Subclinical features in non‐syndromic cleft lip with or without cleft palate (CL/P): review of the evidence that subepithelial orbicularis oris muscle defects are part of an expanded phenotype for CL/P*

Abstract

Non-syndromic cleft lip with or without cleft palate (CL/P) is a common, complex birth defect with a wide phenotypic spectrum. This review summarizes the evidence that subepithelial (occult) defects of the superior orbicularis oris (OO) muscle represent the mildest form of the lip portion of CL/P. The rate of OO defects was assessed via ultrasound in non-CL/P relatives of individuals with CL/P and compared with controls. Descriptive histology of OO muscles from cadavers was carried out. BMP4 was sequenced in non-CL/P individuals with OO defects vs. controls. 1) Non-CL/P relatives of individuals with overt CL/P have a significantly increased frequency of OO defects compared with controls with no family history of CL/P; 2) Preliminary histological studies of cadaver OO muscles show a pattern of disorganized muscle fibers in an individual with OO discontinuities as seen on ultrasound compared with another individual with no OO defect. That is, the defects seen on ultrasound appear to have an anatomical basis; 3) Sequencing BMP4 found a significant increase in potentially damaging mutations in individuals with OO defects vs. controls. Taken together, these data provide significant support for the hypothesis that subepithelial OO muscle defects are a mild manifestation of the lip portion of the CL/P phenotype. Given that subepithelial OO muscle defects are relatively straightforward to identify via ultrasound, such defects show great promise for providing more accurate recurrence risk estimates to relatives in cleft families. Furthermore, inclusion of OO defects in the CL/P phenotypic spectrum should improve the power of genetic studies.