Sage Journals: Discover world-class research

Abstract

Objectives

The interaction between genomics, genetic and environmental factors have been implicated in non-syndromic orofacial cleft development. In the current study, we investigated the contributions of rare and novel genetic variants in known cleft genes using whole exome sequencing (WES) data of Indonesians with non-syndromic orofacial clefts.

Design

WES was conducted on 6 individuals. Variants in their exons were called and annotated. These variants were filtered for novelty and rarity using MAF of 0 and 1%.

Setting

Hospital in Indonesia.

Patients/Participants

Indonesians with non-syndromic orofacial clefts.

Interventions

Deleterious variants were prioritized. Pathogenic amino acid changes effect on protein structure and function were identified using HOPE.

Main Outcome Measure(s)

Rare and novel variants in known cleft genes were filtered and their deleteriousness were predicted using polyphen, SIFT and CADD.

Results

We identified rare (MAF <1%) deleterious variants in 4 craniofacial genes namely MMACHC (rs371937044, MAF = 0.00011). SOS1 (rs190222208, MAF = 0.00045), TULP4 (rs199583035, MAF = 0.067), and MTHFD1L (rs143492706, MAF = 0.0044). MMACHC has a mouse knockout model with facial cleft and failure of palatal fusion. The individual with variant in MMACHC presented with nsCPO.

Conclusions

Our study provides additional evidence for the role of TULP4, SOS1, MTHFD1L and MMACHC genes in nsOFC development. This is the first time MMACHC is implicated in nsOFC development in humans.

Keywords

cleft lip and palate cleft palate genes genetics

Get full access to this article

View all access options for this article.

References

Roth

Bayona

Baddam

Graf

. Craniofacial development: Neural crest in molecular embryology. Head Neck Pathol. Mar 2021;15(1):1‐15.

Leslie

Liu

Carlson

, et al. A genome-wide association study of nonsyndromic cleft palate identifies an etiologic missense variant in GRHL3. Am J Hum Genet. Apr 07 2016;98(4):744‐754. doi:https://doi.org/10.1016/j.ajhg.2016.02.014

Pereira

Fradinho

Carmo

, et al. Associated malformations in children with orofacial clefts in Portugal: A 31-year study. Plast Reconstr Surg Glob Open. Feb 2018;6(2):e1635. doi:https://doi.org/10.1097/GOX.0000000000001635

Nasreddine

El Hajj

Ghassibe-Sabbagh

. Orofacial clefts embryology, classification, epidemiology, and genetics. Mutat Res Rev Mutat Res. 2021;787:108373. doi:https://doi.org/10.1016/j.mrrev.2021.108373

Mossey

Little

. Addressing the challenges of cleft lip and palate research in India. Indian J Plast Surg. Oct 2009;42(Suppl(Suppl)):S9‐S18. doi:https://doi.org/10.4103/0970-0358.57182

Surachman

Poerwosusanta

Harsono

Irwansyah

Adianto

Adam

. Epidemiology of Cleft Lip and Palate at Hospital Social Responsibility Cleft Center the Indonesian Central Army Hospital 2017-2021. Neuroquantology. 2022.

Sarilita

Setiawan

Mossey

. Orofacial clefts in low- and middle-income countries: A scoping review of quality and quantity of research based on literature between 2010-2019. Orthod Craniofac Res. Aug 2021;24(3):421‐429. doi:https://doi.org/10.1111/ocr.12458

Yaqoob

Mahmood

Hanif

Bugvi

Sheikh

. Etiology and genetic factors in clefts of lip and/or palate reported at children's hospital, Lahore, Pakistan. Indian J Hum Genet. 2013;9(2):136‐143.

Murthy

Bhaskar

. Current concepts in genetics of nonsyndromic clefts. Indian J Plast Surg. 2009;42(1):68‐81. doi:https://doi.org/10.4103/0970-0358.53004

10.

Adeyemo

Butali

. Genetics and genomics etiology of nonsyndromic orofacial clefts. Mol Genet Genomic Med. Jan 2017;5(1):3‐7. doi:https://doi.org/10.1002/mgg3.272

11.

Slavec

Karas Kuželički

Locatelli

Geršak

. Genetic markers for non-syndromic orofacial clefts in populations of European ancestry: A meta-analysis. Sci Rep. Jan 24 2022;12(1):1214. doi:https://doi.org/10.1038/s41598-021-02159-5

12.

Alade

Awotoye

Butali

. Genetic and epigenetic studies in non-syndromic oral clefts. Oral Dis. Jul 2022;28(5):1339‐1350. doi:https://doi.org/10.1111/odi.14146

13.

Zuo

, et al. Genome-wide analyses of non-syndromic cleft lip with palate identify 14 novel loci and genetic heterogeneity. Nat Commun. Feb. 24 2017;8:14364. doi:https://doi.org/10.1038/ncomms14364

14.

Leslie

Carlson

Shaffer

, et al. Genome-wide meta-analyses of nonsyndromic orofacial clefts identify novel associations between FOXE1 and all orofacial clefts, and TP63 and cleft lip with or without cleft palate. Hum Genet. Mar 2017;136(3):275‐286. doi:https://doi.org/10.1007/s00439-016-1754-7

15.

Saleem

Zaib

Sun

. Assessment of candidate genes and genetic heterogeneity in human non syndromic orofacial clefts specifically non syndromic cleft lip with or without palate. Heliyon. Dec 2019;5(12):e03019. doi:https://doi.org/10.1016/j.heliyon.2019.e03019

16.

Marini

Asrani

Yang

Rine

Shaw

. Accumulation of rare coding variants in genes implicated in risk of human cleft lip with or without cleft palate. Am J Med Genet A. Jul 2019;179(7):1260‐1269. doi:https://doi.org/10.1002/ajmg.a.61183

17.

Leslie

Taub

Liu

, et al. Identification of functional variants for cleft lip with or without cleft palate in or near PAX7, FGFR2, and NOG by targeted sequencing of GWAS loci. Am J Hum Genet. Mar 05 2015;96(3):397‐411. doi:https://doi.org/10.1016/j.ajhg.2015.01.004

18.

Tumonggor

Karafet

Hallmark

, et al. The Indonesian archipelago: An ancient genetic highway linking Asia and the pacific. J Hum Genet. Mar. 2013;58(3):165‐173. doi:https://doi.org/10.1038/jhg.2012.154

19.

Chandra

. Mortality from the influenza pandemic of 1918-19 in Indonesia. Popul Stud (Camb). Jul 2013;67(2):185‐193. doi:https://doi.org/10.1080/00324728.2012.754486

20.

Baban

Olivini

Lepri

, et al. SOS1 Mutations in Noonan syndrome: Cardiomyopathies and not only congenital heart defects! report of six patients including two novel variants and literature review. Am J Med Genet A. Oct 2019;179(10):2083‐2090. doi:https://doi.org/10.1002/ajmg.a.61312

21.

Bult

Blake

Smith

Kadin

Richardson

. Mouse genome database (MGD). Nucleic Acids Res. 2019;47(D1):D801‐d806.

22.

Cao

Alrejaye

Klein

Goodwin

Oberoi

. A review of craniofacial and dental findings of the RASopathies. Orthod Craniofac Res. Jun 2017;20(Suppl 1):32‐38. doi:https://doi.org/10.1111/ocr.12144

23.

Kumar

Chandar

Koduri

Sankireddy

. Noonan syndrome with cleft palate: A rare case report. Journal of Indian Academy of Oral Medicine and Radiology. 2016;28(2):207.

24.

Landrum

Lee

Benson

, et al. ClinVar: improving access to variant interpretations and supporting evidence. Nucleic Acids Res. 2018;135(1):D1062–D1067.

25.

Lee

Chiu

, et al. Folate cycle enzyme MTHFD1L confers metabolic advantages in hepatocellular carcinoma. J Clin Invest. May 1 2017;127(5):1856‐1872. doi:https://doi.org/10.1172/JCI90253

26.

Wright

. Using DECIPHER v2.0 to analyze big biological sequence data in R. R J. 2016;8(1):352‐359.

27.

Vieira

de Carvalho

Johnson

, et al. Fine mapping of 6q23.1 identifies TULP4 as contributing to clefts. Cleft Palate Craniofac J. Mar. 2015;52(2):128‐134. doi:https://doi.org/10.1597/13-023

28.

Conte

Oti

Dixon

Carels

Rubini

Zhou

. Systematic analysis of copy number variants of a large cohort of orofacial cleft patients identifies candidate genes for orofacial clefts. Hum Genet. Jan 2016;135(1):41‐59. doi:https://doi.org/10.1007/s00439-015-1606-x

29.

Awotoye

Mossey

Hetmanski

, et al. Whole-genome sequencing reveals de-novo mutations associated with nonsyndromic cleft lip/palate. Sci Rep. Jul 11 2022;12(1):11743. doi:https://doi.org/10.1038/s41598-022-15885-1

30.

Paz

Pinales

Castellanos

, et al. Abnormal chondrocyte intercalation in a zebrafish model of. bioRxiv. Jan 21 2023. doi:https://doi.org/10.1101/2023.01.20.524982

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.02 MB

Whole Exome Sequencing Identifies Damaging Variants in Indonesians with Clefts

Abstract

Objectives

Design

Setting

Patients/Participants

Interventions

Main Outcome Measure(s)

Results

Conclusions

Keywords

Get full access to this article

References

Supplementary Material