Talk:Abnormal Development - Cleft Lip and Palate

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Cite this page: Hill, M.A. (2019, October 18) Embryology Abnormal Development - Cleft Lip and Palate. Retrieved from


Accumulation of rare coding variants in genes implicated in risk of human cleft lip with or without cleft palate

Am J Med Genet A. 2019 May 7. doi: 10.1002/ajmg.a.61183. [Epub ahead of print]

Marini NJ1, Asrani K1, Yang W2, Rine J1, Shaw GM2.

Cleft lip with/without cleft palate (CLP) is a common craniofacial malformation with complex etiologies, reflecting both genetic and environmental factors. Most of the suspected genetic risk for CLP has yet to be identified. To further classify risk loci and estimate the contribution of rare variants, we sequenced the exons in 49 candidate genes in 323 CLP cases and 211 nonmalformed controls. Our findings indicated that rare, protein-altering variants displayed markedly higher burdens in CLP cases at relevant loci. First, putative loss-of-function mutations (nonsense, frameshift) were significantly enriched among cases: 13 of 323 cases (~4%) harbored such alleles within these 49 genes, versus one such change in controls (p = 0.01). Second, in gene-level analyses, the burden of rare alleles showed greater case-association for several genes previously implicated in cleft risk. For example, BHMT displayed a 10-fold increase in protein-altering variants in CLP cases (p = .03), including multiple case occurrences of a rare frameshift mutation (K400 fs). Other loci with greater rare, coding allele burdens in cases were in signaling pathways relevant to craniofacial development (WNT9B, BMP4, BMPR1B) as well as the methionine cycle (MTRR). We conclude that rare coding variants may confer risk for isolated CLP.

© 2019 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals, Inc.

KEYWORDS: cleft lip; folic acid; genetic association; rare variants PMID: 31063268 DOI: 10.1002/ajmg.a.61183

Epidemiology and clinical profile of individuals with cleft lip and palate utilising specialised academic treatment centres in South Africa

PLoS One. 2019 May 9;14(5):e0215931. doi: 10.1371/journal.pone.0215931. eCollection 2019.

Hlongwa P1,2, Levin J2, Rispel LC3.

OBJECTIVE: The study was conducted to determine the epidemiology and clinical profile of individuals with cleft lip and/or palate (CLP) utilizing specialized academic treatment centres in South Africa's public health sector.

MATERIALS AND METHODS: The Human Research Ethics Committee of the University of the Witwatersrand in Johannesburg provided ethical approval for the study. We conducted a retrospective record review of all cases of CLP treated at the specialised academic centres for the two-year period from 1 January 2013 until 31 December 2014. We used a structured, pre-tested record review form to obtain demographic, clinical and treatment information on each CLP case. We used Stata 13 to analyse the data and conducted statistical tests at 5% significance level.

RESULTS: We analysed 699 records of individuals with CLP. The estimated prevalence of CLP in the South African public health sector was 0.3 per 1000 live births, with provincial variation of 0.1/1000 to 1.2/1000. The distribution of clefts was: 35.3% cleft palate; 34.6% cleft lip and palate; 19.0% cleft lip and other cleft anomalies at 2%. Of the total number of CLP, 47.5% were male and 52.5% female, and this difference was statistically significant (p<0.001). The majority of clefts occurred on the left for males (35.5%) and palate for females (43.4%), with a male predominance of unilateral cleft lip and palate (53.3%).

CONCLUSION: The study findings should inform the implementation of South Africa's planned birth defect surveillance system and health service planning for individuals with CLP.

PMID: 31071123 DOI: 10.1371/journal.pone.0215931


Knockdown of Crispld2 in zebrafish identifies a novel network for nonsyndromic cleft lip with or without cleft palate candidate genes

Eur J Hum Genet. 2018 Jun 13. doi: 10.1038/s41431-018-0192-5. [Epub ahead of print]

Chiquet BT1,2, Yuan Q3, Swindell EC4,5, Maili L3,4, Plant R3, Dyke J6, Boyer R6, Teichgraeber JF7, Greives MR7, Mulliken JB8, Letra A6,3, Blanton SH9, Hecht JT6,3,4.


Orofacial development is a multifaceted process involving tightly regulated genetic signaling networks, that when perturbed, lead to orofacial abnormalities including cleft lip and/or cleft palate. We and others have shown an association between the cysteine-rich secretory protein LCCL domain containing 2 (CRISPLD2) gene and nonsyndromic cleft lip with or without cleft palate (NSCLP). Further, we demonstrated that knockdown of Crispld2 in zebrafish alters neural crest cell migration patterns resulting in abnormal jaw and palate development. In this study, we performed RNA profiling in zebrafish embryos and identified 249 differentially expressed genes following knockdown of Crispld2. In silico pathway analysis identified a network of seven genes previously implicated in orofacial development for which differential expression was validated in three of the seven genes (CASP8, FOS, and MMP2). Single nucleotide variant (SNV) genotyping of these three genes revealed significant associations between NSCLP and FOS/rs1046117 (GRCh38 chr14:g.75746690 T > C, p = 0.0005) in our nonHispanic white (NHW) families and MMP2/rs243836 (GRCh38 chr16:g.55534236 G > A; p = 0.002) in our Hispanic families. Nominal association was found between NSCLP and CASP8/rs3769825 (GRCh38 chr2:g.202111380 C > A; p < 0.007). Overtransmission of MMP2 haplotypes were identified in the Hispanic families (p < 0.002). Significant gene-gene interactions were identified for FOS-MMP2 in the NHW families and for CASP8-FOS in the NHW simplex family subgroup (p < 0.004). Additional in silico analysis revealed a novel gene regulatory network including five of these newly identified and 23 previously reported NSCLP genes. Our results demonstrate that animal models of orofacial clefting can be powerful tools to identify novel candidate genes and gene regulatory networks underlying NSCLP. PMID: 29899370 DOI: 10.1038/s41431-018-0192-5


Folic acid supplements and risk for oral clefts in the newborn: a population-based study

Br J Nutr. 2015 Sep 7:1-8. [Epub ahead of print]

Gildestad T1, Bjørge T1, Vollset SE1, Klungsøyr K1, Nilsen RM1, Haaland ØA1, Øyen N1.


Results from previous studies on maternal folic acid intake and infant oral clefts are inconclusive. The aim of the present study was to investigate the association between women's use of folic acid and/or multivitamin supplements and the risk for oral cleft in the newborn. We used data from the Medical Birth Registry of Norway based on all births in Norway from 1999 to 2013. A total of 528 220 women had 880 568 pregnancies, resulting in 896 674 live births and stillbirths, of which 1623 had oral clefts (isolated oral clefts, n 1311; non-isolated oral clefts, n 312). Altogether, 21·5 % of women were vitamin supplement users before pregnancy. The birth prevalence of oral clefts was 1·81/1000 live births and stillbirths. Relative risks (RR) were estimated with log-binomial regression. For pregnancies with maternal use of vitamins, the adjusted RR for clefts overall was 0·90 (95 % CI 0·79, 1·04). The adjusted RR for cleft palate only (n 586) was 0·84 (95 % CI 0·66, 1·06) and that for cleft lip with or without cleft palate (n 1037) was 0·94 (95 % CI 0·79, 1·13). Associations were stronger for cleft cases that occurred in combination with other malformations (adjusted RR 0·63; 95 % CI 0·45, 0·88), although vitamin supplements provided no protection against isolated clefts (adjusted RR 0·98; 95 % CI 0·84, 1·15). In conclusion, our study demonstrates no statistically significant association between vitamin use and isolated oral clefts. However, we found lower risk for oral clefts that occurred in combination with other malformations. KEYWORDS: CL(P) cleft lip with or without cleft palate; CPO cleft palate only; MBRN Medical Birth Registry of Norway; MoBa Norwegian Mother and Child Cohort Study; RR relative risk; Epidemiology; Folic acid; Health promotion; Multivitamins; Oral clefts; Reproduction

PMID 26343883

Classification of Cleft Lip/Palate: Then and Now

Cleft Palate Craniofac J. 2015 Sep 4. [Epub ahead of print]

Allori AC, Mulliken JB, Meara JG, Shusterman S, Marcus JR; CleftKit Collaboration.


Cleft lip and/or palate (CL/P) is phenotypically diverse, making classification difficult. This article explores the evolution of ideas regarding CL/P classification and includes the schemes described by Davis and Ritchie (1922), Brophy (1923), Veau (1931), Fogh-Andersen (1943), Kernahan and Stark (1958), Harkins et al. (1962), Broadbent et al. (1968), Spina (1973), and others. Based on these systems, a longhand structured form is proposed for describing CL/P in a way that is clear, comprehensive, and consistent. A complementary shorthand notation is also described to improve the utility and convenience of this structured form. KEYWORDS: CleftKit; classification; cleft lip; cleft palate; nomenclature; nosology; ontology; taxonomy; terminology

PMID 26339868


Functional Significance of MMP3 and TIMP2 Polymorphisms in Cleft Lip/Palate

J Dent Res. 2014 May 5. [Epub ahead of print]

Letra A1, Zhao M, Silva RM, Vieira AR, Hecht JT.


Evidence from biological and human studies strongly supports a role for MMP and TIMP genes as candidate genes for non-syndromic cleft lip with or without cleft palate (NSCL/P). We previously showed the association of promoter polymorphisms in MMP3 (rs3025058 and rs522616) and TIMP2 (rs8179096) with NSCL/P. In this study, we examined the functional significance of these polymorphisms. A specific DNA-protein complex for MMP3 rs522616 A was detected, and this allele by itself showed greater promoter activity than the G allele. However, the effect of rs522616 was ultimately regulated by the rs3025058 allele on the background. For TIMP2 rs8179096, the T allele showed a 2.5-fold increase in promoter activity when compared with allele C, whereas both C and T alleles were found to bind to nuclear factor kappa B. Our results provide new evidence that promoter polymorphisms in MMP3 and TIMP2 are functional and may affect gene transcription with possible effects on craniofacial development leading to NSCL/P. KEYWORDS: EMSA, MMP, TIMP, luciferase, oral cleft, single nucleotide polymorphism

PMID 24799419


A revised classification of the cleft lip and palate

Can J Plast Surg. 2013 Spring;21(1):48-50.

Khan M, Ullah H, Naz S, Iqbal T, Ullah T, Tahir M, Ullah O.

Abstractin English, French

BACKGROUND: Submucous cleft palate is characterized by muscular diastasis of the velum in the presence of intact mucosa with variable combinations of bifid uvula and hard palatal defect. Submucous cleft palate is indicated as a separate entity in most previous classifications but it has never been properly classified on an anatomical basis. OBJECTIVES: To revise the Smith-modified Kernahan 'Y' classification of cleft lip and palate deformities, and to describe the different anatomical subtypes of submucous cleft palate. METHODS: The present study was conducted in Hayatabad Medical Complex, Abasin Hospital and Aman Hospital Peshawar, Pakistan, from November 2010 to December 2011. All patients who presented to the outpatient departments with cleft lip and palate, with the exception of previously operated cases, were included. All cases were described according to the Smith-modified Kernahan 'Y' classification and the authors' revised Smith-modified Kernahan 'Y' classification. All of the data were organized and analyzed using SPSS version 17 (IBM Corporation, USA). RESULTS: A total of 163 cases of cleft lip and palate deformities were studied, of which 59.5% were male and 40.5% were female. Smith modification of the Kernahan 'Y' classification completely described the cleft deformities in 93.9% of patients. However, while the Kernahan 'Y' classification represented the submucous cleft palate, it did not describe its different anatomical subtypes in 6.13% of patients. The revised Smith-modified Kernahan 'Y' classification completely described the cleft deformities of the entire study population, including the different submucous cleft palate patients. DISCUSSION: The Smith alphanumeric modification of the Kernahan 'Y' classification of cleft lip and palate came into existence after a long search and a series of modifications over the past century. This classification system describes the cleft region, site of the cleft, degree of the cleft, rare and asymmetrical clefts, and are computer database friendly. However, this classification did not describe the different anatomical subtypes of submucous cleft palate that have variable relationships with velopharyngeal insufficiency. CONCLUSION: The revised Smith-modified Kernahan 'Y' classification described in the present study can describe all types of cleft lip and palate deformities in addition to the different types of submucous cleft palate deformities. KEYWORDS: Cleft lip, Cleft palate, Submucous cleft palate, Velopharyngeal insufficiency

PMID 24431938

The first most commonly accepted classification was presented by Kernahan and Stark (PMID 17760488) in 1958, who described all common types of cleft lip/palate, complete unilateral cleft lip/palate and the isolated posterior cleft palate in a symbolic classification system. To describe the unusual types of cleft deformities, Kernahan modified his classification into symbolic striped ‘Y’ classification in 1971, which still had many shortcomings (ie, recording asymmetric deformities in bilateral cleft lip, inadequate detail for assessment of palatal deformities associated with speech results and rates of fistula formation and potentially misread data that was difficult to analyze by computer). The striped ‘Y’ classification was further modified by Millard in 1977 (1).
To compensate for the shortcomings of the Kernahan striped ‘Y’ classification, Smith et al (PMID 9810977) modified it in 1998, providing more detailed description of the cleft deformities. Cleft lip was divided into additional types denoted ‘a’ to ‘d’ depending on the extent of involved lip. Similarly, cleft of the secondary palate was subdivided into three segments and the submucous cleft of the palate was denoted by the letter ‘a’. In the Smith modification of the Kernahan classification, the submucous cleft palate was denoted by ‘a’ but it did not describe the different varieties of the submucous cleft palate because it can involve the hard palate to different levels as observed in our study population. Submucous cleft palate is a type of cleft deformity in which muscles are malaligned and malinserted with intact oral mucosa. The hallmark signs usually associated with submucous cleft palate are bifid uvula, V-shaped notching of the hard palate and a translucent line in the midline of the soft palate (zona pellucida) (4,5). Only 10% of patients with submucous cleft palate are symptomatic (4). Velopharyngeal insufficiency is an abnormality of the sphincter formed by the soft palate and the pharynx leading to abnormal speech. The primary issue in the management of the submucous cleft palate is the delayed presentation of the patients. Patients often present after speech has already developed, with abnormal speech as the major complaint. Unfortunately, due to the delayed presentation, surgical repair of the submucous cleft palate does not correct speech (6). Early diagnosis and identification of the types of submucous cleft palate that will lead to a speech abnormality before speech development is the key to successful management of these patients. In the revised Smith-modified Kernahan ‘Y’ classification of the cleft lip and palate presented in the current study, we have incorporated different varieties of the submucous cleft, which can provide an anatomical basis for the severity of velopharyngeal insufficiency.


The origin and early development of the nasal septum in human embryos

Ann Anat. 2010 Apr 20;192(2):82-5. Epub 2010 Jan 25. Steding G, Jian Y. Source Centre of Anatomy, Georg August University Goettingen, Kreuzbergring 36, 37075 Goettingen, Germany.


Based on scanning electron microscopic dissections of human embryos and fetuses of the sixth to the twelfth week (Carnegie stages 16-23 and early fetus), the origin of the nasal septum was studied. The findings show that the nasal septum does not grow downwards. It is derived from the tissue between the primary choanae: as such, its anlage is present from the very beginning. Its contact and fusion with the palatal shelves is made possible by the elevation of the palatal shelves from the vertical into the horizontal position, as the tongue descends. Copyright 2010 Elsevier GmbH. All rights reserved.

PMID 20149609

Incidence of cleft Lip and palate in the state of Andhra Pradesh, South India

Indian J Plast Surg. 2010 Jul;43(2):184-9.

Reddy SG, Reddy RR, Bronkhorst EM, Prasad R, Ettema AM, Sailer HF, Bergé SJ.

SourceGSR Institute of Craniofacial Surgery, Hyderabad, Andhra Pradesh, India.

Abstract OBJECTIVE:To assess the incidence of cleft lip and palate defects in the state of Andhra Pradesh, India.DESIGN SETTING:The study was conducted in 2001 in the state of Andhra Pradesh, India. The state has a population of 76 million. Three districts, Cuddapah, Medak and Krishna, were identified for this study owing to their diversity. They were urban, semi-urban and rural, respectively. Literacy rates and consanguinity of the parents was elicited and was compared to national averages to find correlations to cleft births. Type and side of cleft were recorded to compare with other studies around the world and other parts of India.RESULTS:The birth rate of clefts was found to be 1.09 for every 1000 live births. This study found that 65% of the children born with clefts were males. The distribution of the type of cleft showed 33% had CL, 64% had CLP, 2% had CP and 1% had rare craniofacial clefts. Unilateral cleft lips were found in 79% of the patients. Of the unilateral cleft lips 64% were left sided. There was a significant correlation of children with clefts being born to parents who shared a consanguineous relationship and those who were illiterate with the odds ratio between 5.25 and 7.21 for consanguinity and between 1.55 and 5.85 for illiteracy, respectively.CONCLUSION:The birth rate of clefts was found to be comparable with other Asian studies, but lower than found in other studies in Caucasian populations and higher than in African populations. The incidence was found to be similar to other studies done in other parts of India. The distribution over the various types of cleft was comparable to that found in other studies.

PMID 21217978

Epidemiologic factors causing cleft lip and palate and their regularities of occurrence in Estonia

Stomatologija. 2010;12(4):105-108.

Jagomagi T, Soots M, Saag M.

Department of Stomatology, Faculty of Medicine, University of Tartu, Kastani 16, Tartu 50410, Estonia.

Abstract OBJECTIVES. To study epidemiological factors causing development of cleft lip and palate and their occurrence regularities. MATERIALS AND METHODS. This study included 583 cleft lip and palate patients and the information for statistical analyses was gathered from Tartu University Hospital. RESULTS. 19% of the patients had a cleft lip (CL), 39% of the patients had a cleft palate (CP), and 42 % of the patients had a cleft lip and palate (CLP). The ratio for different cleft types CL: CLP: CP was 1:2:2. In unilateral CLP and CL cases, the left side was affected 2.2 times more frequently than the right side. Boys had a CLP nearly 2.1 times more often than girls. CP was more common for girls (60%) than for boys (40%). 30% of children had multiple malformations. 2.6% of children with clefts were born premature, half of which had accompanying developmental anomalies. The average birth weight for cleft child was ~ 3400 grams. 6.8% of children with clefts had a birth weight below 2.5 kg. In case of children with clefts, the mother's age exceeded 30 years in 1/4 of cases and father's age in 1/3 of cases. Both parents were older than 30 years in 66% of the cases. 1/5 of both parents were older than 30 years. 1/3 of mothers of children with clefts had suffered psychological stress, 1/5 of mothers had done hard physical work. 1/5 of mothers had an exposure to teratogenic toxic substances. 15% of them received medications during the first trimester of pregnancy. 15% of mothers had experienced hormonal disorders. CONCLUSIONS. As a result of the study we found a high occurrence rate of CP (CL: CLP: CP - 1:2:2), which is similar to the studies conducted in Finland and Sweden. The reasons for this ratio need further research.

PMID 21266834

A genome-wide association study of cleft lip with and without cleft palate identifies risk variants near MAFB and ABCA4

Nat Genet. 2010 Jun;42(6):525-9. Epub 2010 May 2.

Beaty TH, Murray JC, Marazita ML, Munger RG, Ruczinski I, Hetmanski JB, Liang KY, Wu T, Murray T, Fallin MD, Redett RA, Raymond G, Schwender H, Jin SC, Cooper ME, Dunnwald M, Mansilla MA, Leslie E, Bullard S, Lidral AC, Moreno LM, Menezes R, Vieira AR, Petrin A, Wilcox AJ, Lie RT, Jabs EW, Wu-Chou YH, Chen PK, Wang H, Ye X, Huang S, Yeow V, Chong SS, Jee SH, Shi B, Christensen K, Melbye M, Doheny KF, Pugh EW, Ling H, Castilla EE, Czeizel AE, Ma L, Field LL, Brody L, Pangilinan F, Mills JL, Molloy AM, Kirke PN, Scott JM, Arcos-Burgos M, Scott AF.

Johns Hopkins University, School of Public Health, Baltimore, Maryland, USA. Erratum in:

Nat Genet. 2010 Aug;42(8):727. Scott, James M [corrected to Scott, John M]. Abstract Case-parent trios were used in a genome-wide association study of cleft lip with and without cleft palate. SNPs near two genes not previously associated with cleft lip with and without cleft palate (MAFB, most significant SNP rs13041247, with odds ratio (OR) per minor allele = 0.704, 95% CI 0.635-0.778, P = 1.44 x 10(-11); and ABCA4, most significant SNP rs560426, with OR = 1.432, 95% CI 1.292-1.587, P = 5.01 x 10(-12)) and two previously identified regions (at chromosome 8q24 and IRF6) attained genome-wide significance. Stratifying trios into European and Asian ancestry groups revealed differences in statistical significance, although estimated effect sizes remained similar. Replication studies from several populations showed confirming evidence, with families of European ancestry giving stronger evidence for markers in 8q24, whereas Asian families showed stronger evidence for association with MAFB and ABCA4. Expression studies support a role for MAFB in palatal development.

PMID 20436469


A simple and precise classification for cleft lip and palate: a five-digit numerical recording system

Cleft Palate Craniofac J. 2007 Sep;44(5):465-8.

Liu Q1, Yang ML, Li ZJ, Bai XF, Wang XK, Lu L, Wang YX.


OBJECTIVE: Numerous methods have been developed for recording cleft lip and palate deformities, but none has been universally accepted due to limitations, inadequate description of the cleft deformities, and varying complexity. DESIGN: The classification system introduced in this article is designed to describe detailed information of the cleft deformities with five-digit codes. The anatomic description of the cleft components is denoted with five Arabic numerals in order of right lip, right alveolus and primary palate, secondary palate, left alveolus and primary palate, and left lip. The extent of the cleft deformities is recorded using the numerals 0 to 4 (i.e., from intact to complete). SETTING: Department of Oral-Maxillofacial Surgery, The Affiliated Hospital of Stomatology, China Medical University. RESULTS: This new classification system allows a numerical description of any kind of complete cleft, incomplete cleft, asymmetry, and complex clefts with an intervening intact segment (all simulated cases). CONCLUSIONS: The simplicity and precision of this five-digit classification system make it easy to understand, and it can be used for computerized data analysis. Comment in Letter to the editor. Liu Q, Yang M L, Li Z J, Bai X F, Wang XK, Lu L, Wang Y X. A simple and precise classification for cleft lip and palate: a five digit numerical recording system. Cleft Palate Craniofac J. 2007;44:465-8. [Cleft Palate Craniofac J. 2009]

PMID 17760488


A modification of the Kernahan "Y" classification in cleft lip and palate deformities

Plast Reconstr Surg. 1998 Nov;102(6):1842-7.

Smith AW1, Khoo AK, Jackson IT.


The search for a universally accepted system of classifying cleft lip and palate deformities has yielded many models of varying complexity. Recently, there has been a trend toward symbolic classification systems that allow members of the cleft team to quickly assess the nature of the deformity. The existing systems, however, have limitations. These include inadequate description of the cleft lip deformity and complexity of nomenclature. A modification of Kernahan's striped Y classification is proposed that addresses these problems. This system was applied to 150 cleft patients, and it was found that it was able to describe all varieties of clefts encountered. In contrast, the Kernahan system could only describe 74.7 percent of the patients adequately. Comment in A modification of the Kernahan "Y" classification in cleft lip and palate deformities. [Plast Reconstr Surg. 1999]

PMID 9810977