Mutational Screening of FGFR1, CER1, and CDON in a Large Cohort of Trigonocephalic Patients

Jehee, Fernanda Sarquis; Alonso, Luís Garcia; Cavalcanti, Denise Pontes; Kim, Chong; Wall, Steven A.; Mulliken, John B.; Sun, Miao; Jabs, Ethylin Wang; Boyadjiev, Simeon A.; Wilkie, Andrew O.M.; Passos‐Bueno, Maria Rita

doi:10.1597/04-206.1

Cited by 14 publications

(4 citation statements)

References 16 publications

(16 reference statements)

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“…One further patient (patient 5) was confirmed to have a whole FREM1 gene deletion as a result of a cytogenetically visible 9p22.3 deletion. No mutations were identified in CER1, consistent with previous reports [13].…”

Section: Resultssupporting

confidence: 91%

“…This region partially overlaps the interstitial deletion identified by Kawara et al, in a patient with trigonocephaly who had a complex cytogenetic re-arrangement [12]. Jehee et al, sequenced CER1, a candidate gene located within that interval, but failed to identify any pathogenic changes in a cohort of 70 syndromic and non-syndromic trigonocephaly patients [13]. It is noteworthy that CER1 is located immediately telomeric to the interval described by Swinkels et al, and that another interesting candidate gene, FREM1, is in close proximity to the breakpoints defined previously [11].…”

Section: Introductionmentioning

confidence: 81%

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Heterozygous Mutations of FREM1 Are Associated with an Increased Risk of Isolated Metopic Craniosynostosis in Humans and Mice

et al. 2011

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The premature fusion of the paired frontal bones results in metopic craniosynostosis (MC) and gives rise to the clinical phenotype of trigonocephaly. Deletions of chromosome 9p22.3 are well described as a cause of MC with variably penetrant midface hypoplasia. In order to identify the gene responsible for the trigonocephaly component of the 9p22.3 syndrome, a cohort of 109 patients were assessed by high-resolution arrays and MLPA for copy number variations (CNVs) involving 9p22. Five CNVs involving FREM1, all of which were de novo variants, were identified by array-based analyses. The remaining 104 patients with MC were then subjected to targeted FREM1 gene re-sequencing, which identified 3 further mutant alleles, one of which was de novo. Consistent with a pathogenic role, mouse Frem1 mRNA and protein expression was demonstrated in the metopic suture as well as in the pericranium and dura mater. Micro-computed tomography based analyses of the mouse posterior frontal (PF) suture, the human metopic suture equivalent, revealed advanced fusion in all mice homozygous for either of two different Frem1 mutant alleles, while heterozygotes exhibited variably penetrant PF suture anomalies. Gene dosage-related penetrance of midfacial hypoplasia was also evident in the Frem1 mutants. These data suggest that CNVs and mutations involving FREM1 can be identified in a significant percentage of people with MC with or without midface hypoplasia. Furthermore, we present Frem1 mutant mice as the first bona fide mouse model of human metopic craniosynostosis and a new model for midfacial hypoplasia.

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Section: Resultssupporting

confidence: 91%

Section: Introductionmentioning

confidence: 81%

Heterozygous Mutations of FREM1 Are Associated with an Increased Risk of Isolated Metopic Craniosynostosis in Humans and Mice

et al. 2011

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“…Recently, Jehee et al [2006] screened 70 syndromic and non-syndromic patients with trigonocephaly for mutations in the coding sequence of CER1 with similar results. Nevertheless, this gene could still be involved in the pathogenesis of trigonocephaly, possibly by disruption of the promoter region.…”

Section: Discussionmentioning

confidence: 85%

Clinical and cytogenetic characterization of 13 Dutch patients with deletion 9p syndrome: Delineation of the critical region for a consensus phenotype

Swinkels¹,

Simons²,

Smeets³

et al. 2008

American J of Med Genetics Pt A

122

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The deletion 9p syndrome is caused by a constitutional monosomy of part of the short arm of chromosome 9. It is clinically characterized by dysmorphic facial features (trigonocephaly, midface hypoplasia, and long philtrum), hypotonia and mental retardation. Deletion 9p is known to be heterogeneous and exhibits variable deletion sizes. The critical region for a consensus phenotype has been reported to be located within a approximately 4-6 Mb interval on 9p22. In the present study, deletion breakpoints were determined in 13 Dutch patients by applying fluorescence in situ hybridization (FISH) and in some specific cases by array-based comparative genomic hybridization (array CGH). No clear genotype-phenotype correlation could be established for various developmental features. However, we were able to narrow down the critical region for deletion 9p syndrome to approximately 300 kb. A functional candidate gene for trigonocephaly, the CER1 gene, appeared to be located just outside this region. Sequence analysis of this gene in nine additional patients with isolated trigonocephaly did not reveal any pathogenic mutations.

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“…Clinical variability between family members carrying the same mutation for one of the known genes that have been associated with trigonocephaly represents a major challenge for genetic counseling. 15 Although the clinical risk for trigonocephaly associated with WBCR duplication is likely to be relatively low, in our opinion, association of this phenotypic trait with poor speech development should prompt a search of the 7q11.23 duplication. Magnetic resonance imaging of the brain, performed in the case reported by Torniero et al 6 and in the child described in this report, revealed abnormal development of the cerebral cortex, which is likely to contribute to cognitive and language impairment.…”

mentioning

confidence: 81%

Dysmorphic features, simplified gyral pattern and 7q11.23 duplication reciprocal to the Williams-Beuren deletion

et al. 2008

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We report a patient with mild pachygyria, ascertained during a screening of subjects with abnormal neuronal migration and/or epilepsy, having a 7q11.23 duplication reciprocal to the Williams-Beuren critical region (WBCR) deletion. He exhibited speech delay and mental retardation together to type II trigonocephaly and other abnormalities. The proband's mother carried the same imbalance, though her phenotype was milder and no abnormal conformation of the cranium was reported. She had suffered a few seizures in infancy, as already described in other duplicated subjects. This genomic imbalance, now described in 17 subjects, including one parent for each of the four probands, is associated with a variable phenotype. Speech impairment is present in most cases; no distinctive facial gestalt is recognizable; seizures have been reported in four subjects and brain magnetic resonance, performed in eight cases, resulted abnormal in six, while detected abnormal neuronal migration in two. Although the clinical description of additional cases is needed to delineate a definite phenotypic core for WBCR duplications, trigonocephaly, also reported in another dup(7)(q11.23) patient, is possibly a trait that, together with speech impairment, may call for clinically oriented specific screening. Abnormal development of the cerebral cortex, reported also in the Williams-Beuren deletion, suggests that at least one gene is present in the critical region whose deletion/duplication impairs neuronal migration.

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Mutational Screening of FGFR1, CER1, and CDON in a Large Cohort of Trigonocephalic Patients

Abstract: FGFR1 (exon 7), CER1, and CDON are not related to trigonocephaly in our sample and should not be considered as causative genes for metopic synostosis. Screening of FGFR1 (exon 7) for diagnostic purposes should not be performed in trigonocephalic patients.

Cited by 14 publications

References 16 publications

Heterozygous Mutations of FREM1 Are Associated with an Increased Risk of Isolated Metopic Craniosynostosis in Humans and Mice

Heterozygous Mutations of FREM1 Are Associated with an Increased Risk of Isolated Metopic Craniosynostosis in Humans and Mice

Clinical and cytogenetic characterization of 13 Dutch patients with deletion 9p syndrome: Delineation of the critical region for a consensus phenotype

Dysmorphic features, simplified gyral pattern and 7q11.23 duplication reciprocal to the Williams-Beuren deletion

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