Cleft Lip/Cleft Palate Panel

Orofacial clefts are the most common type of congenital craniofacial anomaly identified in newborns occurring at a rate of 1-2 per 1,000 live births (IPDTOC Working Group. 2011. PubMed ID: 20507242; Mai et al. 2014. PubMed ID: 25399767). Orofacial clefts result from the failure of the facial prominences to grow or fuse appropriately during the fourth through to the twelfth week of embryogenesis (Burg et al. 2016. PubMed ID: 26973535, Deshpande and Goudy. 2019. PubMed ID: 30828634). The exact timing of the disruption determines the type of cleft (unilateral, bilateral, submucosal, microform, complete, or incomplete) and the degree of upper lip, alveolus, hard palate, soft palate, and uvula involvement (Worley et al. 2018. PubMed ID: 30396411). The common subclinical forms of orofacial clefts include cleft lip only (CLO), cleft lip and palate (CLP) and cleft palate only (CPO). Subclinical forms may present as an isolated primary anomaly (non-syndromic) or be accompanied by additional congenital anomalies or genetic syndromes (syndromic). Approximately 70% of cases with CLO or CLP are non-syndromic, whereas 50% of cases with CPO are non-syndromic (Shi et al. 2008. PubMed ID: 18383123).

Pathogenic variants in the IRF6 gene are one of the most frequent underlying causes of orofacial clefting. IRF6-related disorders span a spectrum from isolated cleft lip and palate and Van der Woude syndrome (VWS) at the mild end to popliteal pterygium syndrome (PPS) at the more severe end.

This test includes genes identified through literature, OMIM, and HGMD searches that have a reported association with orofacial cleft phenotypes.

Orofacial clefts represent a group of clinically and genetically heterogeneous disorders that may result from a chromosomal anomaly, a single gene disorder, a complex disorder resulting from interactions involving multiple genes, or a gestational exposure to environmental risk factors (Raminov et al. 2012. PubMed ID: 21545302). Despite this heterogeneous nature, orofacial clefts display strong familial aggregation, suggesting that heredity plays a major role (Sivertsen et al. 2008. PubMed ID: 18250102, Grosen et al. 2010. PubMed ID: 19752161). Mendelian forms may be inherited in an autosomal dominant (AD), autosomal recessive (AR), and X-linked (XL) manner, or arise de novo.

Van der Woude syndrome is the most common form of orofacial cleft and is frequently associated with missense and nonsense variants in the IRF6 gene (Brito et al. 2012. PubMed ID: 23213504). Pathogenic variants in the IRF6 gene have been reported in 69% (47/68) of patients with syndromic orofacial clefts and 3% (3/95) of patients with non-syndromic familial orofacial clefts (Desmyster et al. 2010. PubMed ID: 21045959). Beyond the IRF6 gene, pathogenic variants in the GRHL3, LRP6, TBX1, and TP63 genes have been detected via whole genome sequencing in 13% (6/46) of families with non-syndromic orofacial clefts (Basha et al. 2018. PubMed ID: 29500247).

Chromosomal abnormalities have been reported in a portion of individuals with orofacial clefts. A systematic review of published studies reported 0.5% to 13% of postnatal cases with syndromic orofacial cleft could be explained by an underlying chromosomal anomaly (Maarse et al. 2012. PubMed ID: 22889852). This rate was substantially reduced for non-syndromic cases, which ranged from 1.0% to 1.8% depending on the subclinical type of orofacial cleft.

See individual gene summaries for information about molecular biology of gene products and spectra of pathogenic variants.

Due to the genetic heterogeneity of the disorders tested in this panel, the clinical sensitivity of this specific grouping of genes is difficult to estimate. Clinical sensitivity varies depending on the subclinical type of cleft, the presentation (syndromic versus non-syndromic), and the degree of familial aggregation (Brito et al. 2012. PubMed ID: 23213504; Raminov et al. 2012. PubMed ID: 21545302; Desmyster et al. 2010. PubMed ID: 21045959). Up to 69% of familial cases of syndromic orofacial cleft and up to 3% of familial cases of non-syndromic orofacial cleft may be explained by the IRF6 gene (Desmyster et al. 2010. PubMed ID: 21045959). In addition, up to 12.5% of cases of syndromic orofacial cleft and 2% of cases of non-syndromic orofacial cleft may be explained by chromosomal abnormalities (Maarse et al. 2012. PubMed ID: 22889852).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 98.1% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).