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

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Likely Pathogenic Variants in One Third of Non-Syndromic Discontinuous Cleft Lip and Palate Patients G C A T T A C G G C A T genes Article Likely Pathogenic Variants in One Third of Non-Syndromic Discontinuous Cleft Lip and Palate Patients Bénédicte Demeer 1,2,3,4 , Nicole Revencu 1,5, Raphael Helaers 1 , Cica Gbaguidi 6, Stéphanie Dakpe 3,4,6 , Geneviève François 7, Bernard Devauchelle 3,4,6,Bénédicte Bayet 8 and Miikka Vikkula 1,* 1 Human Molecular Genetics, de Duve Institute, University of Louvain, 1200 Brussels, Belgium; [email protected] (B.D.); [email protected] (N.R.); [email protected] (R.H.) 2 Center for Human Genetics, CLAD Nord de France, CHU Amiens-Picardie, 80054 Amiens, France 3 Université Picardie Jules Verne, EA CHIMERE, EA 7516, 80054 Amiens, France; [email protected] (S.D.); [email protected] (B.D.) 4 Facing Faces Institute, 80054 Amiens, France 5 Center for Human Genetics, Cliniques universitaires Saint-Luc, University of Louvain, 1200 Brussels, Belgium 6 Department of Maxillofacial Surgery and Stomatology, Centre de Compétence Fentes et Malformations Faciales (MAFACE), CHU Amiens-Picardie, 80054 Amiens, France; [email protected] 7 Department of Pediatrics, Cliniques Universitaires Saint-Luc, University of Louvain, 1200 Brussels, Belgium; [email protected] 8 Centre Labiopalatin, Division of Plastic Surgery, Cliniques Universitaires Saint-Luc, University of Louvain, 1200 Brussels, Belgium; [email protected] * Correspondence: [email protected]; Tel.: +32-2-764-7490 Received: 6 September 2019; Accepted: 19 October 2019; Published: 22 October 2019 Abstract: 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. Keywords: discontinuous cleft; FGFR1; DLG1; WES (whole exome sequencing) 1. Introduction Cleft of the lip and/or palate (CLP) are among the most common birth defects, with an approximate incidence of 1/700 live births and with a wide variability of expression depending on ethnicity, gender and cleft type. Although CLPs are not associated with an elevated rate of mortality in developed Genes 2019, 10, 833; doi:10.3390/genes10100833 www.mdpi.com/journal/genes Genes 2019, 10, x FOR PEER REVIEW 2 of 9 Genes 2019, 10, 833 2 of 9 in developed countries, they represent a significant lifelong morbidity. This requires multidisciplinary treatment and care. countries,CLPs are they classified represent as asyndromic significant and lifelong non-syndromic morbidity. (isolated). This requires The multidisciplinarylatter is not associated treatment with addiandtional care. developmental, structural and/or cognitive anomalies. Syndromic CLPs, which represent 30% CLPsof all areCLPs, classified generally as syndromic follow a and Mendelian non-syndromic inheritance (isolated). with The an latter important is not associatedvariability with in expressivityadditional developmental, and incomplete structural penetrance. and /Theor cognitive other 70% anomalies. of CLPs Syndromicoccur as isolated CLPs, whichlesions represent and are considered30% of all CLPs, to have generally a complex follow etiology a Mendelian with both inheritance genetic and with environmental an important variabilityfactors acting in expressivity in concert. andGiven incomplete the complex penetrance. and The heterogeneous other 70% of CLPsnature occur of non as isolated-syndromic lesions clefts, and different are considered genetic to approacheshave a complex have etiology been employed with both successfully genetic and to environmental identify chromosomal factors acting loci and in concert.genes [1]. With rapid improvementGiven the in complex technology, and heterogeneous in particular nature the development of non-syndromic of next clefts,-generation different genetic sequencing approaches and bioinformatichave been employed algorithms, successfully we now to have identify the ability chromosomal to interrogate loci and the genes entire [1 exome]. With or rapid genome improvement in order toin identif technology,y risk inloci particular [2]. Whole the exome development sequencing of next-generation (WES) has been sequencing successfully and performed bioinformatic for Mendelianalgorithms, disorders, we now have and theis becoming ability to a interrogate useful approach the entire for exomeproving or clinical genome molecular in order todiagnosis identify risk[3]. Thisloci [strategy2]. Whole has exome also been sequencing applied (WES) to identify has been the successfullycauses of complex performed traits for including Mendelian cleft disorders, lip and palateand is [4,5] becoming. a useful approach for proving clinical molecular diagnosis [3]. This strategy has also beenHistorically, applied to identify CLP has the been causes divided of complex into cleft traits of includingthe lip (CL), cleft CL lip with and cleft palate of [the4,5]. palate, which are oftenHistorically, co-classified CLP as has cleft been of the divided lip with into or cleft without of the cleft lip (CL),palate CL (CL/P), with cleftand ofcleft the of palate, the palate which (CP). are Thisoften historical co-classified broad as subdivision cleft of the is lip based with on or a without number cleft of epidemiological palate (CL/P), and features cleft of each the palate condition, (CP). andThis a historical distinct developmental broad subdivision origin is based of the on primary a number palate of epidemiologicaland the secondary features palate. of Segregation each condition, of CL/Pand aand distinct CP has developmental been exceptionally origin reported of the primary for families palate wit andh etiologic the secondary mutations palate. in specific Segregation genes: P63,of CL MSX1,/P and IRF6, CP hasand beenFGFR1 exceptionally [1]. Clefts of reportedthe lip and for palate families show with a range etiologic of phenotypic mutations expression, in specific andgenes: dividingP63, MSX1,CLP in IRF6,a simplisticand FGFR1 way to[ 1CL/P]. Clefts and CP of thehas lipthe andpotential palate to show lose important a range of information. phenotypic Separatelyexpression, a andnaly dividingzing CLs CLP from in the a simplistic rest of the way CL/P to CL group/P and in CP non has-syndromic the potential multiplex to lose important families revealedinformation. differences Separately in linkage analyzing results CLs [6] from. It highlights the rest of the the importance CL/P group of in sub non-syndromic-phenotyping, multiplex and the requirementfamilies revealed of carefully differences stratified in linkage cohorts results to further [6]. Itunderstand highlights the the genet importanceic heterogeneity of sub-phenotyping, underlying nonand-syndromic the requirement CLP (nsCLP). of carefully stratified cohorts to further understand the genetic heterogeneity underlyingOne overlooked non-syndromic sub-phenotype CLP (nsCLP). within CL/Ps is the so called “discontinuous cleft”, which associatesOne overlookeda discontinuity sub-phenotype in clefting of within the primary CL/Ps palate is the and so called of the “discontinuoussecondary palate cleft”, (Figure which 1). Concerningassociates a t discontinuityhe description inof cleftingthis CLP, of some the primary authors palate use the and term of “primary the secondary palate” palate to refer (Figure to the1). anteriorConcerning intermaxillary the description palate, of thiswhereas CLP, others some authorsuse it to use describe the term the “primary tissues formed palate” by to referthe fusion to the betweenanterior the intermaxillary maxillary and palate, medial whereas nasal processes: others use the it lip, to describealveolus an thed anterior tissues formed intermaxillary by the palate fusion [7]between. We use the the maxillary term discontinuous and medial cleft nasal for processes:any cleft of thethe lip,primary alveolus palate and respecting anterior at intermaxillary least part of thepalate intermaxillary [7]. We use palate the term associated discontinuous with any cleft cleft for of any the cleft secondary of the primary palate. This palate atypical respecting phenotype at least haspart been of the reported intermaxillary in the literature palate associatedwith diverse with terminology, any cleft of referred the secondary to as “separate palate. cleft This of atypical the lip andphenotype palate”, has “unconnected been reported cleft”, in the “bridged literature cleft” with and diverse “interrupted terminology, cleft” referred [8,9]. It tohas
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