Testing the face shape hypothesis in twins discordant for nonsyndromic orofacial clefting.

Nonsyndromic orofacial clefts (OFCs) are complex traits characterized by multifactorial inheritance and wide phenotypic variability. Numerous studies have shown subtle differences in the faces of unaffected relatives from cleft families compared to controls, the implication being that such outward differences are an incomplete expression reflecting an underlying genetic predisposition. Twins discordant for OFCs provide a unique opportunity to further test this idea, as the unaffected co-twin shares on average 50% (for dizygotic twins) and 100% (for monozygotic twins) of the genetic risk factors as the affected twin. We used 3D surface imaging and spatially-dense morphometry to compare facial shape in a sample of 44 unaffected co-twins and age- and sex-matched unaffected controls (n = 241). Unaffected co-twins showed statistically significant differences in the midface, lateral upper face, and forehead regions, compared to controls. Furthermore, co-twins were characterized by a distinct pattern of midfacial retrusion, broader upper faces, and greater protrusion of the mandible and brow ridges. This same general facial pattern was shown in both unaffected monozygotic and dizygotic co-twin subsets. These results provide additional support that altered facial shape is a phenotypic marker for OFC susceptibility.

Novel mutations in LRP6 highlight the role of WNT signaling in tooth agenesis.

PURPOSE: We aimed to identify a novel genetic cause of tooth agenesis (TA) and/or orofacial clefting (OFC) by combining whole-exome sequencing (WES) and targeted resequencing in a large cohort of TA and OFC patients. METHODS: WES was performed in two unrelated patients: one with severe TA and OFC and another with severe TA only. After deleterious mutations were identified in a gene encoding low-density lipoprotein receptor-related protein 6 (LRP6), all its exons were resequenced with molecular inversion probes in 67 patients with TA, 1,072 patients with OFC, and 706 controls. RESULTS: We identified a frameshift (c.4594delG, p.Cys1532fs) and a canonical splice-site mutation (c.3398-2A>C, p.?) in LRP6, respectively, in the patient with TA and OFC and in the patient with severe TA only. The targeted resequencing showed significant enrichment of unique LRP6 variants in TA patients but not in nonsyndromic OFC patients. Of the five variants in patients with TA, two affected the canonical splice site and three were missense variants; all variants segregated with the dominant phenotype, and in one case the missense mutation occurred de novo. CONCLUSION: Mutations in LRP6 cause TA in humans.Genet Med 18 11, 1158-1162.

Genotypic and phenotypic variation in six patients with solitary median maxillary central incisor syndrome.

Solitary Median Maxillary Central Incisor occurs in 1 of 50,000 live births. It is the mildest manifestation of the holoprosencephaly spectrum and is genetically heterogeneous. Here we report six patients with solitary median maxillary central incisor, and a range of other phenotypic anomalies with different degrees of severity, varying from mild signs of holoprosencephaly to associated intellectual disability, and with different genetic background. Using array comparative genomic hybridization, pathogenic copy number variants were found in three of the six patients. Two patients had a deletion at the 18p11 chromosomal region that includes TGIF1 while the other patient had a deletion at 7q36, including the SHH gene. In one patient, a mutation in SIX3 was detected with exome sequencing, while in the two remaining patients all known holoprosencephaly genes were excluded using multiplex ligation-dependent probe amplification and sequencing, and remain unsolved. One of the two latter patients had isolated solitary median maxillary central incisor without other visible dentofacial anomalies, while the other had clinical features not part of the known holoprosencephaly spectrum.

Relation between Maximum Oral Muscle Pressure and Dentoalveolar Characteristics in Patients with Cleft Lip and/or Palate: A Prospective Comparative Study.

BACKGROUND: Perioral muscle function, which influences maxillofacial growth and tooth position, can be affected in patients with oral clefts due to their inherent anatomical characteristics and the multiple surgical corrections performed. This research aims to (1) compare the maximum oral muscle pressure of subjects with and without isolated cleft palate (CP) or unilateral cleft lip and palate (UCLP), (2) investigate its influence on their dentoalveolar characteristics, and (3) investigate the influence of functional habits on the maximum oral muscle pressure in patients with and without cleft. MATERIAL AND METHODS: Subjects with and without CP and UCLP seeking treatment at the Department of Orthodontics of University Hospitals Leuven between January 2021 and August 2022 were invited to participate. The Iowa Oral Performance Instrument (IOPI) was used to measure their maximum tongue, lip, and cheek pressure. An imbalance score was calculated to express the relationship between tongue and lip pressure. Upper and lower intercanine (ICD) and intermolar distance (IMD) were measured on 3D digital dental casts, and the presence of functional habits was reported by the patients. The data were analyzed with multivariable linear models, correcting for age and gender. RESULTS: 44 subjects with CP or UCLP (mean age: 12.00 years) and 104 non-affected patients (mean age: 11.13 years) were included. No significant differences in maximum oral muscle pressure or imbalance score were detected between controls and clefts or between cleft types. Significantly smaller upper ICDs and larger upper and lower IMDs were found in patients with clefts. A significant difference between controls and clefts was found in the relationship between oral muscle pressure and transversal jaw width. In cleft patients, the higher the maximum tongue pressure, the wider the upper and lower IMD, the higher the lip pressure, the smaller the upper and lower ICD and IMD, and the higher the imbalance score, the larger the upper and lower IMD and lower ICD. An imbalance favoring the tongue was found in cleft patients. The influence of functional habits on the maximum oral muscle pressure was not statistically different between clefts and controls. CONCLUSION: Patients with CP or UCLP did not present reduced maximum oral muscle pressure compared with patients without a cleft. In cleft patients, tongue pressure was consistently greater than lip pressure, and those who presented a larger maxillary width presented systematically higher imbalance scores (favoring the tongue) than those with narrow maxillae. Therefore, the influence of slow maxillary expansion on maximum oral muscle pressure in cleft patients should not be underestimated.