Monogenic Versus Multifactorial Inheritance in the Development of Isolated Cleft Palate: A Whole Genome Sequencing Study

Abstract

Craniofacial morphogenesis is highly complex, as is the anatomical region involved. Errors during this process, resulting in orofacial clefts, occur in more than 400 genetic syndromes. Some cases of cleft lip and/or palate (CLP) are caused by mutations in single genes; however, complex interactions between genetic and environmental factors are considered to be responsible for the majority of non-syndromic CLP development. The aim of the current study was to identify genetic risk factors in patients with isolated cleft palate (CP) by whole genome sequencing. Patients with isolated CP (n = 30) recruited from the Riga Cleft Lip and Palate Centre, Institute of Stomatology, Riga, were analyzed by whole genome sequencing. Pathogenic or likely pathogenic variants were discovered in genes associated with CP (TBX22, COL2A1, FBN1, PCGF2, and KMT2D) in five patients; hence, rare disease variants were identified in 17% of patients with non-syndromic isolated CP. Our results were relevant to routine genetic counselling practice and genetic testing recommendations. Based on our data, we propose that all newborns with orofacial clefts should be offered genetic testing, at least for a panel of known CLP genes. Only if the results are negative and there is no suggestive family history or additional clinical symptoms (which would support additional exome or genome-wide investigation), should multifactorial empiric recurrence risk prediction tools be applied for families.

How are people with orofacial clefts attended in northwest region of São Paulo state, Brazil?

“…Currently, over 400 genetic disorders are reported to include CL or CLP ( OMIM, 2021 ; Lace et al, 2022 ). They are observed in syndromes with unknow prevalence as Craniofrontonasal and Escobar, rares as Van der Woude (1: 35,000-100,000) and Orofaciodigital (1: 50,000-250,000), and in that with higher prevalent as 22q11.2 deletion syndrome (1: 4,000), Pierre Robin (1: 8,500-14,000) and Charge (1: 8,500-10,000).…”

<strong>Analysis of <em> FOXE1</em> rs4460498 and <em> GSTP-1 I105V </em> associated with non syndromic cleft lip and palate among Deutero Malay Subrace in Indonesia</strong>

“…14,15 The etiology of NS CLP is multifactorial with complex interactions between genetic and environmental factors. 16,17 Genetic factors are believed to be the main factor causing CLP. 10,18 There are candidate genes that are involved in NS CLP disorders, some of them are FOXE1 rs4460498 and GSTP-1 I105V gene polymorphisms.…”