What’s Shape Got to Do With It? Examining the Relationship Between Facial Shape and Orofacial Clefting

Abstract

Nonsyndromic orofacial clefts belong to a class of congenital malformations characterized by a complex and multifactorial etiology. During early facial development, multiple factors can disrupt fusion leading to a cleft; this includes the shape of the embryonic face. The face shape hypothesis (FSH) of orofacial clefting emerged in the 1960s, influenced by morphological differences observed within affected families, comparative studies of mouse models, and advances in modeling genetic liability for complex traits in populations. For the past five decades, studies have documented changes in the shape or spatial arrangement of facial prominences in embryonic mice and altered post-natal facial shape in individuals at elevated risk for orofacial clefting due to their family history. Moreover, recent studies showing how genes that impact facial shape in humans and mice are providing clues about the genetic basis of orofacial clefting. In this review, I discuss the origins of the FSH, provide an overview of the supporting evidence, and discuss ways in which the FSH can inform our understanding of orofacial clefting.

A common cis-regulatory variant impacts normal-range and disease-associated human facial shape through regulation of PKDCC during chondrogenesis

“…These include prenatal exposure to alcohol, nicotine, viruses, maternal diabetes, and methyl donor deficiency, all of which are linked to an increased prevalence of orofacial clefts ( Martinelli et al, 2020 ). Interestingly, unaffected relatives of individuals with nsCL/P show distinctive facial features, which have been quantitatively characterized to define a subclinical ‘endophenotype’ that may reflect a heightened susceptibility to clefting ( Indencleef et al, 2021 ; Weinberg, 2022 ). Subsequent GWAS analysis revealed loci associated with nsCL/P endophenotype in a healthy, unselected population ( Indencleef et al, 2021 ).…”

“…In addition to the genetic underpinnings of normal-range facial variation, GWAS of non-syndromic cleft lip/palate (nsCL/P) has revealed the polygenic architecture of this common birth defect, with risk variants again mapping mostly to the non-coding parts of the genome ( Leslie, 2022 ; Naqvi et al, 2022 ; Weinberg, 2022 ). While CL/P co-occurs with several Mendelian craniofacial syndromes, the majority of cases (~70%) are non-syndromic (meaning, occurring in the absence of other manifestations) and characterized by complex inheritance.…”

What brings you here?—A qualitative study on why therapists become and remain therapists.

“…Religion might also play a role (Ganzevoort, 1993). Christian therapists, for instance, may feel that it is their Christian duty to help others (Weinberg, 2020).…”