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Deleterious coding variants in multi-case families with non-syndromic cleft lip and/or palate phenotypes

Deleterious coding variants in multi-case families with non-syndromic cleft lip and/or palate phenotypes
Deleterious coding variants in multi-case families with non-syndromic cleft lip and/or palate phenotypes
Nonsyndromic Cleft Lip and/or Palate (NSCLP) is regarded as a multifactorial condition in which clefting is an isolated phenotype, distinguished from the largely monogenic, syndromic forms which include clefts among a spectrum of phenotypes. Nonsyndromic clefting has been shown to arise through complex interactions between genetic and environmental factors. However, there is increasing evidence that the broad NSCLP classification may include a proportion of cases showing familial patterns of inheritance and contain highly penetrant deleterious variation in specific genes. Through exome sequencing of multi-case families ascertained in Bogota, Colombia, we identify 28 non-synonymous single nucleotide variants that are considered damaging by at least one predictive score. We discuss the functional impact of candidate variants identified. In one family we find a coding variant in the MSX1 gene which is predicted damaging by multiple scores. This variant is in exon 2, a highly conserved region of the gene. Previous sequencing has suggested that mutations in MSX1 may account for ~2% of NSCLP. Our analysis further supports evidence that a proportion of NSCLP cases arise through monogenic coding mutations, though further work is required to unravel the complex interplay of genetics and environment involved in facial clefting.
1-8
Pengelly, Reuben
af97c0c1-b568-415c-9f59-1823b65be76d
Arias, Liliana
f44e52e3-21f5-4beb-a12b-42bb0b73afd1
Martinez, Julio
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Upstill-Goddard, Rosanna
db6c4d69-2a08-4185-9fc8-cad65f27dde6
Seaby, Eleanor G.
a7290ab8-98ea-4093-9aa7-641d319d6064
Gibson, Jane
855033a6-38f3-4853-8f60-d7d4561226ae
Ennis, Sarah
7b57f188-9d91-4beb-b217-09856146f1e9
Collins, Andrew
7daa83eb-0b21-43b2-af1a-e38fb36e2a64
Briceno, Ignacio
aaf8caee-1ab9-4291-b3ec-0eadd182b75e
Pengelly, Reuben
af97c0c1-b568-415c-9f59-1823b65be76d
Arias, Liliana
f44e52e3-21f5-4beb-a12b-42bb0b73afd1
Martinez, Julio
f24a598b-6222-4475-95e3-4ec9445f5d1f
Upstill-Goddard, Rosanna
db6c4d69-2a08-4185-9fc8-cad65f27dde6
Seaby, Eleanor G.
a7290ab8-98ea-4093-9aa7-641d319d6064
Gibson, Jane
855033a6-38f3-4853-8f60-d7d4561226ae
Ennis, Sarah
7b57f188-9d91-4beb-b217-09856146f1e9
Collins, Andrew
7daa83eb-0b21-43b2-af1a-e38fb36e2a64
Briceno, Ignacio
aaf8caee-1ab9-4291-b3ec-0eadd182b75e

Pengelly, Reuben, Arias, Liliana, Martinez, Julio, Upstill-Goddard, Rosanna, Seaby, Eleanor G., Gibson, Jane, Ennis, Sarah, Collins, Andrew and Briceno, Ignacio (2016) Deleterious coding variants in multi-case families with non-syndromic cleft lip and/or palate phenotypes. Scientific Reports, 6, 1-8, [30457]. (doi:10.1038/srep30457).

Record type: Article

Abstract

Nonsyndromic Cleft Lip and/or Palate (NSCLP) is regarded as a multifactorial condition in which clefting is an isolated phenotype, distinguished from the largely monogenic, syndromic forms which include clefts among a spectrum of phenotypes. Nonsyndromic clefting has been shown to arise through complex interactions between genetic and environmental factors. However, there is increasing evidence that the broad NSCLP classification may include a proportion of cases showing familial patterns of inheritance and contain highly penetrant deleterious variation in specific genes. Through exome sequencing of multi-case families ascertained in Bogota, Colombia, we identify 28 non-synonymous single nucleotide variants that are considered damaging by at least one predictive score. We discuss the functional impact of candidate variants identified. In one family we find a coding variant in the MSX1 gene which is predicted damaging by multiple scores. This variant is in exon 2, a highly conserved region of the gene. Previous sequencing has suggested that mutations in MSX1 may account for ~2% of NSCLP. Our analysis further supports evidence that a proportion of NSCLP cases arise through monogenic coding mutations, though further work is required to unravel the complex interplay of genetics and environment involved in facial clefting.

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Accepted/In Press date: 6 July 2016
e-pub ahead of print date: 26 July 2016
Organisations: Human Development & Health, Centre for Biological Sciences

Identifiers

Local EPrints ID: 397922
URI: http://eprints.soton.ac.uk/id/eprint/397922
PURE UUID: 861fec21-31c9-4169-894b-ac448d5a6a78
ORCID for Reuben Pengelly: ORCID iD orcid.org/0000-0001-7022-645X
ORCID for Jane Gibson: ORCID iD orcid.org/0000-0002-0973-8285
ORCID for Sarah Ennis: ORCID iD orcid.org/0000-0003-2648-0869
ORCID for Andrew Collins: ORCID iD orcid.org/0000-0001-7108-0771

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Date deposited: 11 Jul 2016 13:46
Last modified: 26 Nov 2019 06:38

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Contributors

Author: Reuben Pengelly ORCID iD
Author: Liliana Arias
Author: Julio Martinez
Author: Rosanna Upstill-Goddard
Author: Eleanor G. Seaby
Author: Jane Gibson ORCID iD
Author: Sarah Ennis ORCID iD
Author: Andrew Collins ORCID iD
Author: Ignacio Briceno

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