Genetic Factors Leading to Birth Defects and Diseases of the Newborn

Craniofacial malformations are among the most common birth defects in humans and they often have significant detrimental functional, aesthetic, and social consequences. To date, more than 700 distinct craniofacial disorders have been described. However, the genetic, environmental, and developmental origins of most of these conditions remain to be determined. This gap in our knowledge is hampered in part by the tremendous phenotypic diversity evident in craniofacial syndromes but is also due to our limited understanding of the signals and mechanisms governing normal craniofacial development and variation. The principles of Mendelian inheritance have uncovered the etiology of relatively few complex craniofacial traits and consequently, the variability of craniofacial syndromes and phenotypes both within families and between families is often attributed to variable gene expression and incomplete penetrance. However, it is becoming increasingly apparent that phenotypic variation is often the result of combinatorial genetic and non-genetic factors. Major non-genetic factors include environmental effectors such as pregestational maternal diabetes, which is well-known to increase the risk of craniofacial birth defects. The hyperglycemia characteristic of diabetes causes oxidative stress which in turn can result in genotoxic stress, DNA damage, metabolic alterations, and subsequently perturbed embryogenesis. In this review we explore the importance of gene-environment associations involving diabetes, oxidative stress, and DNA damage during cranial neural crest cell development, which may underpin the phenotypic variability observed in specific craniofacial syndromes.

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FOXE1 mutations in Thai patients with oral clefts

Genetics Research ◽

10.1017/s0016672313000177 ◽

2013 ◽

Vol 95 (5) ◽

pp. 133-137 ◽

Cited By ~ 6

Author(s):

CHALURMPON SRICHOMTHONG ◽

RUNGNAPA ITTIWUT ◽

PICHIT SIRIWAN ◽

KANYA SUPHAPEETIPORN ◽

VORASUK SHOTELERSUK

Keyword(s):

Cleft Palate ◽

Birth Defects ◽

Cleft Lip ◽

Genetic Factors ◽

Heterozygous State ◽

Coding Region ◽

Thai Population ◽

Oral Clefts ◽

Pcr Rflp ◽

Genotype A

SummaryNon-syndromic oral clefts comprising cleft lip with and without cleft palate (CL/P) and cleft palate only (CPO) are common birth defects worldwide. Their aetiology involves both environmental and genetic factors. FOXE1 has previously been reported to be associated with oral clefts in some populations. Here, we investigate whether mutations in FOXE1 play a part in the formation of oral cleft in a Thai population. We first performed PCR–RFLP to genotype a previously reported associated polymorphism, c.-1204C > G (rs111846096), in our cohort. No association was found. In addition, two unrelated unaffected controls were found to be homozygous GG, indicating that homozygous GG at this c.-1204 position was not sufficient for the development of oral clefts. We then sequenced the entire coding region of FOXE1 in 458 unrelated individuals (146 CPOs, 108 CL/Ps and 204 Thai controls). Five different non-synonymous variants, c.274G > T (p.D92Y), c.569C > G (p.P190R), c.569C > T (p.P190L), c.664C > T (p.R222C) and c.1090G > A (p.G364S), were identified in CPOs and one, c.572C > G (p.P191R), in CL/P. All these six variants were in heterozygous state, each identified in one patient, and absent in 204 controls. Except the p.P190R, which was previously reported, the other five variants were novel. Our study identifies probable susceptibility variants of FOXE1 for oral clefts in the Thai population.

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