Katherine A Rauen

McMaster University, Hamilton, Ontario, Canada

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Publications (73)349.68 Total impact

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    ABSTRACT: Costello syndrome (CS) is a RASopathy characterized by a wide range of cardiac, musculoskeletal, dermatological, and developmental abnormalities. The RASopathies are defined as a group of syndromes caused by activated Ras/mitogen-activated protein kinase (MAPK) signaling. Specifically, CS is caused by activating mutations in HRAS. Although receptor tyrosine kinase (RTK) signaling, which is upstream of Ras/MAPK, is known to play a critical role in craniofacial and dental development, the craniofacial and dental features of CS have not been systematically defined in a large group of individuals. In order to address this gap in our understanding and fully characterize the CS phenotype, we evaluated the craniofacial and dental phenotype in a large cohort (n = 41) of CS individuals. We confirmed that the craniofacial features common in CS include macrocephaly, bitemporal narrowing, convex facial profile, full cheeks, and large mouth. Additionally, CS patients have a characteristic dental phenotype that includes malocclusion with anterior open bite and posterior crossbite, enamel hypo-mineralization, delayed tooth development and eruption, gingival hyperplasia, thickening of the alveolar ridge, and high palate. Comparison of the craniofacial and dental phenotype in CS with other RASopathies, such as cardio-facio-cutaneous syndrome (CFC), provides insight into the complexities of Ras/MAPK signaling in human craniofacial and dental development. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 03/2014; · 2.30 Impact Factor
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    ABSTRACT: Constitutional SMARCB1 mutations at 22q11.23 have been found in ∼50% of familial and <10% of sporadic schwannomatosis cases. We sequenced highly conserved regions along 22q from eight individuals with schwannomatosis whose schwannomas involved somatic loss of one copy of 22q, encompassing SMARCB1 and NF2, with a different somatic mutation of the other NF2 allele in every schwannoma but no mutation of the remaining SMARCB1 allele in blood and tumor samples. LZTR1 germline mutations were identified in seven of the eight cases. LZTR1 sequencing in 12 further cases with the same molecular signature identified 9 additional germline mutations. Loss of heterozygosity with retention of an LZTR1 mutation was present in all 25 schwannomas studied. Mutations segregated with disease in all available affected first-degree relatives, although four asymptomatic parents also carried an LZTR1 mutation. Our findings identify LZTR1 as a gene predisposing to an autosomal dominant inherited disorder of multiple schwannomas in ∼80% of 22q-related schwannomatosis cases lacking mutation in SMARCB1.
    Nature Genetics 12/2013; · 35.21 Impact Factor
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    ABSTRACT: Abstract Cardiofaciocutaneous (CFC) syndrome is a RASopathy phenotypically characterized by facial, cardiac, and ectodermal abnormalities. The extent to which this phenotype is expressed in the affected fetus is unclear and a better understanding of the fetal autopsy findings in CFC syndrome could facilitate diagnosis and understanding of the developmental effects of dysregulated BRAF activity. Here we describe the fetal autopsy findings in case of CFC syndrome in a 17 week fetus with a novel BRAF mutation that demonstrate potential similarities and differences with the postnatal presentation of CFC syndrome.
    Pediatric and Developmental Pathology 12/2013; · 0.86 Impact Factor
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    ABSTRACT: Mutations in Ras/mitogen-activated protein kinase (Ras/MAPK) pathway genes lead to a class of disorders known as RASopathies, including neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Costello syndrome (CS), and cardio-facio-cutaneous syndrome (CFC). Previous work has suggested potential genetic and phenotypic overlap between dysregulation of Ras/MAPK signalling and autism spectrum disorders (ASD). Although the literature offers conflicting evidence for association of NF1 and autism, there has been no systematic evaluation of autism traits in the RASopathies as a class to support a role for germline Ras/MAPK activation in ASDs. We examined the association of autism traits with NF1, NS, CS and CFC, comparing affected probands with unaffected sibling controls and subjects with idiopathic ASDs using the qualitative Social Communication Questionnaire (SCQ) and the quantitative Social Responsiveness Scale (SRS). Each of the four major RASopathies showed evidence for increased qualitative and quantitative autism traits compared with sibling controls. Further, each RASopathy exhibited a distinct distribution of quantitative social impairment. Levels of social responsiveness show some evidence of correlation between sibling pairs, and autism-like impairment showed a male bias similar to idiopathic ASDs. Higher prevalence and severity of autism traits in RASopathies compared to unaffected siblings suggests that dysregulation of Ras/MAPK signalling during development may be implicated in ASD risk. Evidence for sex bias and potential sibling correlation suggests that autism traits in the RASopathies share characteristics with autism traits in the general population and clinical ASD population and can shed light on idiopathic ASDs.
    Journal of Medical Genetics 10/2013; · 5.70 Impact Factor
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    ABSTRACT: RASopathies are syndromes caused by gain-of-function mutations in the Ras signaling pathway. One of these conditions, Costello syndrome (CS), is typically caused by an activating de novo germline mutation in HRAS and is characterized by a wide range of cardiac, musculoskeletal, dermatological, and developmental abnormalities. We report that a majority of individuals with CS have hypo-mineralization of enamel, the outer covering of teeth, and that similar defects are present in a CS mouse model. Comprehensive analysis of the mouse model revealed that ameloblasts, the cells that generate enamel, lacked polarity, and the ameloblast progenitor cells were hyperproliferative. Ras signals through two main effector cascades, the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways. To determine through which pathway Ras affects enamel formation, inhibitors targeting either PI3K or MEK1/2, a kinase in the MAPK pathway, were utilized. MEK1/2 inhibition rescued the hypo-mineralized enamel, normalized the ameloblast polarity defect, and restored normal progenitor cell proliferation. In contrast, PI3K inhibition only corrected the progenitor cell proliferation phenotype. We demonstrate for the first time the central role of Ras signaling in enamel formation in CS individuals, and we present the mouse incisor as a model system to dissect the roles of the Ras effector pathways in vivo.
    Human Molecular Genetics 09/2013; · 7.69 Impact Factor
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    Katherine A Rauen
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    ABSTRACT: The RASopathies are a clinically defined group of medical genetic syndromes caused by germline mutations in genes that encode components or regulators of the Ras/mitogen-activated protein kinase (MAPK) pathway. These disorders include neurofibromatosis type 1, Noonan syndrome, Noonan syndrome with multiple lentigines, capillary malformation-arteriovenous malformation syndrome, Costello syndrome, cardio-facio-cutaneous syndrome, and Legius syndrome. Because of the common underlying Ras/MAPK pathway dysregulation, the RASopathies exhibit numerous overlapping phenotypic features. The Ras/MAPK pathway plays an essential role in regulating the cell cycle and cellular growth, differentiation, and senescence, all of which are critical to normal development. Therefore, it is not surprising that Ras/MAPK pathway dysregulation has profound deleterious effects on both embryonic and later stages of development. The Ras/MAPK pathway has been well studied in cancer and is an attractive target for small-molecule inhibition to treat various malignancies. The use of these molecules to ameliorate developmental defects in the RASopathies is under consideration. Expected final online publication date for the Annual Review of Genomics and Human Genetics Volume 14 is August 31, 2013. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
    Annual review of genomics and human genetics 07/2013; · 11.57 Impact Factor
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    ABSTRACT: Objective: Receptor tyrosine kinase (RTK) signaling pathways are known to play a central role in tooth development. Costello Syndrome (CS), is caused by a heterozygous, de novo germline mutation in HRAS, which is downstream of RTK, that results in a constitutively active Ras protein. In order to further understand the role of Ras signaling in tooth development, we performed craniofacial and dental exams on a total of 46 patients with CS at the CS International Family Conferences in 2009 and 2011. Method: Exams included intra- and extraoral photographs, clinical examinations, x-ray reviews, alginate impressions, and exfoliated CS teeth collection. Result: Our dental exams revealed that patients with CS display malocclusion, delayed tooth development and delayed eruption. Interestingly, 88% of individuals with CS presented with an enamel defect characterized clinically by generalized white spots and striations. Micro computed tomography (microCT) and scanning electron microscopy (SEM) of exfoliated primary teeth from CS patients showed a significant decrease in enamel thickness and mineralization compared to control. Next, we analyzed a CS mouse model expressing HRASG12V in the lab and found that the CS mouse model has an enamel defect. Further inspection revealed disorganized enamel structure with demineralized zones. In addition, ameloblast progenitor cells were hyperproliferative in the cervical loop, and ameloblasts were disorganized and expressed decreased levels of enamel matrix proteins. Currently, we are analyzing HRASG12V mice treated with inhibitors at multiple points along the Ras effector pathways in order to determine through which pathway Ras is affecting ameloblast proliferation and differentiation and enamel formation. Conclusion: CS individuals present with a distinct craniofacial and dental phenotype, including an enamel defect. Our study in the CS mouse suggests that ameloblast proliferation and differentiation is disrupted resulting in the enamel defect, revealing an important role for Ras signaling in amelogenesis.
    IADR/AADR/CADR General Session and Exhibition 2013; 03/2013
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    ABSTRACT: We report an 8-month-old boy with Emanuel syndrome who also had the clinical features of Goldenhar syndrome. At birth, he was observed to have bilateral microtia with multiple auricular pits, retrognathia, and a unilateral lipodermoid. Further testing revealed cardiac defects. The finding of a lipodermoid in Emanuel syndrome demonstrates phenotypic overlap between Goldenhar and Emanuel syndromes and suggests a role for genetic analysis in all patients with clinical features that include ear anomalies and lipodermoids. Correct identification of patients with Emanuel syndrome is important for determining whether there is risk of long-term neurodevelopmental disability, and genetic testing can determine parental carrier status to aid in family planning.
    Journal of AAPOS: the official publication of the American Association for Pediatric Ophthalmology and Strabismus / American Association for Pediatric Ophthalmology and Strabismus 03/2013; · 1.07 Impact Factor
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    ABSTRACT: RASopathies are a class of genetic syndromes caused by germline mutations in genes encoding Ras/MAPK pathway components. Cardio-facio-cutaneous (CFC) syndrome is a RASopathy characterized by distinctive craniofacial features, skin and hair abnormalities, and congenital heart defects caused by activating mutations of BRAF, MEK1, MEK2, and KRAS. We define the phenotype of seven patients with de novo deletions of chromosome 19p13.3 including MEK2; they present with a distinct phenotype but have overlapping features with CFC syndrome. Phenotypic features of all seven patients include tall forehead, thick nasal tip, underdeveloped cheekbones, long midface, sinuous upper vermilion border, tall chin, angular jaw, and facial asymmetry. Patients also have developmental delay, hypotonia, heart abnormalities, failure to thrive, obstructive sleep apnea, GE reflux and integument abnormalities. Analysis of EGF stimulated fibroblasts revealed that P-MEK1/2 was ~50% less abundant in cells carrying the MEK2 deletion compared to the control. Significant differences in total MEK2 and Sprouty1 abundance were also observed. Our cohort of seven individuals with MEK2 deletions has overlapping features associated with RASopathies. This is the first report suggesting that, in addition to activating mutations, MEK2 haploinsufficiency can lead to dysregulation of the MAPK pathway.
    Clinical Genetics 02/2013; · 4.25 Impact Factor
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    ABSTRACT: RASopathies are a group of genetic conditions due to alterations of the Ras/MAPK pathway. Neurocutaneous findings are hallmark features of the RASopathies, but musculoskeletal abnormalities are also frequent. The objective was to evaluate handgrip strength in the RASopathies. Individuals with RASopathies (e.g., Noonan syndrome, Costello syndrome, cardio-facio-cutaneous [CFC] syndrome, and neurofibromatosis type 1 [NF1]) and healthy controls were evaluated. Two methods of handgrip strength were tested: GRIP-D Takei Hand Grip Dynamometer and the Martin vigorimeter. A general linear model was fitted to compare average strength among the groups, controlling for confounders such as age, gender, height, and weight. Takei dynamometer: handgrip strength was decreased in each of the syndromes compared with controls. Decreased handgrip strength compared with sibling controls was also seen with the Martin vigorimeter (P < 0.0001). Handgrip strength is decreased in the RASopathies. The etiology of the reduced muscle force is unknown, but likely multifactorial.
    Muscle & Nerve 09/2012; 46(3):394-9. · 2.31 Impact Factor
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    ABSTRACT: Supernumerary marker chromosomes (SMC) are relatively common in prenatal diagnosis. As the clinical outcomes vary greatly, a better understanding of the karyotype-phenotype correlation for different SMCs will be important for genetic counseling. We present two cases of prenatally detected de novo, small SMCs. The markers were present in 80% of amniocyte colonies in Case 1 and 38% of the colonies in Case 2. The SMCs were determined to be derived from chromosome 6 during postnatal confirmation studies. Although the sizes and the chromosomal origin of the SMCs in these two cases appeared to be similar, the clinical outcomes varied. The clinical manifestations observed in Case 1 included small for gestational age, feeding difficulty at birth, hydronephrosis, deviated septum and dysmorphic features, while the phenotype is apparently normal in Case 2. Array comparative genomic hybridization (CGH) was performed and showed increase in dosage for approximately 26 Mb of genetic material from the proximal short and long arms of chromosome 6 in Case 1. Results of array CGH were uninformative in Case 2, either due to mosaicism or lack of detectable euchromatin. The difference in the clinical presentation in these two patients may have resulted from the difference in the actual gene contents of the marker chromosomes and/or the differential distribution of the mosaicism.
    American Journal of Medical Genetics Part A 05/2012; 158A(7):1568-73. · 2.30 Impact Factor
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    ABSTRACT: A 16-year-old man with splenomegaly presented with ascites and bilateral leg eschars. Although he had intermittently elevated absolute monocyte counts, a diagnosis of juvenile myelomonocytic leukemia (JMML) was discounted because of his age and lack of persistent leukocytosis. Detailed examination demonstrated features consistent with Noonan syndrome (NS), including typical facies, growth retardation, a cardiac defect, and a history of a coagulopathy. He underwent a splenectomy where the surgeons encountered a rind of tissue composed of monocytes encasing the abdominal organs. After splenectomy, his leukocytes rose to over 100×10/L with a monocytosis, suggesting JMML. On the basis of the clinical suspicion of NS, mutation analysis revealed a KRAS mutation, which is known to be common to both NS and JMML. Clinicians should have high index of suspicion for JMML in patients with Noonan features, regardless of a patient's age.
    Journal of Pediatric Hematology/Oncology 04/2012; 34(7):569-72. · 0.97 Impact Factor
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    ABSTRACT: Cardio-facio-cutaneous (CFC) syndrome is caused by germline mutations in KRAS, BRAF and MEK1/2. The highly selective and potent MEK inhibitors that have been developed as anti-cancer agents hold potential as therapeutics for CFC syndrome. We have previously shown that the effects of CFC mutations on zebrafish gastrulation can be prevented by a 1-hour treatment with MEK inhibitors within a specific developmental time-window. However, MEK activity is essential for normal development and PD0325901 treatment outside this treatment window leads to additional developmental defects in MEK-dependent tissues. We now test ten different doses of PD0325901 at six developmental time points and assess the effects on body axis length, heart development and craniofacial structures in zebrafish embryos. Notably, we find that a continuous low-level dose of PD0325901 that has only minor inhibition of MEK activity can prevent the action of both the common CFC BRAF(Q257R) kinase-active allele and the BRAF(G596V) kinase-impaired mutant allele through the first 5 days of development. These results provide a detailed study of the effects of PD0325901 in development and show that, unlike in cancer, which requires robust inhibition of MAPK signalling, a partial reduction in phospho-ERK1/2 activity is sufficient to moderate the developmental effects of BRAF(CFC) mutations.
    Disease Models and Mechanisms 03/2012; 5(4):546-52. · 4.96 Impact Factor
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    ABSTRACT: The RASopathies are a class of human genetic syndromes caused by germline mutations in genes that encode protein components of the Ras/mitogen-activated protein kinase (MAPK) pathway. Costello syndrome (CS) is a RASopathy caused by mutations in the HRAS gene, a key regulator of signal transduction. To quantify the specific cutaneous phenotype observed in 46 individuals with Costello syndrome with confirmed HRAS mutations. This was a cross-sectional study. Dermatological surveys were designed by the authors and were completed by parents of mutation-positive individuals with CS at the Costello Syndrome Family Network (CSFN) conferences in 2007 and 2009. Dermatological examinations were performed by the authors at the CSFN conferences. Cutaneous papillomas were reported in 33 of the 46 (72%) participants, with age of onset ranging from infancy to 22years. Individuals with CS are more likely than patients with cardiofaciocutaneous syndrome (CFC) to present with cutaneous papillomas (72% vs. 5%, P<0·001) and palmoplantar keratoderma (76% vs. 36%, P<0·001). Individuals with CS are less likely than individuals with CFC to present with sparse or absent eyebrows (9% vs. 90%, P<0·001) or keratosis pilaris (33% vs. 80%, P=0·001). This study also identified that loose, redundant skin on the hands and feet, 'stippled' dermatoglyphs (pachydermatoglyphia) on the fingertips (eight of 26, 31%) and acanthosis nigricans (17 of 46, 37%) are frequent features of CS. While there is significant phenotypic overlap among syndromes of the Ras/MAPK pathway, individuals with CS are more likely than individuals with CFC syndrome to present with cutaneous papillomas, palmoplantar keratoderma and full eyebrows, and are less likely to present with ulerythema ophryogenes, keratosis pilaris or multiple naevi. The dermatological features of CS, a Ras dysregulation syndrome, share many features with cutaneous paraneoplastic syndromes. This may provide further insight into the role of Ras signalling in cutaneous paraneoplastic syndromes.
    British Journal of Dermatology 11/2011; 166(3):601-7. · 3.76 Impact Factor
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    ABSTRACT: We report on a 7-month-old girl with Smith-Magenis syndrome (SMS) due to a 4.76-Mb deletion of 17p12-17p11.2 detected by array comparative genomic hybridization. She was also affected with a left-sided congenital diaphragmatic hernia (CDH) and cardiac anomalies including an atypical atrioventricular canal defect and a cleft mitral valve. To our knowledge, this is the first reported case of a patient with both SMS and CDH. There are numerous chromosomal regions in which duplications, deletions, inversions, or translocations have been associated with CDH, but none have previously been reported at or close to 17p11.2. We discuss candidate genes for the diaphragmatic defect in this patient. Our case demonstrates that it is important to consider the possibility of SMS in non-isolated cases of diaphragmatic hernia.
    American Journal of Medical Genetics Part A 09/2011; 155A(11):2816-20. · 2.30 Impact Factor
  • William E Tidyman, Han S Lee, Katherine A Rauen
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    ABSTRACT: Cardio-facio-cutaneous syndrome (CFC) and Costello syndrome (CS) are two of the more rare RASopathies caused by altered signal transduction of the Ras/mitogen-activated protein kinase (MAPK) pathway. All of the RASopathies exhibit some degree of hypotonia, but CS and CFC are more severe. To determine if individuals with CS and CFC have an underlying skeletal myopathy, we systematically evaluated skeletal muscle pathology in both conditions. We reviewed pathology reports from six individuals who had undergone a skeletal muscle biopsy, and we reviewed histology slides on two cases with CS and one case with CFC. All patients in the cohort had histopathologic findings, and two consistent abnormalities were identified. The first was the presence of abnormal muscle fiber size and variability, and the second was the presence of type 2 fiber predominance. Given the degree of hypotonia typically present in these patients, the overall architecture of the muscle was relatively normal, without showing indications of severe structural histopathology or metabolic abnormalities. Because the Ras/MAPK pathway is vital for skeletal myogenesis, we evaluated the effects of CS and CFC mutations on myogenesis using C2C12 myoblasts. All CS/CFC mutations inhibited myoblast differentiation as indicated by fewer myosin heavy chain expressing cells and a decrease in the number of myotubes as compared to controls. These findings indicate that CS and CFC may have a true myopathy related to an inherent dysregulation of skeletal myogenesis, which further expands our understanding of the consequences of germline Ras/MAPK mutations.
    American Journal of Medical Genetics Part C Seminars in Medical Genetics 05/2011; 157(2):104-14. · 4.44 Impact Factor
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    ABSTRACT: The RASopathies, one of the largest groups of multiple congenital anomaly syndromes known, are caused by germline mutations in various genes encoding components of the Ras/mitogen-activated protein kinase (MAPK) pathway. The RASopathies have many overlapping characteristics, including craniofacial manifestations, cardiac malformations, cutaneous, musculoskeletal, gastrointestinal, and ocular abnormalities, neurocognitive impairment, hypotonia, and an increased risk of developing cancer. Costello syndrome (CS) and cardio-facio-cutaneous (CFC) syndrome are two of the more rare RASopathies. CS is caused by activating mutations in HRAS, and CFC is caused by dysregulation of signaling in the Ras/MAPK pathway due to mutations in BRAF, MEK1, or MEK2. The Ras/MAPK pathway, which has been well-studied in cancer, is an attractive target for inhibition in the treatment of various malignancies utilizing small molecule therapeutics that specifically inhibit the pathway. With many inhibitors of the Ras/MAPK pathway in clinical trials, the notion of using these molecules to ameliorate developmental defects in CS and CFC is under consideration. CS and CFC, like other syndromes in their class, have a progressive phenotype and may be amenable to inhibition or normalization of signaling.
    American Journal of Medical Genetics Part C Seminars in Medical Genetics 05/2011; 157(2):136-46. · 4.44 Impact Factor
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    ABSTRACT: BRAF, the protein product of BRAF, is a serine/threonine protein kinase and one of the direct downstream effectors of Ras. Somatic mutations in BRAF occur in numerous human cancers, whereas germline BRAF mutations cause cardio-facio-cutaneous (CFC) syndrome. One recurrent somatic mutation, p.V600E, is frequently found in several tumor types, such as melanoma, papillary thyroid carcinoma, colon cancer, and ovarian cancer. However, a germline mutation affecting codon 600 has never been described. Here, we present a patient with CFC syndrome and a de novo germline mutation involving codon 600 of BRAF, thus providing the first evidence that a pathogenic germline mutation involving this critical codon is not only compatible with development but can also cause the CFC phenotype. In vitro functional analysis shows that this mutation, which replaces a valine with a glycine at codon 600 (p.V600G), leads to increased ERK and ELK phosphorylation compared to wild-type BRAF but is less strongly activating than the cancer-associated p.V600E mutation.
    Clinical Genetics 05/2011; 79(5):468-74. · 4.25 Impact Factor
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    ABSTRACT: Congenital diaphragmatic hernia (CDH) is a life threatening birth defect. Most of the genetic factors that contribute to the development of CDH remain unidentified. To identify genomic alterations that contribute to the development of diaphragmatic defects. A cohort of 45 unrelated patients with CDH or diaphragmatic eventrations was screened for genomic alterations by array comparative genomic hybridisation or single nucleotide polymorphism based copy number analysis. Genomic alterations that were likely to have contributed to the development of CDH were identified in 8 patients. Inherited deletions of ZFPM2 were identified in 2 patients with isolated diaphragmatic defects and a large de novo 8q deletion overlapping the same gene was found in a patient with non-isolated CDH. A de novo microdeletion of chromosome 1q41q42 and two de novo microdeletions on chromosome 16p11.2 were identified in patients with non-isolated CDH. Duplications of distal 11q and proximal 13q were found in a patient with non-isolated CDH and a de novo single gene deletion of FZD2 was identified in a patient with a partial pentalogy of Cantrell phenotype. Haploinsufficiency of ZFPM2 can cause dominantly inherited isolated diaphragmatic defects with incomplete penetrance. These data define a new minimal deleted region for CDH on 1q41q42, provide evidence for the existence of CDH related genes on chromosomes 16p11.2, 11q23-24 and 13q12, and suggest a possible role for FZD2 and Wnt signalling in pentalogy of Cantrell phenotypes. These results demonstrate the clinical utility of screening for genomic alterations in individuals with both isolated and non-isolated diaphragmatic defects.
    Journal of Medical Genetics 05/2011; 48(5):299-307. · 5.70 Impact Factor
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    ABSTRACT: Objectives: Cardiofaciocutaneous syndrome (CFC) is a rare developmental disorder with multiple congenital anomalies including craniofacial, dermatologic, optic, cardiac and neurologic defects. CFC is caused by de novo missense mutations in BRAF, MEK1 or MEK2 that result in activated Ras/mitogen activated protein kinase (MAPK) signaling. Ras/MAPK is signaling downstream of receptor tyrosine kinase (RTK), and this pathway is known to play an important role in tooth development. To date, no studies have systematically screened a large cohort of CFC patients for dental characteristics. We examined patients attending the CFC Syndrome International Conference to comprehensively characterize the dental and expand on the craniofacial phenotype of CFC. Methods: We performed craniofacial and dental exams on 26 CFC patients at the 2009 CFC Syndrome International Conference, including clinical examinations, intra- and extra-oral photographs, radiographic reviews and alginate impressions. Results: In light of the importance of RTK signaling in dental development, we were surprised to find that the number, size and morphology of teeth in the CFC patients was normal. However, we did observe a dental and craniofacial phenotype including convex facial profile (84%), open bite (40%), constricted, high arched palate (80%), posterior crossbite (30%) and generalized crowding. In addition, 30% of patients had an open mouth posture and a secondary tongue thrust. Poor oral hygiene was found in over 50% of the patients. Conclusion: We systematically examined a cohort of 26 CFC patients and characterized their craniofacial and dental phenotype. The most common feature was open bite malocclusion with narrow constricted maxillary arches leading to posterior crossbite.
    IADR General Session 2011; 03/2011

Publication Stats

2k Citations
349.68 Total Impact Points

Institutions

  • 2013
    • McMaster University
      • Department of Pediatrics
      Hamilton, Ontario, Canada
  • 2012
    • University of Utah
      • Division of Medical Ethics
      Salt Lake City, UT, United States
    • University of California, Irvine
      • Department of Pediatrics
      Irvine, CA, United States
  • 2000–2012
    • University of California, San Francisco
      • • Division of Medical Genetics
      • • Department of Pediatrics
      San Francisco, California, United States
  • 2011
    • Medical College of Wisconsin
      Milwaukee, Wisconsin, United States
  • 2010
    • Oregon Health and Science University
      • Department of Dermatology
      Portland, Oregon, United States
  • 2008–2010
    • CSU Mentor
      Long Beach, California, United States
    • University of Toronto
      • Hospital for Sick Children
      Toronto, Ontario, Canada
    • Central Manchester University Hospitals NHS Foundation Trust
      Manchester, England, United Kingdom
  • 2006
    • Beth Israel Medical Center
      New York City, New York, United States
    • University of Washington Seattle
      • Department of Pediatrics
      Seattle, WA, United States
  • 2003
    • Children's Hospital & Research Center Oakland
      Oakland, California, United States
    • Mount Sinai School of Medicine
      • Department of Pediatrics
      Manhattan, NY, United States