TY - JOUR
T1 - Whole-genome sequencing reveals de-novo mutations associated with nonsyndromic cleft lip/palate
AU - Awotoye, Waheed
AU - Mossey, Peter A.
AU - Hetmanski, Jacqueline B.
AU - Gowans, Lord J.J.
AU - Eshete, Mekonen A.
AU - Adeyemo, Wasiu L.
AU - Alade, Azeez
AU - Zeng, Erliang
AU - Adamson, Olawale
AU - Naicker, Thirona
AU - Anand, Deepti
AU - Adeleke, Chinyere
AU - Busch, Tamara
AU - Li, Mary
AU - Petrin, Aline
AU - Aregbesola, Babatunde S.
AU - Braimah, Ramat O.
AU - Oginni, Fadekemi O.
AU - Oladele, Ayodeji O.
AU - Oladayo, Abimbola
AU - Kayali, Sami
AU - Olotu, Joy
AU - Hassan, Mohaned
AU - Pape, John
AU - Donkor, Peter
AU - Arthur, Fareed K.N.
AU - Obiri-Yeboah, Solomon
AU - Sabbah, Daniel K.
AU - Agbenorku, Pius
AU - Plange-Rhule, Gyikua
AU - Oti, Alexander Acheampong
AU - Gogal, Rose A.
AU - Beaty, Terri H.
AU - Taub, Margaret
AU - Marazita, Mary L.
AU - Schnieders, Michael J.
AU - Lachke, Salil A.
AU - Adeyemo, Adebowale A.
AU - Murray, Jeffrey C.
AU - Butali, Azeez
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - The majority (85%) of nonsyndromic cleft lip with or without cleft palate (nsCL/P) cases occur sporadically, suggesting a role for de novo mutations (DNMs) in the etiology of nsCL/P. To identify high impact protein-altering DNMs that contribute to the risk of nsCL/P, we conducted whole-genome sequencing (WGS) analyses in 130 African case-parent trios (affected probands and unaffected parents). We identified 162 high confidence protein-altering DNMs some of which are based on available evidence, contribute to the risk of nsCL/P. These include novel protein-truncating DNMs in the ACTL6A, ARHGAP10, MINK1, TMEM5 and TTN genes; as well as missense variants in ACAN, DHRS3, DLX6, EPHB2, FKBP10, KMT2D, RECQL4, SEMA3C, SEMA4D, SHH, TP63, and TULP4. Many of these protein-altering DNMs were predicted to be pathogenic. Analysis using mouse transcriptomics data showed that some of these genes are expressed during the development of primary and secondary palate. Gene-set enrichment analysis of the protein-altering DNMs identified palatal development and neural crest migration among the few processes that were significantly enriched. These processes are directly involved in the etiopathogenesis of clefting. The analysis of the coding sequence in the WGS data provides more evidence of the opportunity for novel findings in the African genome.
AB - The majority (85%) of nonsyndromic cleft lip with or without cleft palate (nsCL/P) cases occur sporadically, suggesting a role for de novo mutations (DNMs) in the etiology of nsCL/P. To identify high impact protein-altering DNMs that contribute to the risk of nsCL/P, we conducted whole-genome sequencing (WGS) analyses in 130 African case-parent trios (affected probands and unaffected parents). We identified 162 high confidence protein-altering DNMs some of which are based on available evidence, contribute to the risk of nsCL/P. These include novel protein-truncating DNMs in the ACTL6A, ARHGAP10, MINK1, TMEM5 and TTN genes; as well as missense variants in ACAN, DHRS3, DLX6, EPHB2, FKBP10, KMT2D, RECQL4, SEMA3C, SEMA4D, SHH, TP63, and TULP4. Many of these protein-altering DNMs were predicted to be pathogenic. Analysis using mouse transcriptomics data showed that some of these genes are expressed during the development of primary and secondary palate. Gene-set enrichment analysis of the protein-altering DNMs identified palatal development and neural crest migration among the few processes that were significantly enriched. These processes are directly involved in the etiopathogenesis of clefting. The analysis of the coding sequence in the WGS data provides more evidence of the opportunity for novel findings in the African genome.
UR - https://www.scopus.com/pages/publications/85133665174
U2 - 10.1038/s41598-022-15885-1
DO - 10.1038/s41598-022-15885-1
M3 - Article
C2 - 35817949
AN - SCOPUS:85133665174
SN - 2045-2322
VL - 12
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 11743
ER -