Co-occurrence of orofacial clefts and clubfoot phenotypes in a sub-Saharan African cohort: Whole-exome sequencing implicates multiple syndromes and genes.
Adult
Africa South of the Sahara
Autophagy-Related Proteins
/ genetics
Child, Preschool
Cleft Lip
/ genetics
Cleft Palate
/ genetics
Clubfoot
/ genetics
DNA Helicases
/ genetics
DNA-Binding Proteins
/ genetics
Extracellular Matrix Proteins
/ genetics
Female
Genetic Heterogeneity
Homeodomain Proteins
/ genetics
Humans
Infant
Infant, Newborn
Ki-67 Antigen
/ genetics
Male
Syndrome
Transcription Factors
/ genetics
Vesicular Transport Proteins
/ genetics
Whole Genome Sequencing
clubfoot
genetic syndromes
orofacial clefts
whole-exome sequencing
Journal
Molecular genetics & genomic medicine
ISSN: 2324-9269
Titre abrégé: Mol Genet Genomic Med
Pays: United States
ID NLM: 101603758
Informations de publication
Date de publication:
04 2021
04 2021
Historique:
revised:
16
02
2021
received:
07
01
2021
accepted:
19
02
2021
pubmed:
16
3
2021
medline:
15
12
2021
entrez:
15
3
2021
Statut:
ppublish
Résumé
Orofacial clefts (OFCs) are congenital malformations of the face and palate, with an incidence of 1 per 700 live births. Clubfoot or congenital talipes equinovarus (CTEV) is a three-dimensional abnormality of the leg, ankle, and feet that leads to the anomalous positioning of foot and ankle joints and has an incidence of 1 per 1000 live births. OFCs and CTEV may occur together or separately in certain genetic syndromes in addition to other congenital abnormalities. Here, we sought to decipher the genetic etiology of OFC and CTEV that occurred together in six probands. At the time of recruitment, the most clinically obvious congenital anomalies in these individuals were the OFC and CTEV. We carried out whole-exome sequencing (WES) on DNA samples from probands and available parents employing the Agilent SureSelect XT kit and Illumina HiSeq2500 platform, followed by bioinformatics analyses. WES variants were validated by clinical Sanger Sequencing. Of the six probands, we observed probable pathogenic genetic variants in four. In three probands with probable pathogenic genetic variants, each individual had variants in three different genes, whereas one proband had probable pathogenic variant in just one gene. In one proband, we observed variants in DIS3L2, a gene associated with Perlman syndrome. A second proband had variants in EPG5 (associated with Vici Syndrome), BARX1 and MKI67, while another proband had potentially etiologic variants in FRAS1 (associated with Fraser Syndrome 1), TCOF1 (associated with Treacher Collins Syndrome 1) and MKI67. The last proband had variants in FRAS1, PRDM16 (associated with Cardiomyopathy, dilated, 1LL/Left ventricular noncompaction 8) and CHD7 (associated with CHARGE syndrome/Hypogonadotropic hypogonadism 5 with or without anosmia). Our results suggest that clubfoot and OFCs are two congenital abnormalities that can co-occur in certain individuals with varying genetic causes and expressivity, warranting the need for deep phenotyping.
Sections du résumé
BACKGROUND
Orofacial clefts (OFCs) are congenital malformations of the face and palate, with an incidence of 1 per 700 live births. Clubfoot or congenital talipes equinovarus (CTEV) is a three-dimensional abnormality of the leg, ankle, and feet that leads to the anomalous positioning of foot and ankle joints and has an incidence of 1 per 1000 live births. OFCs and CTEV may occur together or separately in certain genetic syndromes in addition to other congenital abnormalities. Here, we sought to decipher the genetic etiology of OFC and CTEV that occurred together in six probands.
METHODS
At the time of recruitment, the most clinically obvious congenital anomalies in these individuals were the OFC and CTEV. We carried out whole-exome sequencing (WES) on DNA samples from probands and available parents employing the Agilent SureSelect XT kit and Illumina HiSeq2500 platform, followed by bioinformatics analyses. WES variants were validated by clinical Sanger Sequencing.
RESULTS
Of the six probands, we observed probable pathogenic genetic variants in four. In three probands with probable pathogenic genetic variants, each individual had variants in three different genes, whereas one proband had probable pathogenic variant in just one gene. In one proband, we observed variants in DIS3L2, a gene associated with Perlman syndrome. A second proband had variants in EPG5 (associated with Vici Syndrome), BARX1 and MKI67, while another proband had potentially etiologic variants in FRAS1 (associated with Fraser Syndrome 1), TCOF1 (associated with Treacher Collins Syndrome 1) and MKI67. The last proband had variants in FRAS1, PRDM16 (associated with Cardiomyopathy, dilated, 1LL/Left ventricular noncompaction 8) and CHD7 (associated with CHARGE syndrome/Hypogonadotropic hypogonadism 5 with or without anosmia).
CONCLUSION
Our results suggest that clubfoot and OFCs are two congenital abnormalities that can co-occur in certain individuals with varying genetic causes and expressivity, warranting the need for deep phenotyping.
Identifiants
pubmed: 33719213
doi: 10.1002/mgg3.1655
pmc: PMC8123728
doi:
Substances chimiques
Autophagy-Related Proteins
0
BARX1 protein, human
0
DNA-Binding Proteins
0
EPG5 protein, human
0
Extracellular Matrix Proteins
0
FRAS1 protein, human
0
Homeodomain Proteins
0
Ki-67 Antigen
0
MKI67 protein, human
0
PRDM16 protein, human
0
Transcription Factors
0
Vesicular Transport Proteins
0
DNA Helicases
EC 3.6.4.-
CHD7 protein, human
EC 3.6.4.12
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1655Subventions
Organisme : NIDCR NIH HHS
ID : R37 DE008559
Pays : United States
Organisme : NIDCR NIH HHS
ID : R00 DE022378
Pays : United States
Organisme : NIDCR NIH HHS
ID : R90 DE024296
Pays : United States
Organisme : NIDCR NIH HHS
ID : R01 DE028300
Pays : United States
Organisme : NIDCR NIH HHS
ID : K43 DE029427
Pays : United States
Informations de copyright
© 2021 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.
Références
Genetics. 2014 Jul;197(3):1039-44
pubmed: 24793288
Nucleic Acids Res. 2016 Dec 1;44(21):10437-10453
pubmed: 27431325
Mol Genet Genomic Med. 2017 Jan 12;5(2):164-171
pubmed: 28361103
Hum Genet. 2016 Oct;135(10):1181-9
pubmed: 27395407
Orphanet J Rare Dis. 2016 Feb 29;11:21
pubmed: 26927810
Acta Histochem Cytochem. 2019 Feb 28;52(1):19-26
pubmed: 30923412
Nucleic Acids Res. 2019 Jan 8;47(D1):D1005-D1012
pubmed: 30445434
Hum Mutat. 2019 Oct;40(10):1813-1825
pubmed: 31215115
BMC Med Genet. 2019 Jul 17;20(1):127
pubmed: 31315586
Hua Xi Kou Qiang Yi Xue Za Zhi. 2018 Oct 1;36(5):503-507
pubmed: 30465343
Nat Genet. 2002 Oct;32(2):285-9
pubmed: 12219090
Am J Med Genet A. 2020 Jul;182(7):1664-1672
pubmed: 32369272
Front Oral Biol. 2012;16:1-18
pubmed: 22759666
Br J Oral Maxillofac Surg. 2013 Jul;51(5):384-8
pubmed: 23036831
Congenit Anom (Kyoto). 2017 May;57(3):83-85
pubmed: 27624506
Bioinformatics. 2009 Jul 15;25(14):1754-60
pubmed: 19451168
Cell Death Differ. 2018 Nov;25(11):1996-2009
pubmed: 29523871
J Orthop Surg Res. 2018 Aug 22;13(1):206
pubmed: 30134936
J Dent Res. 2016 Oct;95(11):1245-56
pubmed: 27369588
Am J Hum Genet. 2015 Mar 5;96(3):397-411
pubmed: 25704602
Am J Hum Genet. 2018 Jun 7;102(6):1143-1157
pubmed: 29805042
J Med Genet. 2014 May;51(5):334-9
pubmed: 24667120
Int J Biochem Cell Biol. 2011 Apr;43(4):487-95
pubmed: 21182980
Am J Med Genet A. 2020 Apr;182(4):773-779
pubmed: 31999076
Int Ophthalmol. 2018 Dec;38(6):2677-2682
pubmed: 29058245
Genet Med. 2016 Jan;18(1):49-56
pubmed: 25790162
Curr Rev Musculoskelet Med. 2016 Dec;9(4):470-477
pubmed: 27696325
Medicina (Kaunas). 2019 Aug 22;55(9):
pubmed: 31443525
Eur J Med Genet. 2018 Feb;61(2):107-113
pubmed: 28919208
J Clin Endocrinol Metab. 2020 May 1;105(5):
pubmed: 31689711
Stomatologija. 2008;10(2):62-6
pubmed: 18708738
Int J Pediatr Otorhinolaryngol. 2014 Mar;78(3):504-6
pubmed: 24480118
Ann Hum Genet. 2020 Jan;84(1):80-86
pubmed: 31184778
Genome Res. 2010 Sep;20(9):1297-303
pubmed: 20644199
Mol Syndromol. 2019 Jan;9(6):287-294
pubmed: 30800044
F1000Res. 2016 Nov 30;5:2800
pubmed: 27990279
Nat Genet. 2013 Jan;45(1):83-7
pubmed: 23222957
Nature. 2016 Aug 17;536(7616):285-91
pubmed: 27535533
Genes (Basel). 2019 Dec 07;10(12):
pubmed: 31817908
Clin Genet. 2016 Jul;90(1):90-5
pubmed: 26572954
Hum Genet. 2019 Jun;138(6):681-689
pubmed: 31025105
BMC Bioinformatics. 2010 Nov 08;11:548
pubmed: 21059217
Hua Xi Kou Qiang Yi Xue Za Zhi. 2019 Jun 1;37(3):330-335
pubmed: 31218872
RNA Biol. 2019 Feb;16(2):160-165
pubmed: 30638126
Nat Genet. 2011 May;43(5):491-8
pubmed: 21478889
Hum Mol Genet. 2019 Mar 15;28(6):1038-1051
pubmed: 30452639
N Engl J Med. 2004 Aug 19;351(8):769-80
pubmed: 15317890
Am J Med Genet A. 2008 Sep 1;146A(17):2252-7
pubmed: 18671281
Front Pediatr. 2019 Aug 28;7:343
pubmed: 31555621
Orphanet J Rare Dis. 2019 Jul 15;14(1):178
pubmed: 31307516
Cleft Palate Craniofac J. 2018 May;55(5):736-742
pubmed: 29489415
Nucleic Acids Res. 2019 Jan 8;47(D1):D886-D894
pubmed: 30371827
Eur J Med Genet. 2014 Aug;57(8):464-72
pubmed: 24704792
J Med Genet. 2002 Sep;39(9):623-33
pubmed: 12205104
Nat Methods. 2010 Apr;7(4):248-9
pubmed: 20354512
Am J Med Genet A. 2017 Apr;173(4):1077-1081
pubmed: 28328139
Hum Mutat. 2015 Oct;36(10):928-30
pubmed: 26220891
Am J Hum Genet. 2018 Jan 4;102(1):116-132
pubmed: 29290337
Hum Genet. 2020 Feb;139(2):215-226
pubmed: 31848685
Genet Epidemiol. 2019 Sep;43(6):704-716
pubmed: 31172578
PLoS Genet. 2019 Oct 14;15(10):e1008357
pubmed: 31609978
Int J Oral Maxillofac Surg. 2020 Oct;49(10):1245-1253
pubmed: 31982235
Eur J Med Genet. 2019 Jun;62(6):103534
pubmed: 30189253
Nat Rev Genet. 2011 Mar;12(3):167-78
pubmed: 21331089
Am J Med Genet C Semin Med Genet. 2020 Mar;184(1):129-135
pubmed: 31965688
Nat Protoc. 2009;4(7):1073-81
pubmed: 19561590
Cleft Palate Craniofac J. 2008 Sep;45(5):525-32
pubmed: 18788868
J Child Orthop. 2019 Jun 1;13(3):238-244
pubmed: 31312262