5 and 11 years. On ultrasonographic examination, numerous small cysts were detected in both kidneys at the age of 29 years. Functional studies of the kidneys were normal. In this patient a missense mutation G>A at nucleotide 235 in exon 3 was identified (table 1, fig 3). This transversion leads to a change of a non-polar amino acid alanine (A) to an uncharged polar amino acid threonine (T). We analysed DNA samples from both parents by minisequencing and no abnormalities were found, indicating that this is a de novo mutation. In family IV, the index case was first examined at the age of 6 months. The first diagnostic signs were a prominent metopic ridge and a soft nodule (about 0.5 cm in diameter) medially in the right hallux. Psychomotor development has proceeded within normal limits. In this patient, a deletion of A at nucleotide 1409 in exon 13 leading to a frameshift was identified. This mutation results in a premature stop codon (TAG) at position 472. DNA from both parents was analysed and no mutations were found. None of the four mutations was identified in the DNA of 50 anonymous Finnish blood donors screened by minisequencing. The results of the RT-PCR experiments (fig 4) show that in both the patient and the control sample the products generated by RT-PCR amplifying the area flanking the putative novel splice site are of similar size, indicating that the normal sized mRNA could be found in both samples. However, the splice site specific RT-PCR resulted in the identification of the product only in the patient’s sample. This indicates that the intronic nucleotide change T >G residing 10 nucleotides from the splice acceptor site of exon 6 generates a false splice site and so is most likely the cause of the disease in this patient. Eight OFD1 patients have been diagnosed in Finland, consist- ing of a population of about 5 million, during the last 20 years. In all of them, a mutation in the recently identified OFD1 (Cxorf5) gene was found. Two of them were nonsense, one missense, and one splice mutation. The clinical features were characteristic in every patient. Interestingly, one of our patients had short fourth metatarsals, similar to a patient described by Ferrante et al . Mild or moderate mental retardation was seen in one of the families with the two daughters with learning difficulties. Renal involvement in OFD1 cases may be as high as 50%. 10 In three out of eight Finnish patients, polycystic kidney disease was present, and one of them received a new kidney at the age of 44 years. The mutations that were associated with polycystic kidney disease in the Finnish patients were the splice mutation in intron 5 and a missense mutation G>A at nucleotide 235 in exon 3. In the original report by Ferrante et al , 8 polycystic kidney disease was also associated with mutations in exon 3 but also in intron 4. Polycystic kidney disease usually manifests in adulthood, so two of our patients are too young to be able to draw any conclusions about kidney disease. When analysing the phenotype-genotype correlation con- cerning mental retardation associated with this syndrome, mild to moderate mental retardation or learning difficulties were reported with mutations in exons 3, 13, and 16, and intron 4 in the original study. 8 In this study, only the frameshift mutation in exon 16 was associated with learning difficulties in two out of three members of the same family. Further studies are needed to know whether certain mutations are more frequently associated with kidney disease or mental retardation, the findings that are important in genetic counselling when predicting the outcome of the disease. The OFD1 gene contains 23 coding exons (GenBank acces- sion numbers Y15164 and Y16355) with unknown function. 11 Interestingly, three of the mutations found in this study are located in the same exons 3, 13, and 16 as the mutations reported in the original study by Ferrante et al , 8 suggesting that these exons might represent regions for mutational hot spots. Functional studies of both the wild type OFD1 gene and the mutants are needed to understand the disease mechanism underlying OFD1. In conclusion, we report here the identification of four novel mutations in the OFD1 gene in seven Finnish patients with oral-facial-digital syndrome type I. Our results confirm the causative role of the OFD1 gene in the pathogenesis of this syndrome. We are grateful to the patients and their families for their participation in this study. We thank Sirkka Elfving and Eino Puhakainen for encouragement during this study and the personnel of the Laboratory of Molecular Genetics for technical help. Financial support from Helsinki University Hospital Research Funding is ...
Context 2
... the Department of Medical Genetics of The Family Federation of Finland, which serves the whole country, and the Clinical Genetics Unit of Helsinki University Central Hospital, which serves the densely populated south of Finland in clinical genetics. All the patients were examined (fig 1) and their files and hospital records analysed by one of the authors (SA-M). DNA extracted from peripheral EDTA blood of the patients was screened for mutations in the OFD1 gene using primer sequences kindly provided by Dr Brunella Franco from Telethon Institute of Genetics and Medicine (TIGEM). PCR amplifications of the samples were run through 35 cycles con- sisting of 40 seconds at 94°C (denaturation), 40 seconds at 55 or 50°C (annealing), and one minute at 72°C (extension) with the final extension step of 5-10 minutes covering all 23 exons. Sequencing of PCR products was performed using ABI PRISM7 BigDye Terminator Cycle Sequencing Kit, Version 2.0 (Applied Biosystems, Foster City, CA, USA) in both directions and analysed using an ABI PRISM7 3100 Genetic Analyzer according to the manufacturer’s instructions. The presence of a mutation was confirmed by minisequencing 9 of the DNA in each family member. To exclude the presence of each of the mutations in random subjects, DNA extracted from buffy coat samples of 50 anonymous Finnish blood donors were analysed by minisequencing. Ethical approval for the study was obtained from the ethical committee of Helsinki University Hospital and the Finnish Red Cross Transfusion Service. RNA was isolated from heparin blood samples of the control and the youngest patient from family I (fig 1) carrying the intronic mutation IVS5-10T>G using the QIAamp RNA Blood Mini kit (Qiagen, Hilden, Germany). This mutation generates a putative novel splice site in exon 6. The mRNA was reverse transcribed to cDNA using 1 μ g of total RNA, 10 units of AMV reverse transcriptase (Promega M5101) in the presence of 20 units of recombinant RNase inhibitor (RNasin, Promega, N2511), and 25 nmol dNTPs. The reaction was allowed to take place at 42°C for one hour, after which the cDNA was diluted with 1.7 volumes of DNA-TE-Buffer (10 mmol/l Tris-HCl, pH 7.8, 1 mmol/l EDTA) and stored at − 20°C. cDNA synthesis was primed with the antisense primer 5 ′ -ACTTGTCTGAGTTTCCATATTACAACTC-3 ′ located in the coding sequence of exon 6 of the OFD1 mRNA. For PCR two sense primers were designed. The first one, 5 ′ - CATTAAAATCAACCCTACTTCCAGTCTC-3 ′ , located in exon 4, together with the reverse primer used in the reverse transcription flanked the putative new splice site. The second sense primer 5 ′ -AGGATCTGATAAAGAAAATCAAAAAGGTTT TTTAGGTTT-3 ′ was designed to anneal exclusively over the putative novel splice site to give a product only if this putative new splice site was transcribed (fig 2). We found four novel mutations in the OFD1 gene (table 1, fig 3) in two sporadic patients and in two families, both containing three patients with OFD1 syndrome (fig 1). The clinical features of the patients shown in table 2 were characteristic of OFD1 syndrome. In each case a novel mutation in the recently discovered OFD1 gene was identified; two of them were frameshifts, one was a missense mutation, and one was a splice mutation. In family I, the syndrome was diagnosed in three successive generations (fig 1). The grandmother’s facial features were typical of OFD1. She did not have cleft palate like her daughter and granddaughter. Instead, alveolar notching with miss- ing teeth were seen. No abnormalities of the hands were seen. At the age of 44 years, she had just undergone a kidney trans- plant because of polycystic kidney disease. The kidney disease had been discovered by chance on routine gynaecological examination one year earlier and dialysis treatment was started almost immediately after that. She was unwilling to participate in genetic DNA studies. The daughter had small hands and feet with brachydactyly of the fifth fingers. The syndactyly of her fourth and fifth fingers of the left hand had been operated on as a child. Renal ultrasonography was performed at the age of 23, when the diagnosis of OFD1 was confirmed. Multiple cysts were seen in the right kidney, but no signs of renal failure in the laboratory examinations was found. The granddaughter, aged 1.5 years, has developed nor- mally. In the extremities, there was only mild clinodactyly of the fifth fingers. The cleft palate was asymmetrical. Alveolar notching, suggesting tooth aplasia, and mucobuccal fibrous bands were seen. No signs of retardation were detected in this family. We found a T>G change in intron 5 of the OFD1 gene in the daughter and the granddaughter. The mutation is located 10 nucleotides before the starting nucleotide of exon 6 (fig 3) where it creates a novel splice acceptor site (and adds three novel amino acids to the 5 ′ end of exon 6) resulting in an alternative splicing of mRNA. This was confirmed by the RNA studies described in the Methods section (fig 4). In family II (fig 1), the mother and her two daughters were clinically examined and their facial features and other signs were typical of OFD1 syndrome (table 2). All three patients studied had midline pseudocleft of the upper lip, but no operations had been performed. The tongues of the mother and the older daughter were bilobulated and the younger daughter had multiple lobules in her tongue. No-one in this family had had problems with kidney function and no ultrasonographic examinations of the kidneys were performed. At the age of 42 years, the mother was diagnosed with hyperthyreosis, which was treated with radioactive iodine. The younger daughter had been operated on at the age of 1 year because of a medially located, supernumerary distal phalanx in the right hallux. The left leg grew 3 cm longer than the right leg and at the age of 13 years an orthopaedic operation was performed. The left breast has grown bigger than the right with mastopathic changes. Her mental development has been mildly delayed and she attended a special school. In the older daughter, vaginal bleeding started at the age of 3 months. After investigations, hormonal medication was given for precocious puberty. Epileptic seizures began at the age of 2 1 ⁄ 2 years. Repeated CT scan of the brain showed a hypothalamic hamartoma, which was thought to be the rea- son for the precocious puberty through excretion of hypothalamic hormones. She had short stature with a final height of 1.45 m ( − 3.5 SD) and small hands and feet. The fourth metatarsals were short, especially in the right foot. She attended a special school for handicapped children because of moderate mental retardation and received medication for psychiatric symptoms for a couple of years. In this family, an insertion of AT between nucleotides 1887 and 1888 in exon 16 was detected in all three family members (fig 3). This creates a frameshift resulting in a premature stop codon (TAG) at amino acid position 666 of the OFD1 gene. In family III, the only patient studied had syndactyly of the fourth and fifth fingers of the left hand that had been operated on at the ages of 5 and 11 years. On ultrasonographic examination, numerous small cysts were detected in both kidneys at the age of 29 years. Functional studies of the kidneys were normal. In this patient a missense mutation G>A at nucleotide 235 in exon 3 was identified (table 1, fig 3). This transversion leads to a change of a non-polar amino acid alanine (A) to an uncharged polar amino acid threonine (T). We analysed DNA samples from both parents by minisequencing and no abnormalities were found, indicating that this is a de novo mutation. In family IV, the index case was first examined at the age of 6 months. The first diagnostic signs were a prominent metopic ridge and a soft nodule (about 0.5 cm in diameter) medially in the right hallux. Psychomotor development has proceeded within normal limits. In this patient, a deletion of A at nucleotide 1409 in exon 13 leading to a frameshift was identified. This mutation results in a premature stop codon (TAG) at position 472. DNA from both parents was analysed and no mutations were found. None of the four mutations was identified in the DNA of 50 anonymous Finnish blood donors screened by minisequencing. The results of the RT-PCR experiments (fig 4) show that in both the patient and the control sample the products generated by RT-PCR amplifying the area flanking the putative novel splice site are of similar size, indicating that the normal sized mRNA could be found in both samples. However, the splice site specific RT-PCR resulted in the identification of the product only in the patient’s sample. This indicates that the intronic nucleotide change T >G residing 10 nucleotides from the splice acceptor site of exon 6 generates a false splice site and so is most likely the cause of the disease in this patient. Eight OFD1 patients have been diagnosed in Finland, consist- ing of a population of about 5 million, during the last 20 years. In all of them, a mutation in the recently identified OFD1 (Cxorf5) gene was found. Two of them were nonsense, one missense, and one splice mutation. The clinical features were characteristic in every patient. Interestingly, one of our patients had short fourth metatarsals, similar to a patient described by Ferrante et al . Mild or moderate mental retardation was seen in one of the families with the two daughters with learning difficulties. Renal involvement in OFD1 cases may be as high as 50%. 10 In three out of eight Finnish patients, polycystic kidney disease was present, and one of them received a new kidney at the age of 44 years. The mutations that were associated with polycystic kidney disease in the Finnish patients were the splice mutation in intron 5 and a missense mutation G>A at nucleotide 235 in exon 3. In the original report by Ferrante et al , 8 polycystic kidney disease was also associated with mutations in exon 3 but also in ...
Citations
... The other types are extremely rare. 157 The prevalence of oro-facial-digital syndrome type 1 is unknown, but the annual incidence is estimated to be between 1:250 000 and 1:50 000 live births. 158 It is transmitted as an X-linked dominant trait, which occurs mostly in females; the disease has lethal effects in males. ...
A large number of disorders may affect the oral cavity, including genetic diseases, infections, cancers, blood diseases, skin diseases, endocrine and metabolic disorders, autoimmune and rheumatologic diseases, local lesions, to name a few. Oral mucosa shows a considerable variation in its normal structure and a wide range of conditions may affect it. Such conditions are often harmless or minor and could be primary or secondary to systemic disease. Several of them are quite rare and, hence, the diagnosis is not easy. Clinically, lesions may appear as ulcers, discoloration of the oral mucosa and alterations in size and configuration of oral anatomy. Genetic disorders have specific manifestations and can be caused by a derangement of one or more components of the tissue. Many of them follow the skin or systemic signs of the underlying genetic disease, but in a few cases oral signs could be the first manifestation of the disorder. Among them genodermatoses are prominent. They are inherited disorders characterized by a multisystem involvement. This review describes chondro‐ectodermal dysplasia, dyskeratosis congenita, Ehlers‐Danlos syndrome, hereditary benign intraepithelial dyskeratosis, keratosis follicularis, lipoid proteinosis, multiple hamartoma syndrome, pachyonychia congenita, Peutz‐Jeghers syndrome, tuberous sclerosis and white sponge nevus. Other genetic disorders not included in the genodermatosis group and reported in the present review are: acanthosis nigricans, angio‐osteo‐hypertrophic syndrome, encephalotrigeminal angiomatosis, familial adenomatous polyposis, focal dermal hypoplasia, focal palmoplantar and oral mucosa hyperkeratosis syndrome, gingival fibromatosis, Maffucci's syndrome, neurofibromatosis (type 1) and oro‐facial‐digital syndrome (type 1). Disorders during embryonic development might lead to a wide range of abnormalities in the oral cavity; some of them are quite common but of negligible concern, whereas others are rare but serious, affecting not only the oral mucosa, but also other structures of the oral cavity (ie palate, tongue and gingiva). Fordyce′s granules, leukoedema, cysts of the oral mucosa in newborns, retrocuspid papilla, geographic tongue, fissured tongue, median rhomboid glossitis, hairy tongue, lingual varices and lingual thyroid nodule are described. This review may help dentists, dental hygienists, but also general internists and pediatricians to diagnose different disorders of the oral mucosa, to understand the pathogenesis and to schedule a treatment plan.
... Mutation detection in OFD1 is necessary for definitive diagnosis, especially for genetic counselling, preimplantation genetic diagnosis (PGD) and/or prenatal diagnosis. Fig. 5 demonstrates the frequency of reported OFD1 mutations (6,10,(14)(15)(16)(17)(22)(23)(24)(25)(26)(27)(28)(29)(30). Majority of mutations in OFD1 have been identified in exons 3, 7, 8, 9, 12, 13 and 16, which may represent mutational hotspots. ...
Oral-facial-digital syndrome as heterogeneous developmental conditions is characterized by abnormalities in the oral cavity, facial features and digits. Furthermore, central nervous system (CNS) abnormalities can also be part of this developmental disorder. At least 13 forms of OFDS based on their pattern of signs and symptoms have been identified so far. Type 1 which is now considered to be a ciliopathy accounts for the majority of cases. It is transmitted in an X-linked dominant pattern and caused by mutations in OFD1 gene, which can result in embryonic male lethality. In this study, we present a family suffering from orofaciodigital syndrome type I who referred to Medical Genetics Research Center, Shahid Sadoughi University of Medical Sciences in 2015. Two female siblings and their mother shared a novel 2-base pair deletion (c.1964-1965delGA) in exon 16 of OFD1 gene. Clinically, the sibling had oral, facial and brain abnormalities, whereas their mother is very mildly affected. She also had history of recurrent miscarriage of male fetus.
... It has been suggested that OFD1 mutations that truncate the protein before Asn630 are embryonic lethal in males and cause OFD type I in females. 16,39 All the identified mutations caused truncations prior to Asn630 (Fig 2B, dashed line). Because somatic OFD1 truncation mutations were exclusively identified in male individuals, OFD1 function must be severely impaired in all cells possessing the mutation, suggesting that an absence of OFD1 activity is required for hamartoma formation. ...
... (B) Three coiled coil domains and a LIS1 homology domain (LisH) of OFD1 are shown (UniProt KB, O75665). Truncation mutations in OFD1 prior to Asn630 have been reported to cause OFD type I in females and embryonic lethality in males 16,39 . All the identified mutations caused truncations prior to Asn630 (dashed line). ...
Objective:
Hypothalamic hamartoma (HH) is a congenital anomalous brain tumor. Although most HHs are found without any other systemic features, HH is observed in syndromic disorders such as Pallister-Hall syndrome (PHS) and oral-facial-digital syndrome (OFD). Here, we explore the possible involvement of somatic mutations in HH.
Methods:
We analyzed paired blood and hamartoma samples from 18 individuals, including three with digital anomalies, by whole-exome sequencing. Detected somatic mutations were validated by Sanger sequencing and deep sequencing of target amplicons. The effect of GLI3 mutations on its transcriptional properties was evaluated by luciferase assays using reporters containing eight copies of the GLI-binding site and a mutated control sequence disrupting GLI binding.
Results:
We found hamartoma-specific somatic truncation mutations in GLI3 and OFD1, known regulators of sonic hedgehog (Shh) signaling, in two and three individuals, respectively. Deep sequencing of amplicons covering the mutations showed mutant allele rates of 7-54%. Somatic mutations in OFD1 at Xp22 were found only in male individuals. Potential pathogenic somatic mutations in UBR5 and ZNF263 were also identified in each individual. Germline nonsense mutations in GLI3 and OFD1 were identified in each individual with PHS and OFD type I in our series, respectively. The truncated GLI3 showed stronger repressor activity than the wild-type protein. We did not detect somatic mutations in the remaining 9 individuals.
Interpretation:
Our data indicate that a spectrum of human disorders can be caused by lesion-specific somatic mutations, and suggest that impaired Shh signaling is one of the pathomechanisms of HH.
... Craniofacial malformations occur in over 87% of reported cases and include facial asymmetry, hypertelorism, micrognathia, broadened nasal ridges, cleft palate, high arched palate, lingual hamartomas, hypodontia, and hyperplastic buccal fernula that can lead to clefting (Brugmann, Cordero, & Helms, 2010;Gurrieri et al., 2007;Thauvin-Robinet et al., 2006). Genetics: OFD1, is the only gene to be associated with OFDS1 thus far, although it still does not account for most of the OFDS1 and other OFD subtypes (Ferrante et al., 2001;Rakkolainen, Ala-Mello, Kristo, Orpana, & Jarvela, 2002;Romio et al., 2003). OFD1 is widely expressed from early stages of development in all tissues affected in OFDS1 in both humans and mice (de Conciliis et al., 1998;Ferrante et al., 2003;Romio et al., 2004;Romio et al., 2003). ...
A rare disease is defined as a condition that affects less than 1 in 2000 individuals. Currently more than 7000 rare diseases have been documented, and most are thought to be of genetic origin. Rare diseases primarily affect children, and congenital craniofacial syndromes and disorders constitute a significant proportion of rare diseases, with over 700 having been described to date. Modeling craniofacial disorders in animal models has been instrumental in uncovering the etiology and pathogenesis of numerous conditions and in some cases has even led to potential therapeutic avenues for their prevention. In this chapter, we focus primarily on two general classes of rare disorders, ribosomopathies and ciliopathies, and the surprising finding that the disruption of fundamental, global processes can result in tissue-specific craniofacial defects. In addition, we discuss recent advances in understanding the pathogenesis of an extremely rare and specific craniofacial condition known as syngnathia, based on the first mouse models for this condition. Approximately 1% of all babies are born with a minor or major developmental anomaly, and individuals suffering from rare diseases deserve the same quality of treatment and care and attention to their disease as other patients.
... OFD I syndrome is the only form of OFDS for which the molecular is fully elucidated, when the OFD I gene has been identified [14,15]. Mutations have also been identified in the GLI3 gene in five patients with OFDS and median anomalies including hypothalamic hamartoma/mass, agenesis of corpus callosum, imperforate anus and/or atrial septal defect [15]. ...
... OFD I syndrome is the only form of OFDS for which the molecular is fully elucidated, when the OFD I gene has been identified [14,15]. Mutations have also been identified in the GLI3 gene in five patients with OFDS and median anomalies including hypothalamic hamartoma/mass, agenesis of corpus callosum, imperforate anus and/or atrial septal defect [15]. Also mutations in the TMEM216 gene, recently reported as responsible of Joubert and Meckel syndromes, have also been identified in two patients with OFD VI syndrome [16,17]. ...
We describe a constellation of distinctive skeletal abnormalities in an
8-year-old boy who presented with the full clinical criteria of oro-facial-digital
(OFD) type II (Mohr syndrome): bony changes of obtuse
mandibular angle, bimanual hexadactyly and unilateral synostosis of
the metacarpo-phalanges of 3-4, bilateral coxa valga associated with
moderate hip subluxation, over-tubulation of the long bones, vertical
talus of the left foot and talipes equinovarus of the right foot respectively.
Interestingly, we encountered variable minor malformations in
his parents, confirming the autosomal recessive pattern of inheritance.
There were no microdeletions or microduplications after performing
array-CGH-analysis. We report what might be a constellation of unreported
skeletal abnormalities in a child with OFD type II (Mohr
syndrome)
... 17 Most of the identified mutations in the OFD1 gene led to loss of function due to premature truncation of the protein. 10,12,[23][24][25][26] Moreover, Tsurusaki and his colleagues 27 speculated that mutations downstream of exon 17 leading to a longer, truncated transcript might result in a milder form of OFD1. ...
Oral–facial–digital syndrome type 1 (OFD1) is a male-lethal X-linked dominant disorder characterized by a dysmorphic face, associated with oral cavity and digital anomalies. Polycystic kidney disease is another typical feature of this syndrome. Heterozygous mutations in the OFD1 gene are responsible for this condition. This gene encodes a centrosomal and basal body cilia protein that plays an important role in the early development of the brain, face, limbs and kidneys. In this study we clinically evaluated an affected Emirati female child exhibiting features of OFD1 syndrome. Screening of the OFD1 gene was carried out using a Sanger DNA sequencing method. Moreover, bioinformatics tools were used to predict the pathogenicity of the identified mutation. As a result, we identified a heterozygous single-nucleotide deletion in the donor splice site of exon 20 (c.2757+1delG). Both parents were homozygous for the wild-type alleles. The deletion might be a de novo mutation in nature, but we cannot exclude the possibility of mosaicism in the mother. Prediction analyses showed that the deletion abolishes the authentic splice site leading to the generation of a cryptic splice site. Subsequently, this mutation will result in a frameshift and premature termination codon (p.Lys920ArgfsX2). In this report, we describe the clinical features and molecular studies of an Emirati child with OFD1 syndrome. To our knowledge this is the first report of the clinical and molecular aspect of OFD1 from the UAE.
... 39 To date, there have been 44 cases of PKD associated with OFDS1 reported in the literature, two of who were male (see Table 1). 1,3,[9][10][11][12][13][14][15][16][17]26,[40][41][42][43][44][45][46][47][48][49][50] Several different mutations have been found in OFDS1 patients (see Table 2), 13 www.bjrm.co.uk ...
... Characteristics of the 44 cases of polycystic kidney disease (PKD) associated with orofaciodigital syndrome type 1 (OFDS1) reported in the literature, including presence of chronic kidney failure (CKF) and systemic hypertension (HTN)1,3,[9][10][11][12][13][14][15][16][17]26,[40][41][42][43][44][45][46][47][48][49][50] ...
Orofaciodigital syndrome type 1 (OFDS1) is an X-linked disorder caused by mutations in the orofaciodigital (OFD1) gene that was first reported in 1954 by Papillon-Léage and Psaume. 1 Although males do not typically survive beyond fetal stages, a few patients have survived until shortly after birth, 2–4 and one unusual case of OFDS1 has been reported in a living male with two X chromosomes. 5 OFDS1 belongs to a group of congenital disorders referred to as ciliopathies. Caused by mutations in the genes that encode proteins required for the organisation and/or function of the cilia, they include autosomal dominant and autosomal recessive polycystic kidney disease (PKD), nephronophthisis, Joubert syndrome, Meckel–Gruber syndrome and Bardet–Biedl syndrome, among others. The anomalous proteins in these disorders are located in the centrosome or the cilium, suggesting that the disorders may share pathogenic events. The clinical spectrum of these disorders also overlaps, as they share some phenotypic features such as kidney cysts. 6–8 Clinical features The most prominent clinical features of OFDS1 are congenital malformations of the oral cavity, face and digits. In addition, intellectual disability, brain abnormalities and polycystic kidneys are frequent. Rarely, other abnormalities have been reported, such as cystic dilatations of the bile ducts, liver cysts, pancreatic cysts, ovarian cysts, hearing loss, tibial pseudoarthrosis and intracra-nial berry aneurysms. The clinical expression of OFDS1 overlaps with that of other orofaciodigital syndromes and of PKD. Oral cavity anomalies consist of bifid tongue, lobulated tongue, lingual hamartomas, multiple oral frenula, pseudo cleft of the upper lip, cleft palate, high-arched palate and teeth abnormalities. Facial dysmorphisms include flat face, hypertelorism, hypoplasia of the nasal cartilage , flat nasal root, low-set ears, microretrog-nathia, facial asymmetry, epicanthus, evanescent milia of the face and ears, and dryness, brittleness or alopecia of the scalp hair. Digit anomalies include syn-, brachy-and clinodactyly, which affect the fingers more commonly than the toes. Poly-dactyly occurs more rarely. Central nervous system involvement includes agenesis of the corpus callosum, brain cysts, hydrocephalus and cerebel-lar malformations such as vermis hypoplasia.
... Prawidłowe warianty alleli genu oFD1 składają się z 23 eksonów. Do chwili obecnej zidentyfikowano ponad 120 różnych mutacji genu oFD1 [13,14,15,16,17,18]. Prawidłowy produkt genu -białko oFD1 występuje w 2 postaciach: oFD1-1 (Cxorf5-1) oraz oFD1-2 (Cxorf5-2). ...
Unlabelled:
Ciliopathies are phenotypically and genetically heterogeneous disorders that share ciliary dysfunction as a common pathological mechanism. Ciliary dysfunction results in a broad range of malformations including renal, hepatic and pancreatic cysts, visceral abnormalities, retinal degeneration, anosmia, cerebellar or other brain anomalies, polydactyly, bronchiectasis and infertility. The paper presents a familial case of oral-facial-digital syndrome type 1 in 14 year old girl suspected to polycystic kidney disease.
Conclusions:
Molecular testing in daughters of known OFD1 mutation carriers and mothers of affected daughters seems to be reasonable. Not each case of policystic kidney disease which looks like autosomal dominant policystic kiedney disease is actually the above disease. The insight into the pathogenesis of ciliopathies is mandatory for understanding these combined congenital anomaly syndromes of seemingly unrelated symptoms of hepatorenal and pancreatic fibrocystic disease. Close interdisciplinary approach is mandatory in terms of efficient and reliable diagnostic and therapeutic interventions in patients presenting with ciliopathies.
... Most OFD1 mutations identified to date lead to a premature truncation of the protein [Ferrante et al., 2001;Prattichizzo et al., 2008;Rakkolainen et al., 2002;Romio et al., 2003;Thauvin-Robinet et al., 2006], presumably resulting in a loss-of-function. In a large study of 81 patients with mutations in OFD1 [Prattichizzo et al., 2008], most of the mutations (53.7%) resulted in a frameshift and presumably premature protein truncation. ...
OFD1, now recognized as a ciliopathy, is characterized by malformations of the face, oral cavity and digits, and is transmitted as an X-linked condition with lethality in males. Mutations in OFD1 also cause X-linked Joubert syndrome (JBTS10) and Simpson-Golabi-Behmel syndrome type 2 (SGBS2). We have studied 55 sporadic and six familial cases of suspected OFD1. Comprehensive mutation analysis in OFD1 revealed mutations in 37 female patients from 30 families; 22 mutations have not been previously described including two heterozygous deletions spanning OFD1 and neighbouring genes. Analysis of clinical findings in patients with mutations revealed that oral features are the most reliable diagnostic criteria. A first, detailed evaluation of brain MRIs from seven patients with cognitive defects illustrated extensive variability with the complete brain phenotype consisting of complete agenesis of the corpus callosum, large single or multiple interhemispheric cysts, striking cortical infolding of gyri, ventriculomegaly, mild molar tooth malformation and moderate to severe cerebellar vermis hypoplasia. Although the OFD1 gene apparently escapes X-inactivation, skewed inactivation was observed in seven of 14 patients. The direction of skewing did not correlate with disease severity, reinforcing the hypothesis that additional factors contribute to the extensive intrafamilial variability.
... The CXORF5 gene or OFD1 gene encodes chromosome X open reading frame 5 (CXORF5) protein, which is required for the formation of primary cilia and left-right axis specification [12e14]. Loss-of-function mutations in the CXORF5 gene are associated with X-linked dominant oral-facial-digital syndrome type 1 (OFD1; OMIM 311200) [12,13,15], X-linked recessive SGBS2 [9], and Xlinked recessive Joubert syndrome type 10 (JBTS10; OMIM 300804) [16]. The detection rate of mutations and deletions in the GPC3 gene ranges from 37e70.3% in patients with SGBS [17e19]. ...
With the advent of prenatal sonography, fetal overgrowth can be easily detected. Prenatal-onset overgrowth can be secondary to normal variants of familial tall stature, familial rapid maturation, diabetic macrosomia, and congenital nesidioblastosis, or prenatal-onset overgrowth can be primary due to pathological overgrowth disorders. This article provides a comprehensive review of the prenatal findings and the genetic diagnosis of some of the pathological prenatal-onset overgrowth disorders, such as Simpson-Golabi-Behmel syndrome, Sotos syndrome, and Beckwith-Wiedemann syndrome.