Unmasking familial CPX by WES and identification of novel clinical signs

Revençu, Nicole; Helaers, Raphaël; Devauchelle, Bernard; François, Geneviève; Bayet, Bénédicte; Vikkula, Miikka

doi:10.1002/ajmg.a.40630

Cited by 3 publications

(3 citation statements)

References 32 publications

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“…Substantial evidence is accumulating on rare variants contributing to nsCLP and finding a mutation in a Mendelian CLP disorder can consistently enhance the recurrence risk of nsCLP. Familial studies have been proven to be an effective strategy to identify rare variants and medical screening of such patients has been proposed [5,38,45,46]. Similarly, considering the results in this study, screening patients with discontinuous cleft should be taken into consideration in genetic counseling.…”

Section: Discussionmentioning

confidence: 86%

Likely Pathogenic Variants in One Third of Non-Syndromic Discontinuous Cleft Lip and Palate Patients

Revençu

Helaers

Gbaguidi

et al. 2019

Genes

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Oral clefts are composed of cleft of the lip, cleft of the lip and palate, or cleft of the palate, and they are associated with a wide range of expression and severity. When cleft of the palate is associated with cleft of the lip with preservation of the primary palate, it defines an atypical phenotype called discontinuous cleft. Although this phenotype may represent 5% of clefts of the lip and/or palate (CLP), it is rarely specifically referred to and its pathophysiology is unknown. We conducted whole exome sequencing (WES) and apply a candidate gene approach to non-syndromic discontinuous CLP individuals in order to identify genes and deleterious variants that could underlie this phenotype. We discovered loss-of-function variants in two out of the seven individuals, implicating FGFR1 and DLG1 genes, which represents almost one third of this cohort. Whole exome sequencing of clinically well-defined subgroups of CLP, such as discontinuous cleft, is a relevant approach to study CLP etiopathogenesis. It could facilitate more accurate clinical, epidemiological and fundamental research, ultimately resulting in better diagnosis and care of CLP patients. Non-syndromic discontinuous cleft lip and palate seems to have a strong genetic basis.

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Section: Discussionmentioning

confidence: 86%

Likely Pathogenic Variants in One Third of Non-Syndromic Discontinuous Cleft Lip and Palate Patients

Revençu

Helaers

Gbaguidi

et al. 2019

Genes

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“…One of the families included in this study had an X-linked disease-associated variant in the TBX22 gene, which has never been described before and was inherited from the unaffected mother. TBX22 has been described in several previous studies ( Braybrook et al, 2001 ; Marçano et al, 2004 ; Demeer et al, 2018 ) as a cause of X-linked semi-dominant CP and ankyloglossia (CPX) (OMIM). Further, variants in TBX22 were identified in 2.5% of isolated non-syndromic CP cases ( n = 200) ( Marçano et al, 2004 ), and in 16% of cases in a smaller WES study of 12 non-syndromic patients with CLP and CP ( Demeer et al, 2018 ).…”

Section: Discussionmentioning

confidence: 94%

“…TBX22 has been described in several previous studies ( Braybrook et al, 2001 ; Marçano et al, 2004 ; Demeer et al, 2018 ) as a cause of X-linked semi-dominant CP and ankyloglossia (CPX) (OMIM). Further, variants in TBX22 were identified in 2.5% of isolated non-syndromic CP cases ( n = 200) ( Marçano et al, 2004 ), and in 16% of cases in a smaller WES study of 12 non-syndromic patients with CLP and CP ( Demeer et al, 2018 ). Ankyloglossia is the most frequent disease presentation associated with TBX22 gene variants and is a minor anomaly, rarely considered important to report in patients or their family members ( Braybrook et al, 2001 ).…”

Section: Discussionmentioning

confidence: 94%

Monogenic Versus Multifactorial Inheritance in the Development of Isolated Cleft Palate: A Whole Genome Sequencing Study

et al. 2022

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Craniofacial morphogenesis is highly complex, as is the anatomical region involved. Errors during this process, resulting in orofacial clefts, occur in more than 400 genetic syndromes. Some cases of cleft lip and/or palate (CLP) are caused by mutations in single genes; however, complex interactions between genetic and environmental factors are considered to be responsible for the majority of non-syndromic CLP development. The aim of the current study was to identify genetic risk factors in patients with isolated cleft palate (CP) by whole genome sequencing. Patients with isolated CP (n = 30) recruited from the Riga Cleft Lip and Palate Centre, Institute of Stomatology, Riga, were analyzed by whole genome sequencing. Pathogenic or likely pathogenic variants were discovered in genes associated with CP (TBX22, COL2A1, FBN1, PCGF2, and KMT2D) in five patients; hence, rare disease variants were identified in 17% of patients with non-syndromic isolated CP. Our results were relevant to routine genetic counselling practice and genetic testing recommendations. Based on our data, we propose that all newborns with orofacial clefts should be offered genetic testing, at least for a panel of known CLP genes. Only if the results are negative and there is no suggestive family history or additional clinical symptoms (which would support additional exome or genome-wide investigation), should multifactorial empiric recurrence risk prediction tools be applied for families.

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A Comprehensive Genetic Analysis of Slovenian Families with Multiple Cases of Orofacial Clefts Reveals Novel Variants in the Genes IRF6, GRHL3, and TBX22

Slavec

Geršak

Eberlinc

et al. 2023

IJMS

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Although the aetiology of non-syndromic orofacial clefts (nsOFCs) is usually multifactorial, syndromic OFCs (syOFCs) are often caused by single mutations in known genes. Some syndromes, e.g., Van der Woude syndrome (VWS1; VWS2) and X-linked cleft palate with or without ankyloglossia (CPX), show only minor clinical signs in addition to OFC and are sometimes difficult to differentiate from nsOFCs. We recruited 34 Slovenian multi-case families with apparent nsOFCs (isolated OFCs or OFCs with minor additional facial signs). First, we examined IRF6, GRHL3, and TBX22 by Sanger or whole exome sequencing to identify VWS and CPX families. Next, we examined 72 additional nsOFC genes in the remaining families. Variant validation and co-segregation analysis were performed for each identified variant using Sanger sequencing, real-time quantitative PCR and microarray-based comparative genomic hybridization. We identified six disease-causing variants (three novel) in IRF6, GRHL3, and TBX22 in 21% of families with apparent nsOFCs, suggesting that our sequencing approach is useful for distinguishing syOFCs from nsOFCs. The novel variants, a frameshift variant in exon 7 of IRF6, a splice-altering variant in GRHL3, and a deletion of the coding exons of TBX22, indicate VWS1, VWS2, and CPX, respectively. We also identified five rare variants in nsOFC genes in families without VWS or CPX, but they could not be conclusively linked to nsOFC.

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Unmasking familial CPX by WES and identification of novel clinical signs

Cited by 3 publications

References 32 publications

Likely Pathogenic Variants in One Third of Non-Syndromic Discontinuous Cleft Lip and Palate Patients

Likely Pathogenic Variants in One Third of Non-Syndromic Discontinuous Cleft Lip and Palate Patients

Monogenic Versus Multifactorial Inheritance in the Development of Isolated Cleft Palate: A Whole Genome Sequencing Study

A Comprehensive Genetic Analysis of Slovenian Families with Multiple Cases of Orofacial Clefts Reveals Novel Variants in the Genes IRF6, GRHL3, and TBX22

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