The role of family history as a risk factor for non-syndromic cleft lip and/or palate with multifactorial inheritance

Agung Sosiawan, Mala Kurniati, Coen Pramono Danudiningrat, Dian Agustin Wahjuningrum, Indra Mulyawan

Abstract views = 872 times | downloads = 333 times


Background: Cleft lip with or without cleft palate (CL/P) is a facial growth ‘disorder that occurs during gestation and has multifactorial causes owing to both genetic and environmental factors. Several factors can increase the likelihood of CL/P, and one of them is family history. Differences in results obtained from studies conducted across several countries concerning family history as a risk factor for CL/P suggest there is no consensus on how the condition is inherited. Purpose: This study aims to review the literature on the role of family history as a risk factor contributing to the incidence of non-syndromic CL/P (NSCL/P). Review: This review discusses the etiology of CL/P and the risk factors influencing the incidence of CL/P. The review also examines the criteria for inheriting multifactorial disorders to calculate the risks involved should there be a recurrence of the condition based on family history. Conclusion: CL/P is a type of multifactorial disorder with unclear etiology. Therefore, it is important to investigate the risk factors stemming from family history (which play an important role) related to the recurrence risk. Additionally, there should be focus on increasing genetic education and offering counselling to parents and pregnant women.


cleft lip with or without cleft palate (CL/P); family history; multifactorial; recurrence

Full Text:



Dixon MJ, Marazita ML, Beaty TH, Murray JC. Cleft lip and palate: understanding genetic and environmental influences. Nat Rev Genet. 2011; 12(3): 167–78.

Funato N, Nakamura M. Identification of shared and unique gene families associated with oral clefts. Int J Oral Sci. 2017; 9(2): 104–9.

Burg ML, Chai Y, Yao CA, Magee W, Figueiredo JC. Epidemiology, etiology, and treatment of isolated cleft palate. Front Physiol. 2016; 7(MAR): 67.

Muhamad AH, Azzaldeen A, Nezar W, Firas K. The multifactorial factors influencing cleft lip-literature review. Int J Clin Med Res. 2014; 1(3): 90–6.

McGarry A. The influence of genetics on syndromic and non-syndromic cases of cleft lip and cleft palate. [Washington]: The George Washington University; 2017. p. 1–23.

Nagase Y, Natsume N, Kato T, Hayakawa T. Epidemiological analysis of cleft lip and/or palate by cleft pattern. J Maxillofac Oral Surg. 2010; 9(4): 389–95.

Muhamad AH, Azzaldeen A, Watted N. Cleft lip and palate; a comprehensive review. Int J Basic Appl Med Sci. 2014; 4(1): 338–55.

Martelli DRB, Machado RA, Swerts MSO, Rodrigues LAM, De Aquino SN, Martelli Júnior H. Non syndromic cleft lip and palate: relationship between sex and clinical extension. Braz J Otorhinolaryngol. 2012; 78(5): 116–20.

Lesmana S, Auerkari EI. Genes contributing in cleft lip and cleft palate: a literature review. J Int Dent Med Res. 2016; 9(Special Issue: Universitas Indonesia): 441–8.

Rafik A, Nadifi S. Updating genetics polymorphisms of non-syndromic clefts lip-palates. Am J Mol Biol. 2018; 8: 178–85.

Mossey P, Castilla E. Global registry and database on craniofacial anomalies. In: WHO Registry Meeting on Craniofacial Anomalies. Geneva: World Health Organization; 2003. p. 101.

Chen Q, Wang H, Hetmanski JB, Zhang T, Ruczinski I, Schwender H, Liang KY, Fallin MD, Redett RJ, Raymond G V., Wu Chou Y-H, Chen PK-T, Yeow V, Chong SS, Cheah FSH, Jabs EW, Scott AF, Beaty TH. BMP4 was associated with NSCL/P in an Asian population. PLoS One. 2012; 7(4): e35347.

Panamonta V, Pradubwong S, Panamonta M, Chowchuen B. Global birth prevalence of orofacial clefts: a systematic review. J Med Assoc Thai. 2015; 98 Suppl 7(7): S11-21.

Allam E, Windsor LJ, Stone C. Cleft lip and palate: etiology, epidemiology, preventive and intervention strategies. Anat Physiol. 2013; 4(3): 1000150.

Tolarova MM, Al-Kharafi L, Tolar M, Boyd C. Pediatric Cleft Lip and Palate. Medscape. 2020. Available from: Accessed 2021 Feb 21.

Mahamad Irfanulla Khan AN, Prashanth CS, Srinath N. Genetic etiology of cleft lip and cleft palate. AIMS Mol Sci. 2020; 7(4): 328–48.

Leslie EJ, Carlson JC, Cooper ME, Christensen K, Weinberg SM, Marazita ML. Exploring subclinical phenotypic features in twin pairs discordant for cleft lip and palate. Cleft palate-craniofacial J. 2017; 54(1): 90–3.

Beaty TH, Marazita ML, Leslie EJ. Genetic factors influencing risk to orofacial clefts: today’s challenges and tomorrow’s opportunities. F1000Research. 2016; 5(0): 2800.

Kawalec A, Nelke K, Pawlas K, Gerber H. Risk factors involved in orofacial cleft predisposition - review. Open Med (Warsaw, Poland). 2015; 10(1): 163–75.

Martelli DRB, da Cruz KW, de Barros LM, Silveira MF, Swerts MSO, Martelli Júnior H. Maternal and paternal age, birth order and interpregnancy interval evaluation for cleft lip-palate. Braz J Otorhinolaryngol. 2010; 76(1): 107–12.

Chen Q, Wang H, Schwender H, Zhang T, Hetmanski JB, Chou Y-HW, Ye X, Yeow V, Chong SS, Zhang B, Jabs EW, Parker MM, Scott AF, Beaty TH. Joint testing of genotypic and gene-environment interaction identified novel association for BMP4 with non-syndromic CL/P in an Asian population using data from an International Cleft Consortium. PLoS One. 2014; 9(10): e109038.

Kempa I. Identification of candidate genes involved in the etiology of non-syndromic cleft lip with or without cleft palate and isolated cleft palate. Riga: Rīga Stradiņš University; 2013. p. 1–167.

DeRoo LA, Wilcox AJ, Lie RT, Romitti PA, Pedersen DA, Munger RG, Moreno Uribe LM, Wehby GL. Maternal alcohol binge-drinking in the first trimester and the risk of orofacial clefts in offspring: a large population-based pooling study. Eur J Epidemiol. 2016; 31(10): 1021–34.

Yin X, Li J, Li Y, Zou S. Maternal alcohol consumption and oral clefts: a meta-analysis. Br J Oral Maxillofac Surg. 2019; 57(9): 839–46.

Agarwal D, Gopalan TR. Maternal nutrition and prevention of oral clefts. Int J Med Public Heal. 2011; 1(1): 43–5.

McKinney CM, Chowchuen B, Pitiphat W, Derouen T, Pisek A, Godfrey K. Micronutrients and oral clefts: a case-control study. J Dent Res. 2013; 92(12): 1089–94.

Jackson M, Marks L, May GHW, Wilson JB. The genetic basis of disease. Essays Biochem. 2018; 62(5): 643–723.

Jamilian A, Sarkarat F, Jafari M, Neshandar M, Amini E, Khosravi S, Ghassemi A. Family history and risk factors for cleft lip and palate patients and their associated anomalies. Stomatologija. 2017; 19(3): 78–83.

Curcio AM, Shekhawat P, Reynolds AS, Thakur KT. Neurologic infections during pregnancy. Steegers EA., Cipolla M., Miller E., editors. Handb Clin Neurol. 3rd ed. 2020; 172(January): 79–104.

Angulo-Castro E, Acosta-Alfaro LF, Guadron-Llanos AM, Canizalez-Román A, Gonzalez-Ibarra F, Osuna-Ramírez I, Murillo-Llanes J. Maternal Risk Factors Associated with the Development of Cleft Lip and Cleft Palate in Mexico: A Case-Control Study. Iran J Otorhinolaryngol. 2017; 29(93): 189–95.

Ács L, Bányai D, Nemes B, Nagy K, Ács N, Bánhidy F, Rózsa N. Maternal-related factors in the origin of isolated cleft palate-A population-based case-control study. Orthod Craniofac Res. 2020; 23(2): 174–80.

Spinder N, Bergman JEH, Boezen HM, Vermeulen RCH, Kromhout H, de Walle HEK. Maternal occupational exposure and oral clefts in offspring. Environ Health. 2017; 16(1): 83.

Suhl J, Romitti PA, Rocheleau C, Cao Y, Burns TL, Conway K, Bell EM, Stewart P, Langlois P, National Birth Defects Prevention Study. Parental occupational pesticide exposure and nonsyndromic orofacial clefts. J Occup Environ Hyg. 2018; 15(9): 641–53.

Simpson JL. Polygenic or multifactorial inheritance. Glob Libr Women’s Med. 2012; : 10344.

Lvovs D, Favorova OO, Favorov A V. A polygenic approach to the study of polygenic diseases. Acta Naturae. 2012; 4(3): 59–71.

Scherer A, Christensen GB. Concepts and relevance of genome-wide association studies. Sci Prog. 2016; 99(Pt 1): 59–67.

Sivertsen A, Wilcox AJ, Skjaerven R, Vindenes HA, Abyholm F, Harville E, Lie RT. Familial risk of oral clefts by morphological type and severity: population based cohort study of first degree relatives. BMJ. 2008; 336(7641): 432–4.

Martelli D-R, Bonan P-R-F, Soares M-C, Paranaíba L-R, Martelli-Júnior H. Analysis of familial incidence of non-syndromic cleft lip and palate in a Brazilian population. Med Oral Patol Oral Cir Bucal. 2010; 15(6): e898-901.

Leslie EJ, Marazita ML. Genetics of cleft lip and cleft palate. Am J Med Genet C Semin Med Genet. 2013; 163C(4): 246–58.

Basha M, Demeer B, Revencu N, Helaers R, Theys S, Bou Saba S, Boute O, Devauchelle B, Francois G, Bayet B, Vikkula M. Whole exome sequencing identifies mutations in 10% of patients with familial non-syndromic cleft lip and/or palate in genes mutated in well-known syndromes. J Med Genet. 2018; 55(7): 449–58.

Acuña-González G, Medina-Solís CE, Maupomé G, Escoffie-Ramírez M, Hernández-Romano J, Márquez-Corona M de L, Islas-Márquez AJ, Villalobos-Rodelo JJ. Family history and socioeconomic risk factors for non-syndromic cleft lip and palate: A matched case-control study in a less developed country. Biomedica. 2011; 31(3): 381–91.

Bijanzadeh M. The recurrence risk of genetic complex diseases. J Res Med Sci. 2017; 22(23): 32.


  • There are currently no refbacks.

View My Stats