Genetics and management of the patient with orofacial cleft

Abstract

Cleft lip or palate (CL/P) is a common facial defect present in 1 : 700 live births and results in substantial burden to patients. There are more than 500 CL/P syndromes described, the causes of which may be single-gene mutations, chromosomopathies, and exposure to teratogens. Part of the most prevalent syndromic CL/P has known etiology. Nonsyndromic CL/P, on the other hand, is a complex disorder, whose etiology is still poorly understood. Recent genome-wide association studies have contributed to the elucidation of the genetic causes, by raising reproducible susceptibility genetic variants; their etiopathogenic roles, however, are difficult to predict, as in the case of the chromosomal region 8q24, the most corroborated locus predisposing to nonsyndromic CL/P. Knowing the genetic causes of CL/P will directly impact the genetic counseling, by estimating precise recurrence risks, and the patient management, since the patient, followup may be partially influenced by their genetic background. This paper focuses on the genetic causes of important syndromic CL/P forms (van der Woude syndrome, 22q11 deletion syndrome, and Robin sequence-associated syndromes) and depicts the recent findings in nonsyndromic CL/P research, addressing issues in the conduct of the geneticist.

Figure 1

Representation of the most common types of cleft affecting the palate. (a) Unilateral cleft lip with alveolar involvement; (b) bilateral cleft lip with alveolar involvement; (c) unilateral cleft lip associated with cleft palate; (d) bilateral cleft lip and palate; (e) cleft palate only.

Figure 2

Diagram depicting the main lociassociated with NS CL ± P in the GWAS performed by Birnbaum et al. [72], Grant et al. [73], Mangold et al. [65], and Beaty et al. [64], which mixed case-control and trios (probands and their parents) approaches. Dotted lines represent borderline associations, whereas solid lines represent significant associations at the commonly accepted GWAS threshold (P < 10E − 7). (*) Mangold et al. [65] found evidence of interaction between IRF6 and GREM1, a gene located in 15q13.3 region, in NS CL ± P susceptibility.

Figure 3

Flowchart depicting the genetic evaluation of a CL/P patient.