A craniosynostosis massively parallel sequencing panel study in 309 Australian and New Zealand patients: findings and recommendations

Lee, Eric; Le, Trang T.; Zhu, Ying; Elakis, George; Turner, Anne; Lo, William Tak‐Lam; Venselaar, Hanka; Verrenkamp, Carol Ann; Snow, Nicole; Mowat, David; Kirk, Edwin P.; Sachdev, Rani; Smith, Janine; Brown, Natasha J; Wallis, Mathew; Barnett, Chris; McKenzie, Fiona; Freckmann, Mary Louise; Collins, Felicity; Chopra, Maya; Gregersen, Nerine; Hayes, Ian; Rajagopalan, Sulekha; Tan, Tiong Yang; Stark, Zornitza; Savarirayan, Ravi; Yeung, Alison; Adès, Lesley C.; Gattas, Michael; Gibson, Kate; Gabbett, Michael T.; Amor, David J.; Lattanzi, Wanda; Boyd, Simeon; Haan, Eric; Gianoutsos, Mark P.; Cox, Timothy C.; Buckley, Michael F.; Roscioli, Tony

doi:10.1038/gim.2017.214

Cited by 36 publications

(43 citation statements)

References 21 publications

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“…Given that craniosynostoses are a heterogeneous group of disorders that may include overlapping features, making the correct clinical diagnosis can be challenging. Over the years, several studies tried to identify the genes and the mechanisms for craniosynostosis and developed a more efficient and cost-effective molecular diagnostic strategy for genetic testing, where gene-targeted sequencing of recurrent mutations was carried out (1,8,11,12). Many studies demonstrated in both humans and mice the implication of the FGFR1, FGFR2, FGFR3, FBN1, MSX2, and TWIST genes in the morphogenesis of the cartilage and bones (13,14).…”

Section: Discussionmentioning

confidence: 99%

The utility of molecular genetic techniques in craniosynostosis cases associated with intellectual disability

Bogliș

Tripon

Bănescu

2018

Revista Romana De Medicina De Laborator

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Molecular genetic testing in craniosynostosis leads to the detection of the mutations in the genes encoding fibroblast growth factor receptors (FGFR), providing information about the etiology of the genetic disorder. Muenke syndrome is produced by p.Pro250Arg mutation in FGFR3 gene with evidence of variable expressivity, representing 8% of the syndromic craniosynostoses. Here, we present the identification of a p.Pro250Arg pathogenic mutation (c.749C>G) in the FGFR3 gene using Multiplex Ligation-dependent Probes Amplification (MLPA) analysis in conjunction with Sanger sequencing in a patient with craniosynostosis and mild intellectual disability. The MLPA analysis detected a reduced signal of the probe, at the site of the c.749C>G mutation, defined by the presence of one allele of C749>G mutation in the FGFR3 gene, exon 7. Sanger sequencing was performed for confirmation and identified heterozygous p.Pro250Arg pathogenic variant (c.749C>G) in exon 7 of the FGFR3. In conclusion, we assessed the validity and clinical utility of the combined molecular genetic techniques, MLPA analysis, and Sanger sequencing, for craniosynostosis and intellectual disability, improving not only the diagnostic testing but also the genetic counseling and management of the disorder.

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Section: Discussionmentioning

confidence: 99%

The utility of molecular genetic techniques in craniosynostosis cases associated with intellectual disability

Bogliș

Tripon

Bănescu

2018

Revista Romana De Medicina De Laborator

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“…Since the initial report, two patients with ERF mutations have been described in a cohort of 40 patients with sagittal or multisutural synostosis (Chaudhry et al, ) and three patients with ERF mutations have been described in a cohort of 309 individuals with craniosynostosis who did not have a prior molecular diagnosis (Lee et al, ). A recent exome sequencing study of 291 parent‐offspring trios with nonsyndromic midline craniosynostosis reported a novel frameshift ERF mutation in a father and his two offspring each of whom had nonsyndromic metopic synostosis (Timberlake et al, ).…”

Section: Introductionmentioning

confidence: 99%

ERF‐related craniosynostosis: The phenotypic and developmental profile of a new craniosynostosis syndrome

Glass

O’Hara

Canham

et al. 2019

American J of Med Genetics Pt A

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Mutations in the ERF gene, coding for ETS2 repressor factor, a member of the ETS family of transcription factors cause a recently recognized syndromic form of craniosynostosis (CRS4) with facial dysmorphism, Chiari‐1 malformation, speech and language delay, and learning difficulties and/or behavioral problems. The overall prevalence of ERF mutations in patients with syndromic craniosynostosis is around 2%, and 0.7% in clinically nonsyndromic craniosynostosis. Here, we present findings from 16 unrelated probands with ERF‐related craniosynostosis, with additional data from 20 family members sharing the mutations. Most of the probands exhibited multisutural (including pan‐) synostosis but a pattern involving the sagittal and lambdoid sutures (Mercedes‐Benz pattern) predominated. Importantly the craniosynostosis was often postnatal in onset, insidious and progressive with subtle effects on head morphology resulting in a median age at presentation of 42 months among the probands and, in some instances, permanent visual impairment due to unsuspected raised intracranial pressure (ICP). Facial dysmorphism (exhibited by all of the probands and many of the affected relatives) took the form of orbital hypertelorism, mild exorbitism and malar hypoplasia resembling Crouzon syndrome but, importantly, a Class I occlusal relationship. Speech delay, poor gross and/or fine motor control, hyperactivity and poor concentration were common. Cranial vault surgery for raised ICP and/or Chiari‐1 malformation was expected when multisutural synostosis was observed. Variable expressivity and nonpenetrance among genetically affected relatives was encountered. These observations form the most complete phenotypic and developmental profile of this recently identified craniosynostosis syndrome yet described and have important implications for surgical intervention and follow‐up.

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“…This study has shown not only point mutations and small indels, but also large chromosomal rearrangements can cause TCF12‐related craniosynostosis (Goos et al, ). Recently, a group of researchers has identified 18 variants in TCF12 , 22 out of 309 patients from Australia and New Zealand, of whom 16 of them have been diagnosed with nonsyndromic coronal synostosis (Lee et al, ). When we consider all of these five‐year experiences globally, the overall mutation detection rate in the studied cohorts varies between 4 and 21% depending on the cohort characteristics (di Rocco et al, ; Goos et al, ; Lee et al, ; Paumard‐Hernández et al, ; Sharma et al, ).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, a group of researchers has identified 18 variants in TCF12 , 22 out of 309 patients from Australia and New Zealand, of whom 16 of them have been diagnosed with nonsyndromic coronal synostosis (Lee et al, ). When we consider all of these five‐year experiences globally, the overall mutation detection rate in the studied cohorts varies between 4 and 21% depending on the cohort characteristics (di Rocco et al, ; Goos et al, ; Lee et al, ; Paumard‐Hernández et al, ; Sharma et al, ). Although phenotypic variability exists in patients with TCF12 mutations (Sharma et al, ), this condition has been stated as mild Saethre‐Chotzen syndrome (Twigg & Wilkie, ) as a result of shared clinical findings like strabismus, dental malocclusion, minor ear anomalies, low anterior hairline, limb anomalies, or syndactyly (Sharma et al, ).…”

Section: Discussionmentioning

confidence: 99%

Coronal craniosynostosis due to TCF12 mutations in patients from Turkey

Yilmaz

Mıhçı

Nur

et al. 2019

American J of Med Genetics Pt A

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Craniosynostosis consists of premature fusion of one or more cranial sutures and can be seen as part of a syndrome or diagnosed as nonsyndromic (isolated). Although more than 180 craniosynostosis syndromes have been identified, 70% of the cases are diagnosed as nonsyndromic. On the other hand, genetic causes of the cases are mostly unknown and the overall frequency of the genetic diagnosis is around 25%. In this study, we used targeted Next Generation Sequencing (NGS) analysis to identify the genetic variations of two craniosynostosis cases. We have identified two different truncating mutations, a known NM_207036.1:c.778_779delAT;p.(Met260Valfs*5) and a novel NM_207036.1: c.1102_1108delTCACCTC;p.(Pro369Glnfs*26) TCF12 variants. Additionally, upon physical examination of these two cases, we have observed some shared clinical similarities as well as differences such as bilateral simian crease and hidden cleft palate. This is the first study that reports the TCF12 mutations in Turkish patients with coronal suture synostosis.

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A craniosynostosis massively parallel sequencing panel study in 309 Australian and New Zealand patients: findings and recommendations

Abstract: These findings support the clinical utility of a massively parallel sequencing panel for craniosynostosis. TCF12 and EFNB1 should be included in genetic testing for nonsyndromic coronal craniosynostosis or clinically suspected Saethre-Chotzen syndrome.

Cited by 36 publications

References 21 publications

The utility of molecular genetic techniques in craniosynostosis cases associated with intellectual disability

The utility of molecular genetic techniques in craniosynostosis cases associated with intellectual disability

ERF‐related craniosynostosis: The phenotypic and developmental profile of a new craniosynostosis syndrome

Coronal craniosynostosis due to TCF12 mutations in patients from Turkey

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